Hindawi Publishing CorporationISRN Organic ChemistryVolume 2013 Article ID 417672 27 pageshttpdxdoiorg1011552013417672

Review ArticleChemical Modification of Polysaccharides

Ian Cumpstey

Private Practice UK

Correspondence should be addressed to Ian Cumpstey iancumpsteysjcoxonorg

Received 15 May 2013 Accepted 9 June 2013

Academic Editors D K Chand and E Lee-Ruff

Copyright copy 2013 Ian CumpsteyThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

This review covers methods for modifying the structures of polysaccharides The introduction of hydrophobic acidic basic orother functionality into polysaccharide structures can alter the properties of materials based on these substancesThe developmentof chemical methods to achieve this aim is an ongoing area of research that is expected to become more important as the emphasison using renewable starting materials and sustainable processes increases in the futureThemethods covered in this review includeester and ether formation using saccharide oxygen nucleophiles including enzymatic reactions and aspects of regioselectivity theintroduction of heteroatomic nucleophiles into polysaccharide chains the oxidation of polysaccharides including oxidative glycolcleavage chemical oxidation of primary alcohols to carboxylic acids and enzymatic oxidation of primary alcohols to aldehydesreactions of uronic-acid-based polysaccharides nucleophilic reactions of the amines of chitosan and the formation of unsaturatedpolysaccharide derivatives

1 Introduction

With increasing oil prices and forecasts of a future lack ofavailability renewable non-petrochemical-based alternativesto materials synthesis could become more important Poly-saccharides are the products of a natural carbon-captureprocess photosynthesis followed by further biosyntheticmodifications Some are produced on a very large scale innature and some have industrial relevance with for examplematerials and food applications either in their native orchemically modified forms This review covers methods forthe chemical modification of polysaccharides The topic ofgeneral modification of polysaccharides has been reviewedpreviously [1] and several more specific reviews are refer-enced later In this review I have limited myself to discussingthe synthesis of modifications whereby the polymeric chainremains intactmdashor at least while degradation may take placeto some extent the products are still polysaccharides Theconversion of polysaccharides into small molecules has beenreviewed elsewhere [2 3] and is not covered here

Chemical modification can change the character of thepolysaccharides for example rendering them hydrophobic[4] Some such processes such as the formation of celluloseesters (including nitrocellulose celluloid cellulose acetate)are verywell known and have been carried out at an industriallevel for more than a hundred years The object of this

review is not to cover such well-known processes in detail butrather to describe published results of current research andthe state-of-the-art in polysaccharide derivatisation Neitherhave I gone into details about the possible applications of theproducts but have focussed on aspects related to reactivityand chemical structure The modifications are presentedclassified by reaction type

The structures of the natural (native) polysaccharideswhose chemical modification is described in this review areshown in Figure 1 Structurally the simplestmolecules consistof a monosaccharide repeating unit with hydroxyl groups asthe only functional groups Examples of this type of struc-ture include the very common polysaccharides celluloseand amylose Other related structures such as curdlan a(1205731ndash3)-linked glucan and inulin the only polysaccharidebased on furanosides considered here also have simple struc-tures Amylopectin has a structure similar to amylose (theseto polysaccharides are the components of starch) but it is abranched structure with many amylose-like chains linkedtogether by (1205721ndash6)-branching points Dextran is basically an(1205721ndash6)-linked glucan but itmay have a little or a lot of branch-ing at the secondary hydroxyl groups For example in so-called regular comb dextran every residue in the backbone issubstituted by an (1205721ndash3)-linked glucose unit Xylans a com-ponent of hemicelluloses are made up of a (1205731ndash4)-linked

2 ISRN Organic Chemistry

xylopyranose backbone but it also may be branched forexample by 4-O-methylglucuronic acid or acetylated to agreater or lesser degree Xylose is a pentose so the pyranoseunits in xylan do not have a primary hydroxyl group Guargum and locust bean gum both consist of (1205731ndash4)-linkedmannan backbones substituted by Gal(1205721ndash6) units to someextent In guar gum approximately every other mannoseresidue is substituted with galactose whereas in locust beangum long unsubstituted regions alternate with regions ofheavy galactose branching

Pullulan alternan and lichenan are glucans with morethan one type of glycosidic linkage in the polysaccharidebackbone Pullulan is an unbranched polysaccharide withthree monosaccharides in the repeating unit [Glc(1205721ndash4)Glc(1205721ndash4)Glc(1205721ndash6)] Alternan has two monosaccharides in itsrepeating unit [Glc(1205721ndash3)Glc(1205721ndash6)] but it can also containsome Glc(1205721ndash3) branching Lichenan is an unbranched poly-saccharide based on glucose with mixed (1205731ndash3) and (1205731ndash4)linkages

Some polysaccharides have other functional groups aswell as the simple hydroxyl groups Alginates and pectins arebased on uronic acids their monosaccharide constituents areall oxidised at C-6 to the carboxylic acid level Alginates con-sist of domains of (1205721ndash4)-linked l-guluronic acid interspersedwith domains of (1205731ndash4)-linked mannuronic acid Pectins arepolysaccharides rich in galacturonic acid although this acidcommonly will be found as its methyl ester A simple back-bone of (1205721ndash4)-linked galacturonic acidmethyl estermay alsobe substituted by other monosaccharide branches

A very common polysaccharide based on aminosugarsis chitinchitosan The chitinchitosan relationship can beregarded as a continuum with polysaccharides containingmore of the free base being called chitosan and those mostlyN-acetylated being called chitin

The extent of derivatisation reactions is given in termsof the degree of substitution (DS) The DS is defined asthe number of substitutions made per monomer unit Themaximum DS will depend on the structure and reaction inquestion For example cellulose has three hydroxyl groupsper monomer so in an acetylation of cellulose all three maybe acetylated and themaximumDSwould be 3 But only oneof the alcohols is primary so in an oxidation reaction thatonly acted on primary alcohols the maximum DS would be1 The degree of polymerisation (DP) is another importantfactor giving an average length (expressed in number ofmonomer units) of the polysaccharide A loss in DP duringa reaction indicates that degradation of the polysaccharidebackbone has occurred It has been pointed out that manyreports use cellulose with low DP (which is more soluble)and also that many do not comment on whether there is anydecrease in DP during derivatisation reactions [5] Order ofmagnitude values of the DP of cellulose samples could be ca280 for Avicel and ca 2000 for cotton linters [6]

If uniform partial derivatisation is to be achieved it canbe important that the reaction is conducted in homogeneoussolution This is less important if the goal is complete deriva-tisation of a polysaccharide Running a reaction under homo-geneous conditionsmay also lead to a cleaner product due tofewer side reactions as less forcing conditions (lower reactiontemperature and lower excesses of reagents)may be necessary

than in heterogeneous reactions hence the choice of anappropriate solvent for a polysaccharide substrate is impor-tant ldquoSwellingrdquo of solid material by a solvent will not dissolvethe solid to give a homogeneous solution but it will never-theless increase the accessibility of the reactive groups of thepolymer to reagents in solution

Polysaccharides are often insoluble in water or organicsolvents so solvent mixtures can be used Non-aqueous sol-vent mixtures that dissolve cellulose often consist of anorganic liquid and an inorganic salt Examples include DMA(dimethylacetamide)LiCl DMFLiCl DMI (13-dimethyl-2-imidazolinone)LiCl and DMSOTBAF (tetrabutylammo-nium fluoride) The DMSOEt

3NSO

2mixture is a salt-free

solvent for cellulose It will sometimes be necessary to heat tohigh temperature (150∘C) before cellulose will dissolve inthese solvents but it will then remain in solution on coolingInorganic salts are often formed as by-products in derivatisa-tion reactions (eg stoichiometric NaCl would be formed ina benzylation reaction using NaOHBnCl) so when they areadded at the start of a reaction to aid solubility this is unlikelyto cause problems in itself

Similar solvents or solvent mixtures to those used for cel-lulose are often used for other neutral polysaccharides butmany are more soluble and some are water-soluble Starchis generally more soluble than cellulose Solvents forchitin include LiCl (5)DMA LiClN-methyl-2-pyrroli-done CaCl

2MeOH and hexafluoroisopropyl alcohol

Charged polysaccharides such as chitosan (which may beprotonated on nitrogen) or polyuronates such as alginates(which can form carboxylate salts) will have very differentsolubility properties Hence chitosan is soluble in aqueousorganic or mineral acids below pH 65 and also in DMSO

Ionic liquids (room-temperature ionic liquids) are rela-tively new solvents that have found use in polysaccharidechemistry [7 8]They can dissolve polysaccharides includingcellulose hemicellulose and wood allowing derivatisationreactions to take place under homogeneous conditions Cel-lulose dissolves in ionic liquids aided by conventional heat-ing microwave irradiation or sonication with up to 25(ww) being obtained in [bmim]Cl [9] Other ionic liquidsgave 5ndash10ww solutions of celluloseThe properties of ionicliquids can be fine-tuned by structural modification of oneor other of the two ionic components Increasing the lengthof the alkyl chains in the cation component resulted in a lessefficient dissolution of cellulose Amylose was shown to havea very high solubility in ether-derived ionic liquids Ionic liq-uids have been called ldquogreenrdquo solvents due to their recyclabil-ity and low vapour pressures (low volatility) but a low vapourpressure can limit the recyclability of a solvent as it can makeits purification difficult after it has been used in chemicalreactions As a result volatile and distillable ionic liquids havebeen designed for polysaccharide derivatisation [10]

2 Saccharide Oxygen as Nucleophile

This section covers the formation of ethers and esters inwhich the saccharide oxygen acts as a nucleophile in the reac-tion and is retained in the product Different degrees of reac-tion can be considered As well as very low DS where only

ISRN Organic Chemistry 3

OOHO

HOHO

HOHOHOHO

HO

HO

HO

HO

O

OH OH

OH

OH

OH

OH

Cellulose

O

OO

Amylose

O

OO

Curdlan

O

ODextran

OO

O O

Xylan

O

O

O

Inulin

O

OHO

HO

OH

O

O

HOHO

OH

O O

HOHO

HO OPullulan

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

Guar gum

(a) Hydroxyl groups only

OOHO

OHOOH

O

OO

HO

OH O

OH

Alginates

OHO

HO

COOMeO

OPectin

(b) Uronic acids

OOHO

O

OH

Chitosan

OOHO NH

O

OH

O

Chitin

NH2

(c) Nitrogen containing

Figure 1 Structures of the repeating units of some of the polysaccharides discussed in this review Some of the structures are simplified (seetext) branching is not shown for dextran xylan and pectin the alginate structure shown shows the two linkage types rather than a formalrepeating unit the chitin and chitosan structures shown represent extremes of a continuum of structures

a few hydroxyl groups per polysaccharide chain are deriva-tised and maximum DS where all the hydroxyl groups arederivatised and points in between these extremes we canconsider regioselective reactions in which a single hydroxylgroup on each monosaccharide residue reacts preferentiallyto (say) near completion Regioselective reactions allow thesynthesis of structurally well-defined products But morethan this if a regioselective reaction goes to completionreachingDS= 1 then it can be followed in principle by furtherderivatisations that do not have to be selective but thatcan nevertheless introduce further functionality at specificpositions in a polysaccharide structure

There is a significant disadvantage of working with poly-saccharides when it comes to matters of regioselectivity Inmonomeric molecules when a reaction gives incomplete

regioselectivity (resulting in the formation of regioisomersdisubstituted or trisubstituted products etc) the desiredproduct may be purified from the other components of theproduct mixture by crystallisation or chromatography Inpolysaccharides any such purification is impossible as cor-rectly modified monosaccharide residues of the polysaccha-ride will be covalently linked to incorrectly modified mono-saccharide residues This means that only the most regiose-lective modifying reactions may be used for polysaccharidemodification if a homogeneous polysaccharide structure isrequired

21 Etherification Etherification involves the reaction of analcohol (here a saccharide alcohol) with an alkylating agentin the presence of a base ((1) Figure 2)

R OH X + base RO

+ R998400

R998400 + base middot H+ + Xminus (1)

Typical alkylating agents include alkyl halides (chloridesbromides iodides) or less commonly alkyl sulfonates Nor-mally a strong base will be used to deprotonate the alcohol to

give the alkoxide Alkylation reactions generally have a poorwater-compatibility as water can hydrolyse the alkylatingagent

4 ISRN Organic Chemistry

RO

RO

RO

RO

Si RO

Si

Methyl Me

Trimethylsilyl TMS Thexyldimethylsilyl TMDS

Trityl (triphenylmethyl) Tr Benzyl Bn

RO

O

RO

OHHydroxyalkylCarboxymethyl

Ominus

R998400

Figure 2 Structures of some of the ethers discussed in this review

211 Alkyl and Benzyl Ethers The formation of celluloseethers under homogeneous conditions in typical nonderiv-atising solvents is possible but it is more problematic thanester formation (see below)The solvent of choice for celluloseetherification appears to be DMI (13-dimethyl-2-imidazo-lidinone)LiCl [11] In this solvent much lower excesses ofreagent were required than with alternative solvents First thecellulose was dissolved by briefly heating to 150∘C Treatmentwith NaOH and MeI for 5 h at 70∘C gave 236-tri-O-methyl-cellulose with a DS of 3 It should be pointed out that whenthe NaOH was added the cellulose crashed out of solutionto some extent and so the reaction was in fact not entirelyhomogeneous

Complete etherification (ie tri-O-alkylation) of cellu-lose was also investigated in other solvents for etherificationwith various alkyl groups Different solvents and bases wereevaluated in the benzylation reaction and the best conditionsof those tested were found to be powdered NaOH and BnCl(both in an excess of 10 equivhydroxyl) in a solvent ofDMSOSO

2Et2NH heating at ca 80∘C for 3-4 h [12] DMSO

N2O4and DMALiCl gave slightly worse results Subsequent

papers covered the formation of substituted benzyl ethers andallyl ethers [13] and of simple alkyl ethers [14] of cellulose allunder essentially the same reaction conditions Purificationwas achieved by extraction into chloroform precipitationafter the addition of EtOH and then washing with waterEtOH and hexane

In DMALiCl methyl hydroxyethyl and hydroxypropylethers of cellulose could be formed under homogeneous con-ditions using iodomethane or the epoxides as alkylatingagents [15] But high excesses of reagents were required slowreactions were seen and only products with low DS values(11ndash17) were accessible A DMSOLiCl solvent was used forthe homogeneous etherification (methyl ethyl propyl andbutyl peretherification) of cellulose using dimsyl sodium(from NaH and DMSO) as base [16]

Ionic liquids have been tested as solvents for the etheri-fication of polysaccharides (cellulose and starch) under basicconditions but with little success to date in contrast to ester-ification reactions (see below) [17]

Other polysaccharides have also been shown to undergoperetherification reactions under similar conditions Xylanwas benzylated using BnBr NaOH and 18-crown-6 inDMSO[18] and amylose was converted into its tri-O-benzyl deriva-tive by treatment with NaOH and BnCl in DMSO [19]

A detailed investigation into the benzylation of starch inwater (NaOH BnCl) was reported [20] As expected wide-spread hydrolysis of the BnCl occurred under these condi-tions

The benzylation of chitin was reported [21] 120573-Chitin wassuspended in DMSO and sodium hydride (5 equiv) andbenzyl chloride (10 equiv) were added After heating at 60∘Cfor 24 h the product (DS= 133) was obtained by precipitationfromMeOHWhenmore NaH (7 equiv) was used a productwith DS = 2 was obtained but N-alkylation is likely to occuras well asO-alkylation under such reaction conditions Alter-natively chitin was suspended in DMSO and treated withKOH this insoluble deprotonated chitin was then filtered andwashed to remove water then it was resuspended in DMSOand BnCl was addedThismethod gave the product with aDSof up to 08 [22]

Considering other alkyl ethers amylose and starch weretreated with propyl bromide and NaOH in DMSO to givepropyl ethers with DS of up to 30 [23] The purification ofpolysaccharides with high DS was achieved by precipitationfrom water but those with low DS were more difficult topurify Pullulan was converted into its propyl and butyl etherswith DS between 1 and 26 by treatment with the alkylbromides and NaOH in H

2ODMSO [24]

212 Carboxymethyl Ethers Carboxymethyl cellulose is anindustrially important ionic cellulose ether and the synthesisof this type of derivative based on some hemicellulose poly-saccharides has been investigated to some extentThe synthe-sis of carboxymethyl ethers of xylan was investigated underhomogeneous conditions (in water) or slurry conditions(in i-PrOH or EtOHtoluene) using NaOH as base andClCH

2COONa as alkylating agent [25] Guar gum was

derivatised with carboxymethyl ethers in water or in EtOHtoluene (as for xylan above) to give a product with a DS of08 Repeating the procedure gave further substitution and aproduct with a higher DS [18] Konjac glucomannan wasderivatised with carboxymethyl ethers in methanol to give aproduct with a DS of 03 [18]

213 Hydroxyethyl Ethers Other than cellulose derivativeswhich are produced industrially by epoxide-ring opening

ISRN Organic Chemistry 5

guar gum and xylan were etherified (up to DS = 2) by treat-ment with ethylene oxide or propylene oxide and sodiumhydroxide [18]

22 Esterification Esterification in general will involve thereaction of an alcohol (here a saccharide alcohol) with anacylating agent ((2) Figure 3)

R OH + base+ R998400

R998400R

OX

O

O

+ base middot H+ + Xminus

(2)

RO

SRO

SulfonateCarboxylateO O

OR998400

R998400

Figure 3 General structures carboxylate and sulfonate esters

221 Acetate and Other Carboxylate Esters Carboxylateesters can be formed using carboxylic acids as acylatingagents under strong-acid catalysis (Fischer esterification) orby using an activated derivative such as an acid chloride oranhydride either with base or with a Lewis acid

The strong-acid catalysis method is used to produce cel-lulose acetate an important industrial product [26] But thismethod does not produce the triacetate due to partial tran-sient sulfation during the reaction Cellulose triacetate can beprepared in a similar way using an acid catalyst that does notcovalently attach to the cellulose such as HClO

4

When an activated carboxylic acid derivative (eg acidanhydride acid chloride) reacts with an alcohol under basicconditions the base should be present in a stoichiometricamount (it will be protonated by the acid by-product of thereaction) but it can be a weak base such as pyridine or tri-ethylamine

(1) Homogeneous Reactions Cellulose carboxylates (DS ofup to 24ndash28) were prepared by the reaction of celluloseunder homogeneous conditions in DMALiCl solution withacid chlorides and triethylamine or with acid anhydridesand sulfuric acid [27] The cellulose carboxylate productswere purified by precipitation into water followed by Soxhletextraction intomethanol Similarly starch was esterified withacyl chlorides and pyridine in DMALiCl solution at 100∘Cfor 6 h followed by purification by precipitation [28] Withlong-chain fatty acid chlorides DS values of up to 3were seen

Xylan acetates with DS of up to 2 (ie complete acety-lation) could be prepared either with Ac

2Opyridine in

DMFLiCl or under acid catalysis in AcOH [29] Alterna-tively a xylan acetate with high DS (asymp19) and clean 1HNMRspectra was prepared using Ac

2O and pyridine in DMF [30]

With longer-chain acyl chlorides xylan reacted under homo-geneous conditions inDMFLiCl to give polysaccharideswithlower DS values (03ndash15) [31]

Vinyl carboxylates have also been used as acyl donorsreacting spontaneouslywith cellulose inDMSOTBAF to givepolysaccharides with DS values of up to 26 [32]

The acetylation of cellulose in an ionic liquid sol-vent [amim]Cl (1-allyl-3-methylimidazolium chloride) was

achieved in 2004 using acetic anhydride to give products withDS of ca 25ndash27 [33] The esterification of cellulose in ionicliquids is straightforward for short-chain esters [34] Severalionic liquids gave similarly good results with [bmim]Cl (1-butyl-3-methylimidazolium chloride) being the best Aceticanhydride or acetyl chloride reacted with cellulose withoutany added base within 2 h at 80∘C to give cellulose acetateswith DS of up to 3 However only lower DS values (eg 16for lauryl chloride) were obtainable with fatty acid chloridesin ionic liquids presumably because the partially acylatedpolysaccharide becomesmore andmore nonpolar until it pre-cipitates out of the polar ionic solvent stopping the reaction

The use of carboxylic acids themselves as acylating agentsrather than derivatives such as acid anhydrides or acylchlorides could be attractive as the acids may have a wideravailability and bemore soluble in polar solventsThe Fischeresterification using the carboxylic acid as solvent and withstrong-acid catalysis has already been mentioned but in situactivation of carboxylic acids under mild conditions can alsobe used for polysaccharide acylation When tosyl chloridewas used as an activating agent for with various long-chain carboxylic acids in a DMSOTBAF solvent acylatedcelluloses with DS of up to 26ndash29 could be formed [32 35]Cellulose reacted with carboxylic acids using classic peptidecoupling reagent DCC in nonaqueous solvents (eg DMALiCl) to give derivatised polysaccharides with low DS valuesStarch was acylated under similar conditions by the in situactivation of carboxylic acids with TsCl or CDI (carbonyldi-imidazole) [28]

The acetylation of alginates was less straightforward thanfor neutral polysaccharides [36] The solubility of alginatescan be changed by changing the ionisation state (ie acidversus salt) and (for the salt form) the counterion [egsodium versus tetrabutylammonium (TBA)] TBA-alginateswere soluble inDMSOTBAF but DMALiCl did not dissolveeither the acid or salt (Na or TBA) forms When the alginatesolution was treated with Ac

2O and pyridine only low DS

of up to ca 1 were obtained It is worth mentioning here thatDMSO can react with acylating agents to generate a Swern-type oxidant that can destructively oxidise polysaccharidehydroxyl groups

In amethod for the selectiveO-acylation of chitosan [37]the polysaccharide was suspended in water and a carboxylicacid (C

2ndashC9as well as some halogenated or unsaturated

acids) andH2SO4(2M)were added at room temperatureThe

mixture was then stirred at 80∘C for 4 h and the products(with low DS values of 002ndash02) were purified by pH adjust-ment precipitation from acetone and Soxhlet extractionUnder these conditions the nucleophilicity of the nitrogenis blocked by protonation

6 ISRN Organic Chemistry

(2) Heterogeneous Reactions In a heterogeneous reaction thestarting polysaccharide is insoluble in the reaction solventBut then dissolution may or may not occur during the courseof the reaction only surface groups may be acylated or alter-natively bulk hydroxyls may also react (due to solvent swell-ing of thematerial) themacroscopic structure of thematerialmay be retained after derivatisation (fibre paper cloth ornanofibrils etc)

Heating a suspension of insoluble cellulose in amixture ofpyridine and acylating agent (5 equivGlc = 13 equivOH)can give acylated celluloses with some acylating agents afterpurification by precipitation fromwater [38] Polysaccharideswith DS values of 26ndash29 were obtained with acetyl chlorideand with long-chain acyl chlorides (gtC

10) after 3 hWith piv-

aloyl chloride a much longer reaction time was required toobtain a product with DS = 25 in low yield and with shorterchain acyl chorides (ltC

6) decompositionwas seen A similar

synthesis of cellulose esterswas reported froma suspension ofthe polysaccharide in pyridine and the acid chloride [39 40]while initially heterogeneous cellulose reacted with acetylchloridewithout added base to give cellulose acetates withDSvalues of up to 296 [32]

Konjac glucomannan was acylated with palmitoyl chlo-ride and pyridine in benzene in a heterogeneous reaction inwhich the polysaccharide dissolved during the course of thereaction to give a product with DS up to 27 [18] Arabinoxy-lan was fully esterified under Fischer conditions by suspend-ing the polysaccharide in a carboxylic acid anhydride (aceticpropionic butyric) and treating with catalytic methanesul-fonic acid [41] Also here the polysaccharide dissolved duringthe course of the reaction Mixed anhydrides generated froma carboxylic acid and other more reactive acids (eg trifluo-roacetyl) have also been used as acylating agents with poly-saccharides under heterogeneous conditions [42]

222 Sulfonate Esters Sulfonate esters can act as leavinggroups in SN2 reactions (see below) and many of their appli-cations derive from this aspect of their reactivityTheymay beintroduced with reasonably good regioselectivity for the pri-mary hydroxyl groups and regioselective sulfonate synthesesare described in the section on regioselective reactions (seebelow) But polysaccharide sulfonates with DS gt 2 are alsoaccessible The most commonly seen sulfonates in polysac-charides are toluenesulfonates (tosylates Ts) and methane-sulfonates (mesylates Ms) [43]

The classic reaction conditions for tosylate formationinvolve heating the (initially heterogeneous) polysaccharidewith tosyl chloride in pyridine Three possible side reactionsthat may occur during sulfonate ester formation all arisingfrom nucleophilic displacement of the formed sulfonate esterare as follows (i) cyclisation by attack of one of the secondaryhydroxyl groups (eg O-3) (ii) attack by pyridine to forma C-6 pyridinium salt (iii) attack by chloride to form a C-6chlorideThese side reactions are a result of the long reactiontimes and high temperatures required for the heterogeneousreaction

Thus these side reactions can beminimised or suppressedby using homogeneous conditions [44] Tosylation andmesy-lation reactions of cellulose in solution in DMALiCl gave

uniform and well-defined products with DS values between04 and 23 The tosylation of cellulose underhomogeneousconditions in the ionic liquid [amim]Cl was also recentlyachieved [45]

Sulfonate esters of other polysaccharides have also beensynthesised Chitin was tosylated under homogeneous con-ditions in DMALiCl [46] dextran tosylates were preparedin organic solvent without any added salt [47] and konjacglucomannan was tosylated to give products with DS of up to23 [18] The mesylation of cross-linked particles of pullulanhas been reported [48]

23 Regioselective Etherification and Esterification of Polysac-charides The primary alcohol of a saccharide will with veryfew exceptions always bemore nucleophilic than the second-ary alcoholsThe difference in reactivity between the primaryand secondary alcohols can vary though and complete regio-selective distinction between primary and secondary alcohols(ie normally C-6 versus all of C-2 C-3 and C-4) will oftennot be seenThe respective rate constants for the substitutionof primary and secondary alcohols do not change during areaction and if a primary alcohol reacts more quickly thana secondary alcohol its concentration will decrease morerapidly as the reaction progresses Therefore as the reactionprogresses the rates of reaction of the primary and second-ary alcohols will become similar and regioselectivity willdecrease

Differentiation between the nucleophilicity of the differ-ent secondary hydroxyl groups in a polysaccharide will oftenbe difficult or impossible and polysaccharides containingdifferent substitution patterns may often be formed Havingsaid that there are a few examples of regioselectivity bet-ween the secondary positions of polysaccharides that can beexploited syntheticallyThe regioselective protection of cellu-lose focussing on ether and ester protecting groups has beenreviewed [45] and covered to some extent in other reviews[49 50]

The hydroxyl groups of cellulose are much more reactivein solution than they are in the solid phase because whencellulose dissolves the extensive hydrogen-bonding networkis broken up As a result reactions in solution can be carriedout under milder conditions than in the solid phase andthis allows a higher degree of selectivity Thus regioselectivederivatisations of cellulose and other polysaccharides are gen-erally carried out under homogeneous reaction conditionsand the solvent system DMALiBr (or LiCl) is often used

Only a rather limited number of groupstransformationslive up to the very high regioselectivity criteria that are nec-essary for the modification of polysaccharides These includethe installation of trityl ethers (at O-6) and of bulky silylethers (at O-6 or at both O-2 and O-6) The installation ofcarboxylate esters (at O-6 but not normally selective enough)and tosylate esters (at O-6 but not normally completelyselective or at O-2) are also considered here The installationof halides at C-6 in a phosphane-mediated reaction is alsooften a regioselective process but this in this reaction thepolysaccharide behaves as an electrophile so it is consideredin a later section of this review

ISRN Organic Chemistry 7

OOHO OH

O

OH

OOHO OH

O

OTr

Scheme 1

231 Trityl Ethers The trityl group reacts with cellulose pref-erentially at the primary hydroxyl O-6 on steric grounds(Scheme 1) Trityl ethers may be installed by heating cellulose(rayon) with pyridine and trityl chloride (ie under initiallyheterogeneous conditions with dissolution occurring as thereaction proceeds) and DS values close to 1 with little substi-tution of the secondary positions are obtainable [26 51] Cel-lulose has also been tritylated under homogeneous condi-tions to give products with DS values of 10 [6] The solventsused were DMSON

2O4 DMALiCl or DMSOSO

2DEA

6-O-Trityl derivatives of some other polysaccharides havebeen prepared directly or indirectly Amylose underwent tri-tylation regioselectively at O-6 uneventfully [52] Chitin wasalso tritylated regioselectivity with reaction at O-6 [21] 120573-Chitin was suspended in pyridine and heated at 90∘C for72 h with trityl chloride (10 equiv) and DMAP (3ndash6 equiv)Products with DS values of 075ndash10 were obtained by purifi-cation by precipitation frommethanol A 6-O-trityl derivativeof chitosan was prepared by a three-step sequence First thenitrogen was protected as a phthalimide derivative then O-6 was tritylated and finally N-deprotection gave the 6-O-tritylchitosan with DS = 1 [53]

232 Silyl Ethers Thexyldimethylsilyl chloride (TMDSCl)has been shown to react with cellulose with very good regio-selectivity and different regioselectivities O-6 only or forboth O-2 and O-6 are seen under different reaction condi-tions (Scheme 2) Treatment of cellulose (undissolved ieunder initially heterogeneous conditions) with TMDSC1 inDMF saturated with ammonia at ndash15∘C resulted in the intro-duction of TMDS groups at C-6 only with a DS of 099 [54]When the reaction was carried out under homogeneous con-ditions in DMALiCl and with imidazole as base 26-di-O-thexyldimethylsilylcellulose was formed with a DS of 20 [5556] Moreover this 26-protected derivative can be used forthe regiospecific introduction of substituents at O-3 of cellu-lose 3-O-Methylcellulose and 3-O-allylcellulose have beensynthesised in this way The silyl ethers can be removed bytreatment with TBAF (tetrabutylammonium fluoride) Liq-uid ammonia has also been used as an effective solvent forsilylation reactions of cellulose [57]

233 Carboxylate Esters Regioselectivities (forO-6) are gen-erally lower for carboxylate esterification reactions of cellu-lose than those seen for the formation of trityl ethers or silylethers [45] An investigation of various sterically hinderedacylating agents including pivaloyl chloride adamantoylchloride and 246-trimethylbenzyl chloride in solventsincluding DMALiCl DMSOTBAF and the ionic liquid[amim]Cl failed to give satisfactory regioselectivity [58] But

OOHO OH

O

OHO

OHO OH

O

OTDMS

OOHO OTDMS

O

OTDMSOr

Scheme 2

having said that in a different study excellent regioselectivityfor O-6 of cellulose was observed in an esterification reactionusing benzyl chloride in [amim]Cl without any added base[59]

It is relevant in this context to note that silyl ether protec-tion may be regiospecifically replaced by carboxylate protec-tion [60] When a cellulose derivative bearing trimethylsilylethers is treated with an acyl chloride in the absence of a basethe silyl ethers are regiospecifically replaced by acyl groups(in the presence of a base the silyl ethers remain and thefree hydroxyl groups are acylated) But while this process iswell known for trimethylsilyl ethers it has apparently [45]not yet been investigated for thexyldimethylsilylethers which(as described above) can be introduced into cellulose withexcellent regioselectivity

234 Sulfonate Esters Cellulose reacts preferentially at O-6in tosylation reactions (see above) but the regioselectivity isnot perfect The esterification of cellulose with various sul-fonic acid chlorides including the 246-trimethylbenzenes-ulfonyl group under homogeneous conditions (in DMALiCl) was investigated in an attempt to improve the regios-electivity for substitution at O-6 [61] but in general theproducts contained mixtures of 2- and 6-tosylation

A very interesting result has been obtained concerningthe regioselectivity of the tosylation of starch When starch(70 amylose) was tosylated in solution in DMALiCl O-2reacted preferentially with very good regioselectivity (overO-3 and O-6) to give a product with a DS asymp 1 with the tosylgroups essentially exclusively at C-2 The regioselectivity wasproved by 1H and 13C NMR spectroscopy (Scheme 3) [62]This regioselectivity is counterintuitive and apparently it isalso solvent-dependent Horton had previously reported thatwhen the tosylation of amylose was carried out in pyridinethe more expected product 6-O-tosyl-amylose was formedwith DS asymp 06 (Scheme 3) [63]

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

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Advances in

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Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

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Analytical ChemistryInternational Journal of

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Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

2 ISRN Organic Chemistry

xylopyranose backbone but it also may be branched forexample by 4-O-methylglucuronic acid or acetylated to agreater or lesser degree Xylose is a pentose so the pyranoseunits in xylan do not have a primary hydroxyl group Guargum and locust bean gum both consist of (1205731ndash4)-linkedmannan backbones substituted by Gal(1205721ndash6) units to someextent In guar gum approximately every other mannoseresidue is substituted with galactose whereas in locust beangum long unsubstituted regions alternate with regions ofheavy galactose branching

Pullulan alternan and lichenan are glucans with morethan one type of glycosidic linkage in the polysaccharidebackbone Pullulan is an unbranched polysaccharide withthree monosaccharides in the repeating unit [Glc(1205721ndash4)Glc(1205721ndash4)Glc(1205721ndash6)] Alternan has two monosaccharides in itsrepeating unit [Glc(1205721ndash3)Glc(1205721ndash6)] but it can also containsome Glc(1205721ndash3) branching Lichenan is an unbranched poly-saccharide based on glucose with mixed (1205731ndash3) and (1205731ndash4)linkages

Some polysaccharides have other functional groups aswell as the simple hydroxyl groups Alginates and pectins arebased on uronic acids their monosaccharide constituents areall oxidised at C-6 to the carboxylic acid level Alginates con-sist of domains of (1205721ndash4)-linked l-guluronic acid interspersedwith domains of (1205731ndash4)-linked mannuronic acid Pectins arepolysaccharides rich in galacturonic acid although this acidcommonly will be found as its methyl ester A simple back-bone of (1205721ndash4)-linked galacturonic acidmethyl estermay alsobe substituted by other monosaccharide branches

A very common polysaccharide based on aminosugarsis chitinchitosan The chitinchitosan relationship can beregarded as a continuum with polysaccharides containingmore of the free base being called chitosan and those mostlyN-acetylated being called chitin

The extent of derivatisation reactions is given in termsof the degree of substitution (DS) The DS is defined asthe number of substitutions made per monomer unit Themaximum DS will depend on the structure and reaction inquestion For example cellulose has three hydroxyl groupsper monomer so in an acetylation of cellulose all three maybe acetylated and themaximumDSwould be 3 But only oneof the alcohols is primary so in an oxidation reaction thatonly acted on primary alcohols the maximum DS would be1 The degree of polymerisation (DP) is another importantfactor giving an average length (expressed in number ofmonomer units) of the polysaccharide A loss in DP duringa reaction indicates that degradation of the polysaccharidebackbone has occurred It has been pointed out that manyreports use cellulose with low DP (which is more soluble)and also that many do not comment on whether there is anydecrease in DP during derivatisation reactions [5] Order ofmagnitude values of the DP of cellulose samples could be ca280 for Avicel and ca 2000 for cotton linters [6]

If uniform partial derivatisation is to be achieved it canbe important that the reaction is conducted in homogeneoussolution This is less important if the goal is complete deriva-tisation of a polysaccharide Running a reaction under homo-geneous conditionsmay also lead to a cleaner product due tofewer side reactions as less forcing conditions (lower reactiontemperature and lower excesses of reagents)may be necessary

than in heterogeneous reactions hence the choice of anappropriate solvent for a polysaccharide substrate is impor-tant ldquoSwellingrdquo of solid material by a solvent will not dissolvethe solid to give a homogeneous solution but it will never-theless increase the accessibility of the reactive groups of thepolymer to reagents in solution

Polysaccharides are often insoluble in water or organicsolvents so solvent mixtures can be used Non-aqueous sol-vent mixtures that dissolve cellulose often consist of anorganic liquid and an inorganic salt Examples include DMA(dimethylacetamide)LiCl DMFLiCl DMI (13-dimethyl-2-imidazolinone)LiCl and DMSOTBAF (tetrabutylammo-nium fluoride) The DMSOEt

3NSO

2mixture is a salt-free

solvent for cellulose It will sometimes be necessary to heat tohigh temperature (150∘C) before cellulose will dissolve inthese solvents but it will then remain in solution on coolingInorganic salts are often formed as by-products in derivatisa-tion reactions (eg stoichiometric NaCl would be formed ina benzylation reaction using NaOHBnCl) so when they areadded at the start of a reaction to aid solubility this is unlikelyto cause problems in itself

Similar solvents or solvent mixtures to those used for cel-lulose are often used for other neutral polysaccharides butmany are more soluble and some are water-soluble Starchis generally more soluble than cellulose Solvents forchitin include LiCl (5)DMA LiClN-methyl-2-pyrroli-done CaCl

2MeOH and hexafluoroisopropyl alcohol

Charged polysaccharides such as chitosan (which may beprotonated on nitrogen) or polyuronates such as alginates(which can form carboxylate salts) will have very differentsolubility properties Hence chitosan is soluble in aqueousorganic or mineral acids below pH 65 and also in DMSO

Ionic liquids (room-temperature ionic liquids) are rela-tively new solvents that have found use in polysaccharidechemistry [7 8]They can dissolve polysaccharides includingcellulose hemicellulose and wood allowing derivatisationreactions to take place under homogeneous conditions Cel-lulose dissolves in ionic liquids aided by conventional heat-ing microwave irradiation or sonication with up to 25(ww) being obtained in [bmim]Cl [9] Other ionic liquidsgave 5ndash10ww solutions of celluloseThe properties of ionicliquids can be fine-tuned by structural modification of oneor other of the two ionic components Increasing the lengthof the alkyl chains in the cation component resulted in a lessefficient dissolution of cellulose Amylose was shown to havea very high solubility in ether-derived ionic liquids Ionic liq-uids have been called ldquogreenrdquo solvents due to their recyclabil-ity and low vapour pressures (low volatility) but a low vapourpressure can limit the recyclability of a solvent as it can makeits purification difficult after it has been used in chemicalreactions As a result volatile and distillable ionic liquids havebeen designed for polysaccharide derivatisation [10]

2 Saccharide Oxygen as Nucleophile

This section covers the formation of ethers and esters inwhich the saccharide oxygen acts as a nucleophile in the reac-tion and is retained in the product Different degrees of reac-tion can be considered As well as very low DS where only

ISRN Organic Chemistry 3

OOHO

HOHO

HOHOHOHO

HO

HO

HO

HO

O

OH OH

OH

OH

OH

OH

Cellulose

O

OO

Amylose

O

OO

Curdlan

O

ODextran

OO

O O

Xylan

O

O

O

Inulin

O

OHO

HO

OH

O

O

HOHO

OH

O O

HOHO

HO OPullulan

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

Guar gum

(a) Hydroxyl groups only

OOHO

OHOOH

O

OO

HO

OH O

OH

Alginates

OHO

HO

COOMeO

OPectin

(b) Uronic acids

OOHO

O

OH

Chitosan

OOHO NH

O

OH

O

Chitin

NH2

(c) Nitrogen containing

Figure 1 Structures of the repeating units of some of the polysaccharides discussed in this review Some of the structures are simplified (seetext) branching is not shown for dextran xylan and pectin the alginate structure shown shows the two linkage types rather than a formalrepeating unit the chitin and chitosan structures shown represent extremes of a continuum of structures

a few hydroxyl groups per polysaccharide chain are deriva-tised and maximum DS where all the hydroxyl groups arederivatised and points in between these extremes we canconsider regioselective reactions in which a single hydroxylgroup on each monosaccharide residue reacts preferentiallyto (say) near completion Regioselective reactions allow thesynthesis of structurally well-defined products But morethan this if a regioselective reaction goes to completionreachingDS= 1 then it can be followed in principle by furtherderivatisations that do not have to be selective but thatcan nevertheless introduce further functionality at specificpositions in a polysaccharide structure

There is a significant disadvantage of working with poly-saccharides when it comes to matters of regioselectivity Inmonomeric molecules when a reaction gives incomplete

regioselectivity (resulting in the formation of regioisomersdisubstituted or trisubstituted products etc) the desiredproduct may be purified from the other components of theproduct mixture by crystallisation or chromatography Inpolysaccharides any such purification is impossible as cor-rectly modified monosaccharide residues of the polysaccha-ride will be covalently linked to incorrectly modified mono-saccharide residues This means that only the most regiose-lective modifying reactions may be used for polysaccharidemodification if a homogeneous polysaccharide structure isrequired

21 Etherification Etherification involves the reaction of analcohol (here a saccharide alcohol) with an alkylating agentin the presence of a base ((1) Figure 2)

R OH X + base RO

+ R998400

R998400 + base middot H+ + Xminus (1)

Typical alkylating agents include alkyl halides (chloridesbromides iodides) or less commonly alkyl sulfonates Nor-mally a strong base will be used to deprotonate the alcohol to

give the alkoxide Alkylation reactions generally have a poorwater-compatibility as water can hydrolyse the alkylatingagent

4 ISRN Organic Chemistry

RO

RO

RO

RO

Si RO

Si

Methyl Me

Trimethylsilyl TMS Thexyldimethylsilyl TMDS

Trityl (triphenylmethyl) Tr Benzyl Bn

RO

O

RO

OHHydroxyalkylCarboxymethyl

Ominus

R998400

Figure 2 Structures of some of the ethers discussed in this review

211 Alkyl and Benzyl Ethers The formation of celluloseethers under homogeneous conditions in typical nonderiv-atising solvents is possible but it is more problematic thanester formation (see below)The solvent of choice for celluloseetherification appears to be DMI (13-dimethyl-2-imidazo-lidinone)LiCl [11] In this solvent much lower excesses ofreagent were required than with alternative solvents First thecellulose was dissolved by briefly heating to 150∘C Treatmentwith NaOH and MeI for 5 h at 70∘C gave 236-tri-O-methyl-cellulose with a DS of 3 It should be pointed out that whenthe NaOH was added the cellulose crashed out of solutionto some extent and so the reaction was in fact not entirelyhomogeneous

Complete etherification (ie tri-O-alkylation) of cellu-lose was also investigated in other solvents for etherificationwith various alkyl groups Different solvents and bases wereevaluated in the benzylation reaction and the best conditionsof those tested were found to be powdered NaOH and BnCl(both in an excess of 10 equivhydroxyl) in a solvent ofDMSOSO

2Et2NH heating at ca 80∘C for 3-4 h [12] DMSO

N2O4and DMALiCl gave slightly worse results Subsequent

papers covered the formation of substituted benzyl ethers andallyl ethers [13] and of simple alkyl ethers [14] of cellulose allunder essentially the same reaction conditions Purificationwas achieved by extraction into chloroform precipitationafter the addition of EtOH and then washing with waterEtOH and hexane

In DMALiCl methyl hydroxyethyl and hydroxypropylethers of cellulose could be formed under homogeneous con-ditions using iodomethane or the epoxides as alkylatingagents [15] But high excesses of reagents were required slowreactions were seen and only products with low DS values(11ndash17) were accessible A DMSOLiCl solvent was used forthe homogeneous etherification (methyl ethyl propyl andbutyl peretherification) of cellulose using dimsyl sodium(from NaH and DMSO) as base [16]

Ionic liquids have been tested as solvents for the etheri-fication of polysaccharides (cellulose and starch) under basicconditions but with little success to date in contrast to ester-ification reactions (see below) [17]

Other polysaccharides have also been shown to undergoperetherification reactions under similar conditions Xylanwas benzylated using BnBr NaOH and 18-crown-6 inDMSO[18] and amylose was converted into its tri-O-benzyl deriva-tive by treatment with NaOH and BnCl in DMSO [19]

A detailed investigation into the benzylation of starch inwater (NaOH BnCl) was reported [20] As expected wide-spread hydrolysis of the BnCl occurred under these condi-tions

The benzylation of chitin was reported [21] 120573-Chitin wassuspended in DMSO and sodium hydride (5 equiv) andbenzyl chloride (10 equiv) were added After heating at 60∘Cfor 24 h the product (DS= 133) was obtained by precipitationfromMeOHWhenmore NaH (7 equiv) was used a productwith DS = 2 was obtained but N-alkylation is likely to occuras well asO-alkylation under such reaction conditions Alter-natively chitin was suspended in DMSO and treated withKOH this insoluble deprotonated chitin was then filtered andwashed to remove water then it was resuspended in DMSOand BnCl was addedThismethod gave the product with aDSof up to 08 [22]

Considering other alkyl ethers amylose and starch weretreated with propyl bromide and NaOH in DMSO to givepropyl ethers with DS of up to 30 [23] The purification ofpolysaccharides with high DS was achieved by precipitationfrom water but those with low DS were more difficult topurify Pullulan was converted into its propyl and butyl etherswith DS between 1 and 26 by treatment with the alkylbromides and NaOH in H

2ODMSO [24]

212 Carboxymethyl Ethers Carboxymethyl cellulose is anindustrially important ionic cellulose ether and the synthesisof this type of derivative based on some hemicellulose poly-saccharides has been investigated to some extentThe synthe-sis of carboxymethyl ethers of xylan was investigated underhomogeneous conditions (in water) or slurry conditions(in i-PrOH or EtOHtoluene) using NaOH as base andClCH

2COONa as alkylating agent [25] Guar gum was

derivatised with carboxymethyl ethers in water or in EtOHtoluene (as for xylan above) to give a product with a DS of08 Repeating the procedure gave further substitution and aproduct with a higher DS [18] Konjac glucomannan wasderivatised with carboxymethyl ethers in methanol to give aproduct with a DS of 03 [18]

213 Hydroxyethyl Ethers Other than cellulose derivativeswhich are produced industrially by epoxide-ring opening

ISRN Organic Chemistry 5

guar gum and xylan were etherified (up to DS = 2) by treat-ment with ethylene oxide or propylene oxide and sodiumhydroxide [18]

22 Esterification Esterification in general will involve thereaction of an alcohol (here a saccharide alcohol) with anacylating agent ((2) Figure 3)

R OH + base+ R998400

R998400R

OX

O

O

+ base middot H+ + Xminus

(2)

RO

SRO

SulfonateCarboxylateO O

OR998400

R998400

Figure 3 General structures carboxylate and sulfonate esters

221 Acetate and Other Carboxylate Esters Carboxylateesters can be formed using carboxylic acids as acylatingagents under strong-acid catalysis (Fischer esterification) orby using an activated derivative such as an acid chloride oranhydride either with base or with a Lewis acid

The strong-acid catalysis method is used to produce cel-lulose acetate an important industrial product [26] But thismethod does not produce the triacetate due to partial tran-sient sulfation during the reaction Cellulose triacetate can beprepared in a similar way using an acid catalyst that does notcovalently attach to the cellulose such as HClO

4

When an activated carboxylic acid derivative (eg acidanhydride acid chloride) reacts with an alcohol under basicconditions the base should be present in a stoichiometricamount (it will be protonated by the acid by-product of thereaction) but it can be a weak base such as pyridine or tri-ethylamine

(1) Homogeneous Reactions Cellulose carboxylates (DS ofup to 24ndash28) were prepared by the reaction of celluloseunder homogeneous conditions in DMALiCl solution withacid chlorides and triethylamine or with acid anhydridesand sulfuric acid [27] The cellulose carboxylate productswere purified by precipitation into water followed by Soxhletextraction intomethanol Similarly starch was esterified withacyl chlorides and pyridine in DMALiCl solution at 100∘Cfor 6 h followed by purification by precipitation [28] Withlong-chain fatty acid chlorides DS values of up to 3were seen

Xylan acetates with DS of up to 2 (ie complete acety-lation) could be prepared either with Ac

2Opyridine in

DMFLiCl or under acid catalysis in AcOH [29] Alterna-tively a xylan acetate with high DS (asymp19) and clean 1HNMRspectra was prepared using Ac

2O and pyridine in DMF [30]

With longer-chain acyl chlorides xylan reacted under homo-geneous conditions inDMFLiCl to give polysaccharideswithlower DS values (03ndash15) [31]

Vinyl carboxylates have also been used as acyl donorsreacting spontaneouslywith cellulose inDMSOTBAF to givepolysaccharides with DS values of up to 26 [32]

The acetylation of cellulose in an ionic liquid sol-vent [amim]Cl (1-allyl-3-methylimidazolium chloride) was

achieved in 2004 using acetic anhydride to give products withDS of ca 25ndash27 [33] The esterification of cellulose in ionicliquids is straightforward for short-chain esters [34] Severalionic liquids gave similarly good results with [bmim]Cl (1-butyl-3-methylimidazolium chloride) being the best Aceticanhydride or acetyl chloride reacted with cellulose withoutany added base within 2 h at 80∘C to give cellulose acetateswith DS of up to 3 However only lower DS values (eg 16for lauryl chloride) were obtainable with fatty acid chloridesin ionic liquids presumably because the partially acylatedpolysaccharide becomesmore andmore nonpolar until it pre-cipitates out of the polar ionic solvent stopping the reaction

The use of carboxylic acids themselves as acylating agentsrather than derivatives such as acid anhydrides or acylchlorides could be attractive as the acids may have a wideravailability and bemore soluble in polar solventsThe Fischeresterification using the carboxylic acid as solvent and withstrong-acid catalysis has already been mentioned but in situactivation of carboxylic acids under mild conditions can alsobe used for polysaccharide acylation When tosyl chloridewas used as an activating agent for with various long-chain carboxylic acids in a DMSOTBAF solvent acylatedcelluloses with DS of up to 26ndash29 could be formed [32 35]Cellulose reacted with carboxylic acids using classic peptidecoupling reagent DCC in nonaqueous solvents (eg DMALiCl) to give derivatised polysaccharides with low DS valuesStarch was acylated under similar conditions by the in situactivation of carboxylic acids with TsCl or CDI (carbonyldi-imidazole) [28]

The acetylation of alginates was less straightforward thanfor neutral polysaccharides [36] The solubility of alginatescan be changed by changing the ionisation state (ie acidversus salt) and (for the salt form) the counterion [egsodium versus tetrabutylammonium (TBA)] TBA-alginateswere soluble inDMSOTBAF but DMALiCl did not dissolveeither the acid or salt (Na or TBA) forms When the alginatesolution was treated with Ac

2O and pyridine only low DS

of up to ca 1 were obtained It is worth mentioning here thatDMSO can react with acylating agents to generate a Swern-type oxidant that can destructively oxidise polysaccharidehydroxyl groups

In amethod for the selectiveO-acylation of chitosan [37]the polysaccharide was suspended in water and a carboxylicacid (C

2ndashC9as well as some halogenated or unsaturated

acids) andH2SO4(2M)were added at room temperatureThe

mixture was then stirred at 80∘C for 4 h and the products(with low DS values of 002ndash02) were purified by pH adjust-ment precipitation from acetone and Soxhlet extractionUnder these conditions the nucleophilicity of the nitrogenis blocked by protonation

6 ISRN Organic Chemistry

(2) Heterogeneous Reactions In a heterogeneous reaction thestarting polysaccharide is insoluble in the reaction solventBut then dissolution may or may not occur during the courseof the reaction only surface groups may be acylated or alter-natively bulk hydroxyls may also react (due to solvent swell-ing of thematerial) themacroscopic structure of thematerialmay be retained after derivatisation (fibre paper cloth ornanofibrils etc)

Heating a suspension of insoluble cellulose in amixture ofpyridine and acylating agent (5 equivGlc = 13 equivOH)can give acylated celluloses with some acylating agents afterpurification by precipitation fromwater [38] Polysaccharideswith DS values of 26ndash29 were obtained with acetyl chlorideand with long-chain acyl chlorides (gtC

10) after 3 hWith piv-

aloyl chloride a much longer reaction time was required toobtain a product with DS = 25 in low yield and with shorterchain acyl chorides (ltC

6) decompositionwas seen A similar

synthesis of cellulose esterswas reported froma suspension ofthe polysaccharide in pyridine and the acid chloride [39 40]while initially heterogeneous cellulose reacted with acetylchloridewithout added base to give cellulose acetates withDSvalues of up to 296 [32]

Konjac glucomannan was acylated with palmitoyl chlo-ride and pyridine in benzene in a heterogeneous reaction inwhich the polysaccharide dissolved during the course of thereaction to give a product with DS up to 27 [18] Arabinoxy-lan was fully esterified under Fischer conditions by suspend-ing the polysaccharide in a carboxylic acid anhydride (aceticpropionic butyric) and treating with catalytic methanesul-fonic acid [41] Also here the polysaccharide dissolved duringthe course of the reaction Mixed anhydrides generated froma carboxylic acid and other more reactive acids (eg trifluo-roacetyl) have also been used as acylating agents with poly-saccharides under heterogeneous conditions [42]

222 Sulfonate Esters Sulfonate esters can act as leavinggroups in SN2 reactions (see below) and many of their appli-cations derive from this aspect of their reactivityTheymay beintroduced with reasonably good regioselectivity for the pri-mary hydroxyl groups and regioselective sulfonate synthesesare described in the section on regioselective reactions (seebelow) But polysaccharide sulfonates with DS gt 2 are alsoaccessible The most commonly seen sulfonates in polysac-charides are toluenesulfonates (tosylates Ts) and methane-sulfonates (mesylates Ms) [43]

The classic reaction conditions for tosylate formationinvolve heating the (initially heterogeneous) polysaccharidewith tosyl chloride in pyridine Three possible side reactionsthat may occur during sulfonate ester formation all arisingfrom nucleophilic displacement of the formed sulfonate esterare as follows (i) cyclisation by attack of one of the secondaryhydroxyl groups (eg O-3) (ii) attack by pyridine to forma C-6 pyridinium salt (iii) attack by chloride to form a C-6chlorideThese side reactions are a result of the long reactiontimes and high temperatures required for the heterogeneousreaction

Thus these side reactions can beminimised or suppressedby using homogeneous conditions [44] Tosylation andmesy-lation reactions of cellulose in solution in DMALiCl gave

uniform and well-defined products with DS values between04 and 23 The tosylation of cellulose underhomogeneousconditions in the ionic liquid [amim]Cl was also recentlyachieved [45]

Sulfonate esters of other polysaccharides have also beensynthesised Chitin was tosylated under homogeneous con-ditions in DMALiCl [46] dextran tosylates were preparedin organic solvent without any added salt [47] and konjacglucomannan was tosylated to give products with DS of up to23 [18] The mesylation of cross-linked particles of pullulanhas been reported [48]

23 Regioselective Etherification and Esterification of Polysac-charides The primary alcohol of a saccharide will with veryfew exceptions always bemore nucleophilic than the second-ary alcoholsThe difference in reactivity between the primaryand secondary alcohols can vary though and complete regio-selective distinction between primary and secondary alcohols(ie normally C-6 versus all of C-2 C-3 and C-4) will oftennot be seenThe respective rate constants for the substitutionof primary and secondary alcohols do not change during areaction and if a primary alcohol reacts more quickly thana secondary alcohol its concentration will decrease morerapidly as the reaction progresses Therefore as the reactionprogresses the rates of reaction of the primary and second-ary alcohols will become similar and regioselectivity willdecrease

Differentiation between the nucleophilicity of the differ-ent secondary hydroxyl groups in a polysaccharide will oftenbe difficult or impossible and polysaccharides containingdifferent substitution patterns may often be formed Havingsaid that there are a few examples of regioselectivity bet-ween the secondary positions of polysaccharides that can beexploited syntheticallyThe regioselective protection of cellu-lose focussing on ether and ester protecting groups has beenreviewed [45] and covered to some extent in other reviews[49 50]

The hydroxyl groups of cellulose are much more reactivein solution than they are in the solid phase because whencellulose dissolves the extensive hydrogen-bonding networkis broken up As a result reactions in solution can be carriedout under milder conditions than in the solid phase andthis allows a higher degree of selectivity Thus regioselectivederivatisations of cellulose and other polysaccharides are gen-erally carried out under homogeneous reaction conditionsand the solvent system DMALiBr (or LiCl) is often used

Only a rather limited number of groupstransformationslive up to the very high regioselectivity criteria that are nec-essary for the modification of polysaccharides These includethe installation of trityl ethers (at O-6) and of bulky silylethers (at O-6 or at both O-2 and O-6) The installation ofcarboxylate esters (at O-6 but not normally selective enough)and tosylate esters (at O-6 but not normally completelyselective or at O-2) are also considered here The installationof halides at C-6 in a phosphane-mediated reaction is alsooften a regioselective process but this in this reaction thepolysaccharide behaves as an electrophile so it is consideredin a later section of this review

ISRN Organic Chemistry 7

OOHO OH

O

OH

OOHO OH

O

OTr

Scheme 1

231 Trityl Ethers The trityl group reacts with cellulose pref-erentially at the primary hydroxyl O-6 on steric grounds(Scheme 1) Trityl ethers may be installed by heating cellulose(rayon) with pyridine and trityl chloride (ie under initiallyheterogeneous conditions with dissolution occurring as thereaction proceeds) and DS values close to 1 with little substi-tution of the secondary positions are obtainable [26 51] Cel-lulose has also been tritylated under homogeneous condi-tions to give products with DS values of 10 [6] The solventsused were DMSON

2O4 DMALiCl or DMSOSO

2DEA

6-O-Trityl derivatives of some other polysaccharides havebeen prepared directly or indirectly Amylose underwent tri-tylation regioselectively at O-6 uneventfully [52] Chitin wasalso tritylated regioselectivity with reaction at O-6 [21] 120573-Chitin was suspended in pyridine and heated at 90∘C for72 h with trityl chloride (10 equiv) and DMAP (3ndash6 equiv)Products with DS values of 075ndash10 were obtained by purifi-cation by precipitation frommethanol A 6-O-trityl derivativeof chitosan was prepared by a three-step sequence First thenitrogen was protected as a phthalimide derivative then O-6 was tritylated and finally N-deprotection gave the 6-O-tritylchitosan with DS = 1 [53]

232 Silyl Ethers Thexyldimethylsilyl chloride (TMDSCl)has been shown to react with cellulose with very good regio-selectivity and different regioselectivities O-6 only or forboth O-2 and O-6 are seen under different reaction condi-tions (Scheme 2) Treatment of cellulose (undissolved ieunder initially heterogeneous conditions) with TMDSC1 inDMF saturated with ammonia at ndash15∘C resulted in the intro-duction of TMDS groups at C-6 only with a DS of 099 [54]When the reaction was carried out under homogeneous con-ditions in DMALiCl and with imidazole as base 26-di-O-thexyldimethylsilylcellulose was formed with a DS of 20 [5556] Moreover this 26-protected derivative can be used forthe regiospecific introduction of substituents at O-3 of cellu-lose 3-O-Methylcellulose and 3-O-allylcellulose have beensynthesised in this way The silyl ethers can be removed bytreatment with TBAF (tetrabutylammonium fluoride) Liq-uid ammonia has also been used as an effective solvent forsilylation reactions of cellulose [57]

233 Carboxylate Esters Regioselectivities (forO-6) are gen-erally lower for carboxylate esterification reactions of cellu-lose than those seen for the formation of trityl ethers or silylethers [45] An investigation of various sterically hinderedacylating agents including pivaloyl chloride adamantoylchloride and 246-trimethylbenzyl chloride in solventsincluding DMALiCl DMSOTBAF and the ionic liquid[amim]Cl failed to give satisfactory regioselectivity [58] But

OOHO OH

O

OHO

OHO OH

O

OTDMS

OOHO OTDMS

O

OTDMSOr

Scheme 2

having said that in a different study excellent regioselectivityfor O-6 of cellulose was observed in an esterification reactionusing benzyl chloride in [amim]Cl without any added base[59]

It is relevant in this context to note that silyl ether protec-tion may be regiospecifically replaced by carboxylate protec-tion [60] When a cellulose derivative bearing trimethylsilylethers is treated with an acyl chloride in the absence of a basethe silyl ethers are regiospecifically replaced by acyl groups(in the presence of a base the silyl ethers remain and thefree hydroxyl groups are acylated) But while this process iswell known for trimethylsilyl ethers it has apparently [45]not yet been investigated for thexyldimethylsilylethers which(as described above) can be introduced into cellulose withexcellent regioselectivity

234 Sulfonate Esters Cellulose reacts preferentially at O-6in tosylation reactions (see above) but the regioselectivity isnot perfect The esterification of cellulose with various sul-fonic acid chlorides including the 246-trimethylbenzenes-ulfonyl group under homogeneous conditions (in DMALiCl) was investigated in an attempt to improve the regios-electivity for substitution at O-6 [61] but in general theproducts contained mixtures of 2- and 6-tosylation

A very interesting result has been obtained concerningthe regioselectivity of the tosylation of starch When starch(70 amylose) was tosylated in solution in DMALiCl O-2reacted preferentially with very good regioselectivity (overO-3 and O-6) to give a product with a DS asymp 1 with the tosylgroups essentially exclusively at C-2 The regioselectivity wasproved by 1H and 13C NMR spectroscopy (Scheme 3) [62]This regioselectivity is counterintuitive and apparently it isalso solvent-dependent Horton had previously reported thatwhen the tosylation of amylose was carried out in pyridinethe more expected product 6-O-tosyl-amylose was formedwith DS asymp 06 (Scheme 3) [63]

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

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Advances in

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

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Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Organic Chemistry International

ElectrochemistryInternational Journal of

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CatalystsJournal of

ISRN Organic Chemistry 3

OOHO

HOHO

HOHOHOHO

HO

HO

HO

HO

O

OH OH

OH

OH

OH

OH

Cellulose

O

OO

Amylose

O

OO

Curdlan

O

ODextran

OO

O O

Xylan

O

O

O

Inulin

O

OHO

HO

OH

O

O

HOHO

OH

O O

HOHO

HO OPullulan

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

Guar gum

(a) Hydroxyl groups only

OOHO

OHOOH

O

OO

HO

OH O

OH

Alginates

OHO

HO

COOMeO

OPectin

(b) Uronic acids

OOHO

O

OH

Chitosan

OOHO NH

O

OH

O

Chitin

NH2

(c) Nitrogen containing

Figure 1 Structures of the repeating units of some of the polysaccharides discussed in this review Some of the structures are simplified (seetext) branching is not shown for dextran xylan and pectin the alginate structure shown shows the two linkage types rather than a formalrepeating unit the chitin and chitosan structures shown represent extremes of a continuum of structures

a few hydroxyl groups per polysaccharide chain are deriva-tised and maximum DS where all the hydroxyl groups arederivatised and points in between these extremes we canconsider regioselective reactions in which a single hydroxylgroup on each monosaccharide residue reacts preferentiallyto (say) near completion Regioselective reactions allow thesynthesis of structurally well-defined products But morethan this if a regioselective reaction goes to completionreachingDS= 1 then it can be followed in principle by furtherderivatisations that do not have to be selective but thatcan nevertheless introduce further functionality at specificpositions in a polysaccharide structure

There is a significant disadvantage of working with poly-saccharides when it comes to matters of regioselectivity Inmonomeric molecules when a reaction gives incomplete

regioselectivity (resulting in the formation of regioisomersdisubstituted or trisubstituted products etc) the desiredproduct may be purified from the other components of theproduct mixture by crystallisation or chromatography Inpolysaccharides any such purification is impossible as cor-rectly modified monosaccharide residues of the polysaccha-ride will be covalently linked to incorrectly modified mono-saccharide residues This means that only the most regiose-lective modifying reactions may be used for polysaccharidemodification if a homogeneous polysaccharide structure isrequired

21 Etherification Etherification involves the reaction of analcohol (here a saccharide alcohol) with an alkylating agentin the presence of a base ((1) Figure 2)

R OH X + base RO

+ R998400

R998400 + base middot H+ + Xminus (1)

Typical alkylating agents include alkyl halides (chloridesbromides iodides) or less commonly alkyl sulfonates Nor-mally a strong base will be used to deprotonate the alcohol to

give the alkoxide Alkylation reactions generally have a poorwater-compatibility as water can hydrolyse the alkylatingagent

4 ISRN Organic Chemistry

RO

RO

RO

RO

Si RO

Si

Methyl Me

Trimethylsilyl TMS Thexyldimethylsilyl TMDS

Trityl (triphenylmethyl) Tr Benzyl Bn

RO

O

RO

OHHydroxyalkylCarboxymethyl

Ominus

R998400

Figure 2 Structures of some of the ethers discussed in this review

211 Alkyl and Benzyl Ethers The formation of celluloseethers under homogeneous conditions in typical nonderiv-atising solvents is possible but it is more problematic thanester formation (see below)The solvent of choice for celluloseetherification appears to be DMI (13-dimethyl-2-imidazo-lidinone)LiCl [11] In this solvent much lower excesses ofreagent were required than with alternative solvents First thecellulose was dissolved by briefly heating to 150∘C Treatmentwith NaOH and MeI for 5 h at 70∘C gave 236-tri-O-methyl-cellulose with a DS of 3 It should be pointed out that whenthe NaOH was added the cellulose crashed out of solutionto some extent and so the reaction was in fact not entirelyhomogeneous

Complete etherification (ie tri-O-alkylation) of cellu-lose was also investigated in other solvents for etherificationwith various alkyl groups Different solvents and bases wereevaluated in the benzylation reaction and the best conditionsof those tested were found to be powdered NaOH and BnCl(both in an excess of 10 equivhydroxyl) in a solvent ofDMSOSO

2Et2NH heating at ca 80∘C for 3-4 h [12] DMSO

N2O4and DMALiCl gave slightly worse results Subsequent

papers covered the formation of substituted benzyl ethers andallyl ethers [13] and of simple alkyl ethers [14] of cellulose allunder essentially the same reaction conditions Purificationwas achieved by extraction into chloroform precipitationafter the addition of EtOH and then washing with waterEtOH and hexane

In DMALiCl methyl hydroxyethyl and hydroxypropylethers of cellulose could be formed under homogeneous con-ditions using iodomethane or the epoxides as alkylatingagents [15] But high excesses of reagents were required slowreactions were seen and only products with low DS values(11ndash17) were accessible A DMSOLiCl solvent was used forthe homogeneous etherification (methyl ethyl propyl andbutyl peretherification) of cellulose using dimsyl sodium(from NaH and DMSO) as base [16]

Ionic liquids have been tested as solvents for the etheri-fication of polysaccharides (cellulose and starch) under basicconditions but with little success to date in contrast to ester-ification reactions (see below) [17]

Other polysaccharides have also been shown to undergoperetherification reactions under similar conditions Xylanwas benzylated using BnBr NaOH and 18-crown-6 inDMSO[18] and amylose was converted into its tri-O-benzyl deriva-tive by treatment with NaOH and BnCl in DMSO [19]

A detailed investigation into the benzylation of starch inwater (NaOH BnCl) was reported [20] As expected wide-spread hydrolysis of the BnCl occurred under these condi-tions

The benzylation of chitin was reported [21] 120573-Chitin wassuspended in DMSO and sodium hydride (5 equiv) andbenzyl chloride (10 equiv) were added After heating at 60∘Cfor 24 h the product (DS= 133) was obtained by precipitationfromMeOHWhenmore NaH (7 equiv) was used a productwith DS = 2 was obtained but N-alkylation is likely to occuras well asO-alkylation under such reaction conditions Alter-natively chitin was suspended in DMSO and treated withKOH this insoluble deprotonated chitin was then filtered andwashed to remove water then it was resuspended in DMSOand BnCl was addedThismethod gave the product with aDSof up to 08 [22]

Considering other alkyl ethers amylose and starch weretreated with propyl bromide and NaOH in DMSO to givepropyl ethers with DS of up to 30 [23] The purification ofpolysaccharides with high DS was achieved by precipitationfrom water but those with low DS were more difficult topurify Pullulan was converted into its propyl and butyl etherswith DS between 1 and 26 by treatment with the alkylbromides and NaOH in H

2ODMSO [24]

212 Carboxymethyl Ethers Carboxymethyl cellulose is anindustrially important ionic cellulose ether and the synthesisof this type of derivative based on some hemicellulose poly-saccharides has been investigated to some extentThe synthe-sis of carboxymethyl ethers of xylan was investigated underhomogeneous conditions (in water) or slurry conditions(in i-PrOH or EtOHtoluene) using NaOH as base andClCH

2COONa as alkylating agent [25] Guar gum was

derivatised with carboxymethyl ethers in water or in EtOHtoluene (as for xylan above) to give a product with a DS of08 Repeating the procedure gave further substitution and aproduct with a higher DS [18] Konjac glucomannan wasderivatised with carboxymethyl ethers in methanol to give aproduct with a DS of 03 [18]

213 Hydroxyethyl Ethers Other than cellulose derivativeswhich are produced industrially by epoxide-ring opening

ISRN Organic Chemistry 5

guar gum and xylan were etherified (up to DS = 2) by treat-ment with ethylene oxide or propylene oxide and sodiumhydroxide [18]

22 Esterification Esterification in general will involve thereaction of an alcohol (here a saccharide alcohol) with anacylating agent ((2) Figure 3)

R OH + base+ R998400

R998400R

OX

O

O

+ base middot H+ + Xminus

(2)

RO

SRO

SulfonateCarboxylateO O

OR998400

R998400

Figure 3 General structures carboxylate and sulfonate esters

221 Acetate and Other Carboxylate Esters Carboxylateesters can be formed using carboxylic acids as acylatingagents under strong-acid catalysis (Fischer esterification) orby using an activated derivative such as an acid chloride oranhydride either with base or with a Lewis acid

The strong-acid catalysis method is used to produce cel-lulose acetate an important industrial product [26] But thismethod does not produce the triacetate due to partial tran-sient sulfation during the reaction Cellulose triacetate can beprepared in a similar way using an acid catalyst that does notcovalently attach to the cellulose such as HClO

4

When an activated carboxylic acid derivative (eg acidanhydride acid chloride) reacts with an alcohol under basicconditions the base should be present in a stoichiometricamount (it will be protonated by the acid by-product of thereaction) but it can be a weak base such as pyridine or tri-ethylamine

(1) Homogeneous Reactions Cellulose carboxylates (DS ofup to 24ndash28) were prepared by the reaction of celluloseunder homogeneous conditions in DMALiCl solution withacid chlorides and triethylamine or with acid anhydridesand sulfuric acid [27] The cellulose carboxylate productswere purified by precipitation into water followed by Soxhletextraction intomethanol Similarly starch was esterified withacyl chlorides and pyridine in DMALiCl solution at 100∘Cfor 6 h followed by purification by precipitation [28] Withlong-chain fatty acid chlorides DS values of up to 3were seen

Xylan acetates with DS of up to 2 (ie complete acety-lation) could be prepared either with Ac

2Opyridine in

DMFLiCl or under acid catalysis in AcOH [29] Alterna-tively a xylan acetate with high DS (asymp19) and clean 1HNMRspectra was prepared using Ac

2O and pyridine in DMF [30]

With longer-chain acyl chlorides xylan reacted under homo-geneous conditions inDMFLiCl to give polysaccharideswithlower DS values (03ndash15) [31]

Vinyl carboxylates have also been used as acyl donorsreacting spontaneouslywith cellulose inDMSOTBAF to givepolysaccharides with DS values of up to 26 [32]

The acetylation of cellulose in an ionic liquid sol-vent [amim]Cl (1-allyl-3-methylimidazolium chloride) was

achieved in 2004 using acetic anhydride to give products withDS of ca 25ndash27 [33] The esterification of cellulose in ionicliquids is straightforward for short-chain esters [34] Severalionic liquids gave similarly good results with [bmim]Cl (1-butyl-3-methylimidazolium chloride) being the best Aceticanhydride or acetyl chloride reacted with cellulose withoutany added base within 2 h at 80∘C to give cellulose acetateswith DS of up to 3 However only lower DS values (eg 16for lauryl chloride) were obtainable with fatty acid chloridesin ionic liquids presumably because the partially acylatedpolysaccharide becomesmore andmore nonpolar until it pre-cipitates out of the polar ionic solvent stopping the reaction

The use of carboxylic acids themselves as acylating agentsrather than derivatives such as acid anhydrides or acylchlorides could be attractive as the acids may have a wideravailability and bemore soluble in polar solventsThe Fischeresterification using the carboxylic acid as solvent and withstrong-acid catalysis has already been mentioned but in situactivation of carboxylic acids under mild conditions can alsobe used for polysaccharide acylation When tosyl chloridewas used as an activating agent for with various long-chain carboxylic acids in a DMSOTBAF solvent acylatedcelluloses with DS of up to 26ndash29 could be formed [32 35]Cellulose reacted with carboxylic acids using classic peptidecoupling reagent DCC in nonaqueous solvents (eg DMALiCl) to give derivatised polysaccharides with low DS valuesStarch was acylated under similar conditions by the in situactivation of carboxylic acids with TsCl or CDI (carbonyldi-imidazole) [28]

The acetylation of alginates was less straightforward thanfor neutral polysaccharides [36] The solubility of alginatescan be changed by changing the ionisation state (ie acidversus salt) and (for the salt form) the counterion [egsodium versus tetrabutylammonium (TBA)] TBA-alginateswere soluble inDMSOTBAF but DMALiCl did not dissolveeither the acid or salt (Na or TBA) forms When the alginatesolution was treated with Ac

2O and pyridine only low DS

of up to ca 1 were obtained It is worth mentioning here thatDMSO can react with acylating agents to generate a Swern-type oxidant that can destructively oxidise polysaccharidehydroxyl groups

In amethod for the selectiveO-acylation of chitosan [37]the polysaccharide was suspended in water and a carboxylicacid (C

2ndashC9as well as some halogenated or unsaturated

acids) andH2SO4(2M)were added at room temperatureThe

mixture was then stirred at 80∘C for 4 h and the products(with low DS values of 002ndash02) were purified by pH adjust-ment precipitation from acetone and Soxhlet extractionUnder these conditions the nucleophilicity of the nitrogenis blocked by protonation

6 ISRN Organic Chemistry

(2) Heterogeneous Reactions In a heterogeneous reaction thestarting polysaccharide is insoluble in the reaction solventBut then dissolution may or may not occur during the courseof the reaction only surface groups may be acylated or alter-natively bulk hydroxyls may also react (due to solvent swell-ing of thematerial) themacroscopic structure of thematerialmay be retained after derivatisation (fibre paper cloth ornanofibrils etc)

Heating a suspension of insoluble cellulose in amixture ofpyridine and acylating agent (5 equivGlc = 13 equivOH)can give acylated celluloses with some acylating agents afterpurification by precipitation fromwater [38] Polysaccharideswith DS values of 26ndash29 were obtained with acetyl chlorideand with long-chain acyl chlorides (gtC

10) after 3 hWith piv-

aloyl chloride a much longer reaction time was required toobtain a product with DS = 25 in low yield and with shorterchain acyl chorides (ltC

6) decompositionwas seen A similar

synthesis of cellulose esterswas reported froma suspension ofthe polysaccharide in pyridine and the acid chloride [39 40]while initially heterogeneous cellulose reacted with acetylchloridewithout added base to give cellulose acetates withDSvalues of up to 296 [32]

Konjac glucomannan was acylated with palmitoyl chlo-ride and pyridine in benzene in a heterogeneous reaction inwhich the polysaccharide dissolved during the course of thereaction to give a product with DS up to 27 [18] Arabinoxy-lan was fully esterified under Fischer conditions by suspend-ing the polysaccharide in a carboxylic acid anhydride (aceticpropionic butyric) and treating with catalytic methanesul-fonic acid [41] Also here the polysaccharide dissolved duringthe course of the reaction Mixed anhydrides generated froma carboxylic acid and other more reactive acids (eg trifluo-roacetyl) have also been used as acylating agents with poly-saccharides under heterogeneous conditions [42]

222 Sulfonate Esters Sulfonate esters can act as leavinggroups in SN2 reactions (see below) and many of their appli-cations derive from this aspect of their reactivityTheymay beintroduced with reasonably good regioselectivity for the pri-mary hydroxyl groups and regioselective sulfonate synthesesare described in the section on regioselective reactions (seebelow) But polysaccharide sulfonates with DS gt 2 are alsoaccessible The most commonly seen sulfonates in polysac-charides are toluenesulfonates (tosylates Ts) and methane-sulfonates (mesylates Ms) [43]

The classic reaction conditions for tosylate formationinvolve heating the (initially heterogeneous) polysaccharidewith tosyl chloride in pyridine Three possible side reactionsthat may occur during sulfonate ester formation all arisingfrom nucleophilic displacement of the formed sulfonate esterare as follows (i) cyclisation by attack of one of the secondaryhydroxyl groups (eg O-3) (ii) attack by pyridine to forma C-6 pyridinium salt (iii) attack by chloride to form a C-6chlorideThese side reactions are a result of the long reactiontimes and high temperatures required for the heterogeneousreaction

Thus these side reactions can beminimised or suppressedby using homogeneous conditions [44] Tosylation andmesy-lation reactions of cellulose in solution in DMALiCl gave

uniform and well-defined products with DS values between04 and 23 The tosylation of cellulose underhomogeneousconditions in the ionic liquid [amim]Cl was also recentlyachieved [45]

Sulfonate esters of other polysaccharides have also beensynthesised Chitin was tosylated under homogeneous con-ditions in DMALiCl [46] dextran tosylates were preparedin organic solvent without any added salt [47] and konjacglucomannan was tosylated to give products with DS of up to23 [18] The mesylation of cross-linked particles of pullulanhas been reported [48]

23 Regioselective Etherification and Esterification of Polysac-charides The primary alcohol of a saccharide will with veryfew exceptions always bemore nucleophilic than the second-ary alcoholsThe difference in reactivity between the primaryand secondary alcohols can vary though and complete regio-selective distinction between primary and secondary alcohols(ie normally C-6 versus all of C-2 C-3 and C-4) will oftennot be seenThe respective rate constants for the substitutionof primary and secondary alcohols do not change during areaction and if a primary alcohol reacts more quickly thana secondary alcohol its concentration will decrease morerapidly as the reaction progresses Therefore as the reactionprogresses the rates of reaction of the primary and second-ary alcohols will become similar and regioselectivity willdecrease

Differentiation between the nucleophilicity of the differ-ent secondary hydroxyl groups in a polysaccharide will oftenbe difficult or impossible and polysaccharides containingdifferent substitution patterns may often be formed Havingsaid that there are a few examples of regioselectivity bet-ween the secondary positions of polysaccharides that can beexploited syntheticallyThe regioselective protection of cellu-lose focussing on ether and ester protecting groups has beenreviewed [45] and covered to some extent in other reviews[49 50]

The hydroxyl groups of cellulose are much more reactivein solution than they are in the solid phase because whencellulose dissolves the extensive hydrogen-bonding networkis broken up As a result reactions in solution can be carriedout under milder conditions than in the solid phase andthis allows a higher degree of selectivity Thus regioselectivederivatisations of cellulose and other polysaccharides are gen-erally carried out under homogeneous reaction conditionsand the solvent system DMALiBr (or LiCl) is often used

Only a rather limited number of groupstransformationslive up to the very high regioselectivity criteria that are nec-essary for the modification of polysaccharides These includethe installation of trityl ethers (at O-6) and of bulky silylethers (at O-6 or at both O-2 and O-6) The installation ofcarboxylate esters (at O-6 but not normally selective enough)and tosylate esters (at O-6 but not normally completelyselective or at O-2) are also considered here The installationof halides at C-6 in a phosphane-mediated reaction is alsooften a regioselective process but this in this reaction thepolysaccharide behaves as an electrophile so it is consideredin a later section of this review

ISRN Organic Chemistry 7

OOHO OH

O

OH

OOHO OH

O

OTr

Scheme 1

231 Trityl Ethers The trityl group reacts with cellulose pref-erentially at the primary hydroxyl O-6 on steric grounds(Scheme 1) Trityl ethers may be installed by heating cellulose(rayon) with pyridine and trityl chloride (ie under initiallyheterogeneous conditions with dissolution occurring as thereaction proceeds) and DS values close to 1 with little substi-tution of the secondary positions are obtainable [26 51] Cel-lulose has also been tritylated under homogeneous condi-tions to give products with DS values of 10 [6] The solventsused were DMSON

2O4 DMALiCl or DMSOSO

2DEA

6-O-Trityl derivatives of some other polysaccharides havebeen prepared directly or indirectly Amylose underwent tri-tylation regioselectively at O-6 uneventfully [52] Chitin wasalso tritylated regioselectivity with reaction at O-6 [21] 120573-Chitin was suspended in pyridine and heated at 90∘C for72 h with trityl chloride (10 equiv) and DMAP (3ndash6 equiv)Products with DS values of 075ndash10 were obtained by purifi-cation by precipitation frommethanol A 6-O-trityl derivativeof chitosan was prepared by a three-step sequence First thenitrogen was protected as a phthalimide derivative then O-6 was tritylated and finally N-deprotection gave the 6-O-tritylchitosan with DS = 1 [53]

232 Silyl Ethers Thexyldimethylsilyl chloride (TMDSCl)has been shown to react with cellulose with very good regio-selectivity and different regioselectivities O-6 only or forboth O-2 and O-6 are seen under different reaction condi-tions (Scheme 2) Treatment of cellulose (undissolved ieunder initially heterogeneous conditions) with TMDSC1 inDMF saturated with ammonia at ndash15∘C resulted in the intro-duction of TMDS groups at C-6 only with a DS of 099 [54]When the reaction was carried out under homogeneous con-ditions in DMALiCl and with imidazole as base 26-di-O-thexyldimethylsilylcellulose was formed with a DS of 20 [5556] Moreover this 26-protected derivative can be used forthe regiospecific introduction of substituents at O-3 of cellu-lose 3-O-Methylcellulose and 3-O-allylcellulose have beensynthesised in this way The silyl ethers can be removed bytreatment with TBAF (tetrabutylammonium fluoride) Liq-uid ammonia has also been used as an effective solvent forsilylation reactions of cellulose [57]

233 Carboxylate Esters Regioselectivities (forO-6) are gen-erally lower for carboxylate esterification reactions of cellu-lose than those seen for the formation of trityl ethers or silylethers [45] An investigation of various sterically hinderedacylating agents including pivaloyl chloride adamantoylchloride and 246-trimethylbenzyl chloride in solventsincluding DMALiCl DMSOTBAF and the ionic liquid[amim]Cl failed to give satisfactory regioselectivity [58] But

OOHO OH

O

OHO

OHO OH

O

OTDMS

OOHO OTDMS

O

OTDMSOr

Scheme 2

having said that in a different study excellent regioselectivityfor O-6 of cellulose was observed in an esterification reactionusing benzyl chloride in [amim]Cl without any added base[59]

It is relevant in this context to note that silyl ether protec-tion may be regiospecifically replaced by carboxylate protec-tion [60] When a cellulose derivative bearing trimethylsilylethers is treated with an acyl chloride in the absence of a basethe silyl ethers are regiospecifically replaced by acyl groups(in the presence of a base the silyl ethers remain and thefree hydroxyl groups are acylated) But while this process iswell known for trimethylsilyl ethers it has apparently [45]not yet been investigated for thexyldimethylsilylethers which(as described above) can be introduced into cellulose withexcellent regioselectivity

234 Sulfonate Esters Cellulose reacts preferentially at O-6in tosylation reactions (see above) but the regioselectivity isnot perfect The esterification of cellulose with various sul-fonic acid chlorides including the 246-trimethylbenzenes-ulfonyl group under homogeneous conditions (in DMALiCl) was investigated in an attempt to improve the regios-electivity for substitution at O-6 [61] but in general theproducts contained mixtures of 2- and 6-tosylation

A very interesting result has been obtained concerningthe regioselectivity of the tosylation of starch When starch(70 amylose) was tosylated in solution in DMALiCl O-2reacted preferentially with very good regioselectivity (overO-3 and O-6) to give a product with a DS asymp 1 with the tosylgroups essentially exclusively at C-2 The regioselectivity wasproved by 1H and 13C NMR spectroscopy (Scheme 3) [62]This regioselectivity is counterintuitive and apparently it isalso solvent-dependent Horton had previously reported thatwhen the tosylation of amylose was carried out in pyridinethe more expected product 6-O-tosyl-amylose was formedwith DS asymp 06 (Scheme 3) [63]

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

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CatalystsJournal of

4 ISRN Organic Chemistry

RO

RO

RO

RO

Si RO

Si

Methyl Me

Trimethylsilyl TMS Thexyldimethylsilyl TMDS

Trityl (triphenylmethyl) Tr Benzyl Bn

RO

O

RO

OHHydroxyalkylCarboxymethyl

Ominus

R998400

Figure 2 Structures of some of the ethers discussed in this review

211 Alkyl and Benzyl Ethers The formation of celluloseethers under homogeneous conditions in typical nonderiv-atising solvents is possible but it is more problematic thanester formation (see below)The solvent of choice for celluloseetherification appears to be DMI (13-dimethyl-2-imidazo-lidinone)LiCl [11] In this solvent much lower excesses ofreagent were required than with alternative solvents First thecellulose was dissolved by briefly heating to 150∘C Treatmentwith NaOH and MeI for 5 h at 70∘C gave 236-tri-O-methyl-cellulose with a DS of 3 It should be pointed out that whenthe NaOH was added the cellulose crashed out of solutionto some extent and so the reaction was in fact not entirelyhomogeneous

Complete etherification (ie tri-O-alkylation) of cellu-lose was also investigated in other solvents for etherificationwith various alkyl groups Different solvents and bases wereevaluated in the benzylation reaction and the best conditionsof those tested were found to be powdered NaOH and BnCl(both in an excess of 10 equivhydroxyl) in a solvent ofDMSOSO

2Et2NH heating at ca 80∘C for 3-4 h [12] DMSO

N2O4and DMALiCl gave slightly worse results Subsequent

papers covered the formation of substituted benzyl ethers andallyl ethers [13] and of simple alkyl ethers [14] of cellulose allunder essentially the same reaction conditions Purificationwas achieved by extraction into chloroform precipitationafter the addition of EtOH and then washing with waterEtOH and hexane

In DMALiCl methyl hydroxyethyl and hydroxypropylethers of cellulose could be formed under homogeneous con-ditions using iodomethane or the epoxides as alkylatingagents [15] But high excesses of reagents were required slowreactions were seen and only products with low DS values(11ndash17) were accessible A DMSOLiCl solvent was used forthe homogeneous etherification (methyl ethyl propyl andbutyl peretherification) of cellulose using dimsyl sodium(from NaH and DMSO) as base [16]

Ionic liquids have been tested as solvents for the etheri-fication of polysaccharides (cellulose and starch) under basicconditions but with little success to date in contrast to ester-ification reactions (see below) [17]

Other polysaccharides have also been shown to undergoperetherification reactions under similar conditions Xylanwas benzylated using BnBr NaOH and 18-crown-6 inDMSO[18] and amylose was converted into its tri-O-benzyl deriva-tive by treatment with NaOH and BnCl in DMSO [19]

A detailed investigation into the benzylation of starch inwater (NaOH BnCl) was reported [20] As expected wide-spread hydrolysis of the BnCl occurred under these condi-tions

The benzylation of chitin was reported [21] 120573-Chitin wassuspended in DMSO and sodium hydride (5 equiv) andbenzyl chloride (10 equiv) were added After heating at 60∘Cfor 24 h the product (DS= 133) was obtained by precipitationfromMeOHWhenmore NaH (7 equiv) was used a productwith DS = 2 was obtained but N-alkylation is likely to occuras well asO-alkylation under such reaction conditions Alter-natively chitin was suspended in DMSO and treated withKOH this insoluble deprotonated chitin was then filtered andwashed to remove water then it was resuspended in DMSOand BnCl was addedThismethod gave the product with aDSof up to 08 [22]

Considering other alkyl ethers amylose and starch weretreated with propyl bromide and NaOH in DMSO to givepropyl ethers with DS of up to 30 [23] The purification ofpolysaccharides with high DS was achieved by precipitationfrom water but those with low DS were more difficult topurify Pullulan was converted into its propyl and butyl etherswith DS between 1 and 26 by treatment with the alkylbromides and NaOH in H

2ODMSO [24]

212 Carboxymethyl Ethers Carboxymethyl cellulose is anindustrially important ionic cellulose ether and the synthesisof this type of derivative based on some hemicellulose poly-saccharides has been investigated to some extentThe synthe-sis of carboxymethyl ethers of xylan was investigated underhomogeneous conditions (in water) or slurry conditions(in i-PrOH or EtOHtoluene) using NaOH as base andClCH

2COONa as alkylating agent [25] Guar gum was

derivatised with carboxymethyl ethers in water or in EtOHtoluene (as for xylan above) to give a product with a DS of08 Repeating the procedure gave further substitution and aproduct with a higher DS [18] Konjac glucomannan wasderivatised with carboxymethyl ethers in methanol to give aproduct with a DS of 03 [18]

213 Hydroxyethyl Ethers Other than cellulose derivativeswhich are produced industrially by epoxide-ring opening

ISRN Organic Chemistry 5

guar gum and xylan were etherified (up to DS = 2) by treat-ment with ethylene oxide or propylene oxide and sodiumhydroxide [18]

22 Esterification Esterification in general will involve thereaction of an alcohol (here a saccharide alcohol) with anacylating agent ((2) Figure 3)

R OH + base+ R998400

R998400R

OX

O

O

+ base middot H+ + Xminus

(2)

RO

SRO

SulfonateCarboxylateO O

OR998400

R998400

Figure 3 General structures carboxylate and sulfonate esters

221 Acetate and Other Carboxylate Esters Carboxylateesters can be formed using carboxylic acids as acylatingagents under strong-acid catalysis (Fischer esterification) orby using an activated derivative such as an acid chloride oranhydride either with base or with a Lewis acid

The strong-acid catalysis method is used to produce cel-lulose acetate an important industrial product [26] But thismethod does not produce the triacetate due to partial tran-sient sulfation during the reaction Cellulose triacetate can beprepared in a similar way using an acid catalyst that does notcovalently attach to the cellulose such as HClO

4

When an activated carboxylic acid derivative (eg acidanhydride acid chloride) reacts with an alcohol under basicconditions the base should be present in a stoichiometricamount (it will be protonated by the acid by-product of thereaction) but it can be a weak base such as pyridine or tri-ethylamine

(1) Homogeneous Reactions Cellulose carboxylates (DS ofup to 24ndash28) were prepared by the reaction of celluloseunder homogeneous conditions in DMALiCl solution withacid chlorides and triethylamine or with acid anhydridesand sulfuric acid [27] The cellulose carboxylate productswere purified by precipitation into water followed by Soxhletextraction intomethanol Similarly starch was esterified withacyl chlorides and pyridine in DMALiCl solution at 100∘Cfor 6 h followed by purification by precipitation [28] Withlong-chain fatty acid chlorides DS values of up to 3were seen

Xylan acetates with DS of up to 2 (ie complete acety-lation) could be prepared either with Ac

2Opyridine in

DMFLiCl or under acid catalysis in AcOH [29] Alterna-tively a xylan acetate with high DS (asymp19) and clean 1HNMRspectra was prepared using Ac

2O and pyridine in DMF [30]

With longer-chain acyl chlorides xylan reacted under homo-geneous conditions inDMFLiCl to give polysaccharideswithlower DS values (03ndash15) [31]

Vinyl carboxylates have also been used as acyl donorsreacting spontaneouslywith cellulose inDMSOTBAF to givepolysaccharides with DS values of up to 26 [32]

The acetylation of cellulose in an ionic liquid sol-vent [amim]Cl (1-allyl-3-methylimidazolium chloride) was

achieved in 2004 using acetic anhydride to give products withDS of ca 25ndash27 [33] The esterification of cellulose in ionicliquids is straightforward for short-chain esters [34] Severalionic liquids gave similarly good results with [bmim]Cl (1-butyl-3-methylimidazolium chloride) being the best Aceticanhydride or acetyl chloride reacted with cellulose withoutany added base within 2 h at 80∘C to give cellulose acetateswith DS of up to 3 However only lower DS values (eg 16for lauryl chloride) were obtainable with fatty acid chloridesin ionic liquids presumably because the partially acylatedpolysaccharide becomesmore andmore nonpolar until it pre-cipitates out of the polar ionic solvent stopping the reaction

The use of carboxylic acids themselves as acylating agentsrather than derivatives such as acid anhydrides or acylchlorides could be attractive as the acids may have a wideravailability and bemore soluble in polar solventsThe Fischeresterification using the carboxylic acid as solvent and withstrong-acid catalysis has already been mentioned but in situactivation of carboxylic acids under mild conditions can alsobe used for polysaccharide acylation When tosyl chloridewas used as an activating agent for with various long-chain carboxylic acids in a DMSOTBAF solvent acylatedcelluloses with DS of up to 26ndash29 could be formed [32 35]Cellulose reacted with carboxylic acids using classic peptidecoupling reagent DCC in nonaqueous solvents (eg DMALiCl) to give derivatised polysaccharides with low DS valuesStarch was acylated under similar conditions by the in situactivation of carboxylic acids with TsCl or CDI (carbonyldi-imidazole) [28]

The acetylation of alginates was less straightforward thanfor neutral polysaccharides [36] The solubility of alginatescan be changed by changing the ionisation state (ie acidversus salt) and (for the salt form) the counterion [egsodium versus tetrabutylammonium (TBA)] TBA-alginateswere soluble inDMSOTBAF but DMALiCl did not dissolveeither the acid or salt (Na or TBA) forms When the alginatesolution was treated with Ac

2O and pyridine only low DS

of up to ca 1 were obtained It is worth mentioning here thatDMSO can react with acylating agents to generate a Swern-type oxidant that can destructively oxidise polysaccharidehydroxyl groups

In amethod for the selectiveO-acylation of chitosan [37]the polysaccharide was suspended in water and a carboxylicacid (C

2ndashC9as well as some halogenated or unsaturated

acids) andH2SO4(2M)were added at room temperatureThe

mixture was then stirred at 80∘C for 4 h and the products(with low DS values of 002ndash02) were purified by pH adjust-ment precipitation from acetone and Soxhlet extractionUnder these conditions the nucleophilicity of the nitrogenis blocked by protonation

6 ISRN Organic Chemistry

(2) Heterogeneous Reactions In a heterogeneous reaction thestarting polysaccharide is insoluble in the reaction solventBut then dissolution may or may not occur during the courseof the reaction only surface groups may be acylated or alter-natively bulk hydroxyls may also react (due to solvent swell-ing of thematerial) themacroscopic structure of thematerialmay be retained after derivatisation (fibre paper cloth ornanofibrils etc)

Heating a suspension of insoluble cellulose in amixture ofpyridine and acylating agent (5 equivGlc = 13 equivOH)can give acylated celluloses with some acylating agents afterpurification by precipitation fromwater [38] Polysaccharideswith DS values of 26ndash29 were obtained with acetyl chlorideand with long-chain acyl chlorides (gtC

10) after 3 hWith piv-

aloyl chloride a much longer reaction time was required toobtain a product with DS = 25 in low yield and with shorterchain acyl chorides (ltC

6) decompositionwas seen A similar

synthesis of cellulose esterswas reported froma suspension ofthe polysaccharide in pyridine and the acid chloride [39 40]while initially heterogeneous cellulose reacted with acetylchloridewithout added base to give cellulose acetates withDSvalues of up to 296 [32]

Konjac glucomannan was acylated with palmitoyl chlo-ride and pyridine in benzene in a heterogeneous reaction inwhich the polysaccharide dissolved during the course of thereaction to give a product with DS up to 27 [18] Arabinoxy-lan was fully esterified under Fischer conditions by suspend-ing the polysaccharide in a carboxylic acid anhydride (aceticpropionic butyric) and treating with catalytic methanesul-fonic acid [41] Also here the polysaccharide dissolved duringthe course of the reaction Mixed anhydrides generated froma carboxylic acid and other more reactive acids (eg trifluo-roacetyl) have also been used as acylating agents with poly-saccharides under heterogeneous conditions [42]

222 Sulfonate Esters Sulfonate esters can act as leavinggroups in SN2 reactions (see below) and many of their appli-cations derive from this aspect of their reactivityTheymay beintroduced with reasonably good regioselectivity for the pri-mary hydroxyl groups and regioselective sulfonate synthesesare described in the section on regioselective reactions (seebelow) But polysaccharide sulfonates with DS gt 2 are alsoaccessible The most commonly seen sulfonates in polysac-charides are toluenesulfonates (tosylates Ts) and methane-sulfonates (mesylates Ms) [43]

The classic reaction conditions for tosylate formationinvolve heating the (initially heterogeneous) polysaccharidewith tosyl chloride in pyridine Three possible side reactionsthat may occur during sulfonate ester formation all arisingfrom nucleophilic displacement of the formed sulfonate esterare as follows (i) cyclisation by attack of one of the secondaryhydroxyl groups (eg O-3) (ii) attack by pyridine to forma C-6 pyridinium salt (iii) attack by chloride to form a C-6chlorideThese side reactions are a result of the long reactiontimes and high temperatures required for the heterogeneousreaction

Thus these side reactions can beminimised or suppressedby using homogeneous conditions [44] Tosylation andmesy-lation reactions of cellulose in solution in DMALiCl gave

uniform and well-defined products with DS values between04 and 23 The tosylation of cellulose underhomogeneousconditions in the ionic liquid [amim]Cl was also recentlyachieved [45]

Sulfonate esters of other polysaccharides have also beensynthesised Chitin was tosylated under homogeneous con-ditions in DMALiCl [46] dextran tosylates were preparedin organic solvent without any added salt [47] and konjacglucomannan was tosylated to give products with DS of up to23 [18] The mesylation of cross-linked particles of pullulanhas been reported [48]

23 Regioselective Etherification and Esterification of Polysac-charides The primary alcohol of a saccharide will with veryfew exceptions always bemore nucleophilic than the second-ary alcoholsThe difference in reactivity between the primaryand secondary alcohols can vary though and complete regio-selective distinction between primary and secondary alcohols(ie normally C-6 versus all of C-2 C-3 and C-4) will oftennot be seenThe respective rate constants for the substitutionof primary and secondary alcohols do not change during areaction and if a primary alcohol reacts more quickly thana secondary alcohol its concentration will decrease morerapidly as the reaction progresses Therefore as the reactionprogresses the rates of reaction of the primary and second-ary alcohols will become similar and regioselectivity willdecrease

Differentiation between the nucleophilicity of the differ-ent secondary hydroxyl groups in a polysaccharide will oftenbe difficult or impossible and polysaccharides containingdifferent substitution patterns may often be formed Havingsaid that there are a few examples of regioselectivity bet-ween the secondary positions of polysaccharides that can beexploited syntheticallyThe regioselective protection of cellu-lose focussing on ether and ester protecting groups has beenreviewed [45] and covered to some extent in other reviews[49 50]

The hydroxyl groups of cellulose are much more reactivein solution than they are in the solid phase because whencellulose dissolves the extensive hydrogen-bonding networkis broken up As a result reactions in solution can be carriedout under milder conditions than in the solid phase andthis allows a higher degree of selectivity Thus regioselectivederivatisations of cellulose and other polysaccharides are gen-erally carried out under homogeneous reaction conditionsand the solvent system DMALiBr (or LiCl) is often used

Only a rather limited number of groupstransformationslive up to the very high regioselectivity criteria that are nec-essary for the modification of polysaccharides These includethe installation of trityl ethers (at O-6) and of bulky silylethers (at O-6 or at both O-2 and O-6) The installation ofcarboxylate esters (at O-6 but not normally selective enough)and tosylate esters (at O-6 but not normally completelyselective or at O-2) are also considered here The installationof halides at C-6 in a phosphane-mediated reaction is alsooften a regioselective process but this in this reaction thepolysaccharide behaves as an electrophile so it is consideredin a later section of this review

ISRN Organic Chemistry 7

OOHO OH

O

OH

OOHO OH

O

OTr

Scheme 1

231 Trityl Ethers The trityl group reacts with cellulose pref-erentially at the primary hydroxyl O-6 on steric grounds(Scheme 1) Trityl ethers may be installed by heating cellulose(rayon) with pyridine and trityl chloride (ie under initiallyheterogeneous conditions with dissolution occurring as thereaction proceeds) and DS values close to 1 with little substi-tution of the secondary positions are obtainable [26 51] Cel-lulose has also been tritylated under homogeneous condi-tions to give products with DS values of 10 [6] The solventsused were DMSON

2O4 DMALiCl or DMSOSO

2DEA

6-O-Trityl derivatives of some other polysaccharides havebeen prepared directly or indirectly Amylose underwent tri-tylation regioselectively at O-6 uneventfully [52] Chitin wasalso tritylated regioselectivity with reaction at O-6 [21] 120573-Chitin was suspended in pyridine and heated at 90∘C for72 h with trityl chloride (10 equiv) and DMAP (3ndash6 equiv)Products with DS values of 075ndash10 were obtained by purifi-cation by precipitation frommethanol A 6-O-trityl derivativeof chitosan was prepared by a three-step sequence First thenitrogen was protected as a phthalimide derivative then O-6 was tritylated and finally N-deprotection gave the 6-O-tritylchitosan with DS = 1 [53]

232 Silyl Ethers Thexyldimethylsilyl chloride (TMDSCl)has been shown to react with cellulose with very good regio-selectivity and different regioselectivities O-6 only or forboth O-2 and O-6 are seen under different reaction condi-tions (Scheme 2) Treatment of cellulose (undissolved ieunder initially heterogeneous conditions) with TMDSC1 inDMF saturated with ammonia at ndash15∘C resulted in the intro-duction of TMDS groups at C-6 only with a DS of 099 [54]When the reaction was carried out under homogeneous con-ditions in DMALiCl and with imidazole as base 26-di-O-thexyldimethylsilylcellulose was formed with a DS of 20 [5556] Moreover this 26-protected derivative can be used forthe regiospecific introduction of substituents at O-3 of cellu-lose 3-O-Methylcellulose and 3-O-allylcellulose have beensynthesised in this way The silyl ethers can be removed bytreatment with TBAF (tetrabutylammonium fluoride) Liq-uid ammonia has also been used as an effective solvent forsilylation reactions of cellulose [57]

233 Carboxylate Esters Regioselectivities (forO-6) are gen-erally lower for carboxylate esterification reactions of cellu-lose than those seen for the formation of trityl ethers or silylethers [45] An investigation of various sterically hinderedacylating agents including pivaloyl chloride adamantoylchloride and 246-trimethylbenzyl chloride in solventsincluding DMALiCl DMSOTBAF and the ionic liquid[amim]Cl failed to give satisfactory regioselectivity [58] But

OOHO OH

O

OHO

OHO OH

O

OTDMS

OOHO OTDMS

O

OTDMSOr

Scheme 2

having said that in a different study excellent regioselectivityfor O-6 of cellulose was observed in an esterification reactionusing benzyl chloride in [amim]Cl without any added base[59]

It is relevant in this context to note that silyl ether protec-tion may be regiospecifically replaced by carboxylate protec-tion [60] When a cellulose derivative bearing trimethylsilylethers is treated with an acyl chloride in the absence of a basethe silyl ethers are regiospecifically replaced by acyl groups(in the presence of a base the silyl ethers remain and thefree hydroxyl groups are acylated) But while this process iswell known for trimethylsilyl ethers it has apparently [45]not yet been investigated for thexyldimethylsilylethers which(as described above) can be introduced into cellulose withexcellent regioselectivity

234 Sulfonate Esters Cellulose reacts preferentially at O-6in tosylation reactions (see above) but the regioselectivity isnot perfect The esterification of cellulose with various sul-fonic acid chlorides including the 246-trimethylbenzenes-ulfonyl group under homogeneous conditions (in DMALiCl) was investigated in an attempt to improve the regios-electivity for substitution at O-6 [61] but in general theproducts contained mixtures of 2- and 6-tosylation

A very interesting result has been obtained concerningthe regioselectivity of the tosylation of starch When starch(70 amylose) was tosylated in solution in DMALiCl O-2reacted preferentially with very good regioselectivity (overO-3 and O-6) to give a product with a DS asymp 1 with the tosylgroups essentially exclusively at C-2 The regioselectivity wasproved by 1H and 13C NMR spectroscopy (Scheme 3) [62]This regioselectivity is counterintuitive and apparently it isalso solvent-dependent Horton had previously reported thatwhen the tosylation of amylose was carried out in pyridinethe more expected product 6-O-tosyl-amylose was formedwith DS asymp 06 (Scheme 3) [63]

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

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CatalystsJournal of

ISRN Organic Chemistry 5

guar gum and xylan were etherified (up to DS = 2) by treat-ment with ethylene oxide or propylene oxide and sodiumhydroxide [18]

22 Esterification Esterification in general will involve thereaction of an alcohol (here a saccharide alcohol) with anacylating agent ((2) Figure 3)

R OH + base+ R998400

R998400R

OX

O

O

+ base middot H+ + Xminus

(2)

RO

SRO

SulfonateCarboxylateO O

OR998400

R998400

Figure 3 General structures carboxylate and sulfonate esters

221 Acetate and Other Carboxylate Esters Carboxylateesters can be formed using carboxylic acids as acylatingagents under strong-acid catalysis (Fischer esterification) orby using an activated derivative such as an acid chloride oranhydride either with base or with a Lewis acid

The strong-acid catalysis method is used to produce cel-lulose acetate an important industrial product [26] But thismethod does not produce the triacetate due to partial tran-sient sulfation during the reaction Cellulose triacetate can beprepared in a similar way using an acid catalyst that does notcovalently attach to the cellulose such as HClO

4

When an activated carboxylic acid derivative (eg acidanhydride acid chloride) reacts with an alcohol under basicconditions the base should be present in a stoichiometricamount (it will be protonated by the acid by-product of thereaction) but it can be a weak base such as pyridine or tri-ethylamine

(1) Homogeneous Reactions Cellulose carboxylates (DS ofup to 24ndash28) were prepared by the reaction of celluloseunder homogeneous conditions in DMALiCl solution withacid chlorides and triethylamine or with acid anhydridesand sulfuric acid [27] The cellulose carboxylate productswere purified by precipitation into water followed by Soxhletextraction intomethanol Similarly starch was esterified withacyl chlorides and pyridine in DMALiCl solution at 100∘Cfor 6 h followed by purification by precipitation [28] Withlong-chain fatty acid chlorides DS values of up to 3were seen

Xylan acetates with DS of up to 2 (ie complete acety-lation) could be prepared either with Ac

2Opyridine in

DMFLiCl or under acid catalysis in AcOH [29] Alterna-tively a xylan acetate with high DS (asymp19) and clean 1HNMRspectra was prepared using Ac

2O and pyridine in DMF [30]

With longer-chain acyl chlorides xylan reacted under homo-geneous conditions inDMFLiCl to give polysaccharideswithlower DS values (03ndash15) [31]

Vinyl carboxylates have also been used as acyl donorsreacting spontaneouslywith cellulose inDMSOTBAF to givepolysaccharides with DS values of up to 26 [32]

The acetylation of cellulose in an ionic liquid sol-vent [amim]Cl (1-allyl-3-methylimidazolium chloride) was

achieved in 2004 using acetic anhydride to give products withDS of ca 25ndash27 [33] The esterification of cellulose in ionicliquids is straightforward for short-chain esters [34] Severalionic liquids gave similarly good results with [bmim]Cl (1-butyl-3-methylimidazolium chloride) being the best Aceticanhydride or acetyl chloride reacted with cellulose withoutany added base within 2 h at 80∘C to give cellulose acetateswith DS of up to 3 However only lower DS values (eg 16for lauryl chloride) were obtainable with fatty acid chloridesin ionic liquids presumably because the partially acylatedpolysaccharide becomesmore andmore nonpolar until it pre-cipitates out of the polar ionic solvent stopping the reaction

The use of carboxylic acids themselves as acylating agentsrather than derivatives such as acid anhydrides or acylchlorides could be attractive as the acids may have a wideravailability and bemore soluble in polar solventsThe Fischeresterification using the carboxylic acid as solvent and withstrong-acid catalysis has already been mentioned but in situactivation of carboxylic acids under mild conditions can alsobe used for polysaccharide acylation When tosyl chloridewas used as an activating agent for with various long-chain carboxylic acids in a DMSOTBAF solvent acylatedcelluloses with DS of up to 26ndash29 could be formed [32 35]Cellulose reacted with carboxylic acids using classic peptidecoupling reagent DCC in nonaqueous solvents (eg DMALiCl) to give derivatised polysaccharides with low DS valuesStarch was acylated under similar conditions by the in situactivation of carboxylic acids with TsCl or CDI (carbonyldi-imidazole) [28]

The acetylation of alginates was less straightforward thanfor neutral polysaccharides [36] The solubility of alginatescan be changed by changing the ionisation state (ie acidversus salt) and (for the salt form) the counterion [egsodium versus tetrabutylammonium (TBA)] TBA-alginateswere soluble inDMSOTBAF but DMALiCl did not dissolveeither the acid or salt (Na or TBA) forms When the alginatesolution was treated with Ac

2O and pyridine only low DS

of up to ca 1 were obtained It is worth mentioning here thatDMSO can react with acylating agents to generate a Swern-type oxidant that can destructively oxidise polysaccharidehydroxyl groups

In amethod for the selectiveO-acylation of chitosan [37]the polysaccharide was suspended in water and a carboxylicacid (C

2ndashC9as well as some halogenated or unsaturated

acids) andH2SO4(2M)were added at room temperatureThe

mixture was then stirred at 80∘C for 4 h and the products(with low DS values of 002ndash02) were purified by pH adjust-ment precipitation from acetone and Soxhlet extractionUnder these conditions the nucleophilicity of the nitrogenis blocked by protonation

6 ISRN Organic Chemistry

(2) Heterogeneous Reactions In a heterogeneous reaction thestarting polysaccharide is insoluble in the reaction solventBut then dissolution may or may not occur during the courseof the reaction only surface groups may be acylated or alter-natively bulk hydroxyls may also react (due to solvent swell-ing of thematerial) themacroscopic structure of thematerialmay be retained after derivatisation (fibre paper cloth ornanofibrils etc)

Heating a suspension of insoluble cellulose in amixture ofpyridine and acylating agent (5 equivGlc = 13 equivOH)can give acylated celluloses with some acylating agents afterpurification by precipitation fromwater [38] Polysaccharideswith DS values of 26ndash29 were obtained with acetyl chlorideand with long-chain acyl chlorides (gtC

10) after 3 hWith piv-

aloyl chloride a much longer reaction time was required toobtain a product with DS = 25 in low yield and with shorterchain acyl chorides (ltC

6) decompositionwas seen A similar

synthesis of cellulose esterswas reported froma suspension ofthe polysaccharide in pyridine and the acid chloride [39 40]while initially heterogeneous cellulose reacted with acetylchloridewithout added base to give cellulose acetates withDSvalues of up to 296 [32]

Konjac glucomannan was acylated with palmitoyl chlo-ride and pyridine in benzene in a heterogeneous reaction inwhich the polysaccharide dissolved during the course of thereaction to give a product with DS up to 27 [18] Arabinoxy-lan was fully esterified under Fischer conditions by suspend-ing the polysaccharide in a carboxylic acid anhydride (aceticpropionic butyric) and treating with catalytic methanesul-fonic acid [41] Also here the polysaccharide dissolved duringthe course of the reaction Mixed anhydrides generated froma carboxylic acid and other more reactive acids (eg trifluo-roacetyl) have also been used as acylating agents with poly-saccharides under heterogeneous conditions [42]

222 Sulfonate Esters Sulfonate esters can act as leavinggroups in SN2 reactions (see below) and many of their appli-cations derive from this aspect of their reactivityTheymay beintroduced with reasonably good regioselectivity for the pri-mary hydroxyl groups and regioselective sulfonate synthesesare described in the section on regioselective reactions (seebelow) But polysaccharide sulfonates with DS gt 2 are alsoaccessible The most commonly seen sulfonates in polysac-charides are toluenesulfonates (tosylates Ts) and methane-sulfonates (mesylates Ms) [43]

The classic reaction conditions for tosylate formationinvolve heating the (initially heterogeneous) polysaccharidewith tosyl chloride in pyridine Three possible side reactionsthat may occur during sulfonate ester formation all arisingfrom nucleophilic displacement of the formed sulfonate esterare as follows (i) cyclisation by attack of one of the secondaryhydroxyl groups (eg O-3) (ii) attack by pyridine to forma C-6 pyridinium salt (iii) attack by chloride to form a C-6chlorideThese side reactions are a result of the long reactiontimes and high temperatures required for the heterogeneousreaction

Thus these side reactions can beminimised or suppressedby using homogeneous conditions [44] Tosylation andmesy-lation reactions of cellulose in solution in DMALiCl gave

uniform and well-defined products with DS values between04 and 23 The tosylation of cellulose underhomogeneousconditions in the ionic liquid [amim]Cl was also recentlyachieved [45]

Sulfonate esters of other polysaccharides have also beensynthesised Chitin was tosylated under homogeneous con-ditions in DMALiCl [46] dextran tosylates were preparedin organic solvent without any added salt [47] and konjacglucomannan was tosylated to give products with DS of up to23 [18] The mesylation of cross-linked particles of pullulanhas been reported [48]

23 Regioselective Etherification and Esterification of Polysac-charides The primary alcohol of a saccharide will with veryfew exceptions always bemore nucleophilic than the second-ary alcoholsThe difference in reactivity between the primaryand secondary alcohols can vary though and complete regio-selective distinction between primary and secondary alcohols(ie normally C-6 versus all of C-2 C-3 and C-4) will oftennot be seenThe respective rate constants for the substitutionof primary and secondary alcohols do not change during areaction and if a primary alcohol reacts more quickly thana secondary alcohol its concentration will decrease morerapidly as the reaction progresses Therefore as the reactionprogresses the rates of reaction of the primary and second-ary alcohols will become similar and regioselectivity willdecrease

Differentiation between the nucleophilicity of the differ-ent secondary hydroxyl groups in a polysaccharide will oftenbe difficult or impossible and polysaccharides containingdifferent substitution patterns may often be formed Havingsaid that there are a few examples of regioselectivity bet-ween the secondary positions of polysaccharides that can beexploited syntheticallyThe regioselective protection of cellu-lose focussing on ether and ester protecting groups has beenreviewed [45] and covered to some extent in other reviews[49 50]

The hydroxyl groups of cellulose are much more reactivein solution than they are in the solid phase because whencellulose dissolves the extensive hydrogen-bonding networkis broken up As a result reactions in solution can be carriedout under milder conditions than in the solid phase andthis allows a higher degree of selectivity Thus regioselectivederivatisations of cellulose and other polysaccharides are gen-erally carried out under homogeneous reaction conditionsand the solvent system DMALiBr (or LiCl) is often used

Only a rather limited number of groupstransformationslive up to the very high regioselectivity criteria that are nec-essary for the modification of polysaccharides These includethe installation of trityl ethers (at O-6) and of bulky silylethers (at O-6 or at both O-2 and O-6) The installation ofcarboxylate esters (at O-6 but not normally selective enough)and tosylate esters (at O-6 but not normally completelyselective or at O-2) are also considered here The installationof halides at C-6 in a phosphane-mediated reaction is alsooften a regioselective process but this in this reaction thepolysaccharide behaves as an electrophile so it is consideredin a later section of this review

ISRN Organic Chemistry 7

OOHO OH

O

OH

OOHO OH

O

OTr

Scheme 1

231 Trityl Ethers The trityl group reacts with cellulose pref-erentially at the primary hydroxyl O-6 on steric grounds(Scheme 1) Trityl ethers may be installed by heating cellulose(rayon) with pyridine and trityl chloride (ie under initiallyheterogeneous conditions with dissolution occurring as thereaction proceeds) and DS values close to 1 with little substi-tution of the secondary positions are obtainable [26 51] Cel-lulose has also been tritylated under homogeneous condi-tions to give products with DS values of 10 [6] The solventsused were DMSON

2O4 DMALiCl or DMSOSO

2DEA

6-O-Trityl derivatives of some other polysaccharides havebeen prepared directly or indirectly Amylose underwent tri-tylation regioselectively at O-6 uneventfully [52] Chitin wasalso tritylated regioselectivity with reaction at O-6 [21] 120573-Chitin was suspended in pyridine and heated at 90∘C for72 h with trityl chloride (10 equiv) and DMAP (3ndash6 equiv)Products with DS values of 075ndash10 were obtained by purifi-cation by precipitation frommethanol A 6-O-trityl derivativeof chitosan was prepared by a three-step sequence First thenitrogen was protected as a phthalimide derivative then O-6 was tritylated and finally N-deprotection gave the 6-O-tritylchitosan with DS = 1 [53]

232 Silyl Ethers Thexyldimethylsilyl chloride (TMDSCl)has been shown to react with cellulose with very good regio-selectivity and different regioselectivities O-6 only or forboth O-2 and O-6 are seen under different reaction condi-tions (Scheme 2) Treatment of cellulose (undissolved ieunder initially heterogeneous conditions) with TMDSC1 inDMF saturated with ammonia at ndash15∘C resulted in the intro-duction of TMDS groups at C-6 only with a DS of 099 [54]When the reaction was carried out under homogeneous con-ditions in DMALiCl and with imidazole as base 26-di-O-thexyldimethylsilylcellulose was formed with a DS of 20 [5556] Moreover this 26-protected derivative can be used forthe regiospecific introduction of substituents at O-3 of cellu-lose 3-O-Methylcellulose and 3-O-allylcellulose have beensynthesised in this way The silyl ethers can be removed bytreatment with TBAF (tetrabutylammonium fluoride) Liq-uid ammonia has also been used as an effective solvent forsilylation reactions of cellulose [57]

233 Carboxylate Esters Regioselectivities (forO-6) are gen-erally lower for carboxylate esterification reactions of cellu-lose than those seen for the formation of trityl ethers or silylethers [45] An investigation of various sterically hinderedacylating agents including pivaloyl chloride adamantoylchloride and 246-trimethylbenzyl chloride in solventsincluding DMALiCl DMSOTBAF and the ionic liquid[amim]Cl failed to give satisfactory regioselectivity [58] But

OOHO OH

O

OHO

OHO OH

O

OTDMS

OOHO OTDMS

O

OTDMSOr

Scheme 2

having said that in a different study excellent regioselectivityfor O-6 of cellulose was observed in an esterification reactionusing benzyl chloride in [amim]Cl without any added base[59]

It is relevant in this context to note that silyl ether protec-tion may be regiospecifically replaced by carboxylate protec-tion [60] When a cellulose derivative bearing trimethylsilylethers is treated with an acyl chloride in the absence of a basethe silyl ethers are regiospecifically replaced by acyl groups(in the presence of a base the silyl ethers remain and thefree hydroxyl groups are acylated) But while this process iswell known for trimethylsilyl ethers it has apparently [45]not yet been investigated for thexyldimethylsilylethers which(as described above) can be introduced into cellulose withexcellent regioselectivity

234 Sulfonate Esters Cellulose reacts preferentially at O-6in tosylation reactions (see above) but the regioselectivity isnot perfect The esterification of cellulose with various sul-fonic acid chlorides including the 246-trimethylbenzenes-ulfonyl group under homogeneous conditions (in DMALiCl) was investigated in an attempt to improve the regios-electivity for substitution at O-6 [61] but in general theproducts contained mixtures of 2- and 6-tosylation

A very interesting result has been obtained concerningthe regioselectivity of the tosylation of starch When starch(70 amylose) was tosylated in solution in DMALiCl O-2reacted preferentially with very good regioselectivity (overO-3 and O-6) to give a product with a DS asymp 1 with the tosylgroups essentially exclusively at C-2 The regioselectivity wasproved by 1H and 13C NMR spectroscopy (Scheme 3) [62]This regioselectivity is counterintuitive and apparently it isalso solvent-dependent Horton had previously reported thatwhen the tosylation of amylose was carried out in pyridinethe more expected product 6-O-tosyl-amylose was formedwith DS asymp 06 (Scheme 3) [63]

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

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CatalystsJournal of

6 ISRN Organic Chemistry

(2) Heterogeneous Reactions In a heterogeneous reaction thestarting polysaccharide is insoluble in the reaction solventBut then dissolution may or may not occur during the courseof the reaction only surface groups may be acylated or alter-natively bulk hydroxyls may also react (due to solvent swell-ing of thematerial) themacroscopic structure of thematerialmay be retained after derivatisation (fibre paper cloth ornanofibrils etc)

Heating a suspension of insoluble cellulose in amixture ofpyridine and acylating agent (5 equivGlc = 13 equivOH)can give acylated celluloses with some acylating agents afterpurification by precipitation fromwater [38] Polysaccharideswith DS values of 26ndash29 were obtained with acetyl chlorideand with long-chain acyl chlorides (gtC

10) after 3 hWith piv-

aloyl chloride a much longer reaction time was required toobtain a product with DS = 25 in low yield and with shorterchain acyl chorides (ltC

6) decompositionwas seen A similar

synthesis of cellulose esterswas reported froma suspension ofthe polysaccharide in pyridine and the acid chloride [39 40]while initially heterogeneous cellulose reacted with acetylchloridewithout added base to give cellulose acetates withDSvalues of up to 296 [32]

Konjac glucomannan was acylated with palmitoyl chlo-ride and pyridine in benzene in a heterogeneous reaction inwhich the polysaccharide dissolved during the course of thereaction to give a product with DS up to 27 [18] Arabinoxy-lan was fully esterified under Fischer conditions by suspend-ing the polysaccharide in a carboxylic acid anhydride (aceticpropionic butyric) and treating with catalytic methanesul-fonic acid [41] Also here the polysaccharide dissolved duringthe course of the reaction Mixed anhydrides generated froma carboxylic acid and other more reactive acids (eg trifluo-roacetyl) have also been used as acylating agents with poly-saccharides under heterogeneous conditions [42]

222 Sulfonate Esters Sulfonate esters can act as leavinggroups in SN2 reactions (see below) and many of their appli-cations derive from this aspect of their reactivityTheymay beintroduced with reasonably good regioselectivity for the pri-mary hydroxyl groups and regioselective sulfonate synthesesare described in the section on regioselective reactions (seebelow) But polysaccharide sulfonates with DS gt 2 are alsoaccessible The most commonly seen sulfonates in polysac-charides are toluenesulfonates (tosylates Ts) and methane-sulfonates (mesylates Ms) [43]

The classic reaction conditions for tosylate formationinvolve heating the (initially heterogeneous) polysaccharidewith tosyl chloride in pyridine Three possible side reactionsthat may occur during sulfonate ester formation all arisingfrom nucleophilic displacement of the formed sulfonate esterare as follows (i) cyclisation by attack of one of the secondaryhydroxyl groups (eg O-3) (ii) attack by pyridine to forma C-6 pyridinium salt (iii) attack by chloride to form a C-6chlorideThese side reactions are a result of the long reactiontimes and high temperatures required for the heterogeneousreaction

Thus these side reactions can beminimised or suppressedby using homogeneous conditions [44] Tosylation andmesy-lation reactions of cellulose in solution in DMALiCl gave

uniform and well-defined products with DS values between04 and 23 The tosylation of cellulose underhomogeneousconditions in the ionic liquid [amim]Cl was also recentlyachieved [45]

Sulfonate esters of other polysaccharides have also beensynthesised Chitin was tosylated under homogeneous con-ditions in DMALiCl [46] dextran tosylates were preparedin organic solvent without any added salt [47] and konjacglucomannan was tosylated to give products with DS of up to23 [18] The mesylation of cross-linked particles of pullulanhas been reported [48]

23 Regioselective Etherification and Esterification of Polysac-charides The primary alcohol of a saccharide will with veryfew exceptions always bemore nucleophilic than the second-ary alcoholsThe difference in reactivity between the primaryand secondary alcohols can vary though and complete regio-selective distinction between primary and secondary alcohols(ie normally C-6 versus all of C-2 C-3 and C-4) will oftennot be seenThe respective rate constants for the substitutionof primary and secondary alcohols do not change during areaction and if a primary alcohol reacts more quickly thana secondary alcohol its concentration will decrease morerapidly as the reaction progresses Therefore as the reactionprogresses the rates of reaction of the primary and second-ary alcohols will become similar and regioselectivity willdecrease

Differentiation between the nucleophilicity of the differ-ent secondary hydroxyl groups in a polysaccharide will oftenbe difficult or impossible and polysaccharides containingdifferent substitution patterns may often be formed Havingsaid that there are a few examples of regioselectivity bet-ween the secondary positions of polysaccharides that can beexploited syntheticallyThe regioselective protection of cellu-lose focussing on ether and ester protecting groups has beenreviewed [45] and covered to some extent in other reviews[49 50]

The hydroxyl groups of cellulose are much more reactivein solution than they are in the solid phase because whencellulose dissolves the extensive hydrogen-bonding networkis broken up As a result reactions in solution can be carriedout under milder conditions than in the solid phase andthis allows a higher degree of selectivity Thus regioselectivederivatisations of cellulose and other polysaccharides are gen-erally carried out under homogeneous reaction conditionsand the solvent system DMALiBr (or LiCl) is often used

Only a rather limited number of groupstransformationslive up to the very high regioselectivity criteria that are nec-essary for the modification of polysaccharides These includethe installation of trityl ethers (at O-6) and of bulky silylethers (at O-6 or at both O-2 and O-6) The installation ofcarboxylate esters (at O-6 but not normally selective enough)and tosylate esters (at O-6 but not normally completelyselective or at O-2) are also considered here The installationof halides at C-6 in a phosphane-mediated reaction is alsooften a regioselective process but this in this reaction thepolysaccharide behaves as an electrophile so it is consideredin a later section of this review

ISRN Organic Chemistry 7

OOHO OH

O

OH

OOHO OH

O

OTr

Scheme 1

231 Trityl Ethers The trityl group reacts with cellulose pref-erentially at the primary hydroxyl O-6 on steric grounds(Scheme 1) Trityl ethers may be installed by heating cellulose(rayon) with pyridine and trityl chloride (ie under initiallyheterogeneous conditions with dissolution occurring as thereaction proceeds) and DS values close to 1 with little substi-tution of the secondary positions are obtainable [26 51] Cel-lulose has also been tritylated under homogeneous condi-tions to give products with DS values of 10 [6] The solventsused were DMSON

2O4 DMALiCl or DMSOSO

2DEA

6-O-Trityl derivatives of some other polysaccharides havebeen prepared directly or indirectly Amylose underwent tri-tylation regioselectively at O-6 uneventfully [52] Chitin wasalso tritylated regioselectivity with reaction at O-6 [21] 120573-Chitin was suspended in pyridine and heated at 90∘C for72 h with trityl chloride (10 equiv) and DMAP (3ndash6 equiv)Products with DS values of 075ndash10 were obtained by purifi-cation by precipitation frommethanol A 6-O-trityl derivativeof chitosan was prepared by a three-step sequence First thenitrogen was protected as a phthalimide derivative then O-6 was tritylated and finally N-deprotection gave the 6-O-tritylchitosan with DS = 1 [53]

232 Silyl Ethers Thexyldimethylsilyl chloride (TMDSCl)has been shown to react with cellulose with very good regio-selectivity and different regioselectivities O-6 only or forboth O-2 and O-6 are seen under different reaction condi-tions (Scheme 2) Treatment of cellulose (undissolved ieunder initially heterogeneous conditions) with TMDSC1 inDMF saturated with ammonia at ndash15∘C resulted in the intro-duction of TMDS groups at C-6 only with a DS of 099 [54]When the reaction was carried out under homogeneous con-ditions in DMALiCl and with imidazole as base 26-di-O-thexyldimethylsilylcellulose was formed with a DS of 20 [5556] Moreover this 26-protected derivative can be used forthe regiospecific introduction of substituents at O-3 of cellu-lose 3-O-Methylcellulose and 3-O-allylcellulose have beensynthesised in this way The silyl ethers can be removed bytreatment with TBAF (tetrabutylammonium fluoride) Liq-uid ammonia has also been used as an effective solvent forsilylation reactions of cellulose [57]

233 Carboxylate Esters Regioselectivities (forO-6) are gen-erally lower for carboxylate esterification reactions of cellu-lose than those seen for the formation of trityl ethers or silylethers [45] An investigation of various sterically hinderedacylating agents including pivaloyl chloride adamantoylchloride and 246-trimethylbenzyl chloride in solventsincluding DMALiCl DMSOTBAF and the ionic liquid[amim]Cl failed to give satisfactory regioselectivity [58] But

OOHO OH

O

OHO

OHO OH

O

OTDMS

OOHO OTDMS

O

OTDMSOr

Scheme 2

having said that in a different study excellent regioselectivityfor O-6 of cellulose was observed in an esterification reactionusing benzyl chloride in [amim]Cl without any added base[59]

It is relevant in this context to note that silyl ether protec-tion may be regiospecifically replaced by carboxylate protec-tion [60] When a cellulose derivative bearing trimethylsilylethers is treated with an acyl chloride in the absence of a basethe silyl ethers are regiospecifically replaced by acyl groups(in the presence of a base the silyl ethers remain and thefree hydroxyl groups are acylated) But while this process iswell known for trimethylsilyl ethers it has apparently [45]not yet been investigated for thexyldimethylsilylethers which(as described above) can be introduced into cellulose withexcellent regioselectivity

234 Sulfonate Esters Cellulose reacts preferentially at O-6in tosylation reactions (see above) but the regioselectivity isnot perfect The esterification of cellulose with various sul-fonic acid chlorides including the 246-trimethylbenzenes-ulfonyl group under homogeneous conditions (in DMALiCl) was investigated in an attempt to improve the regios-electivity for substitution at O-6 [61] but in general theproducts contained mixtures of 2- and 6-tosylation

A very interesting result has been obtained concerningthe regioselectivity of the tosylation of starch When starch(70 amylose) was tosylated in solution in DMALiCl O-2reacted preferentially with very good regioselectivity (overO-3 and O-6) to give a product with a DS asymp 1 with the tosylgroups essentially exclusively at C-2 The regioselectivity wasproved by 1H and 13C NMR spectroscopy (Scheme 3) [62]This regioselectivity is counterintuitive and apparently it isalso solvent-dependent Horton had previously reported thatwhen the tosylation of amylose was carried out in pyridinethe more expected product 6-O-tosyl-amylose was formedwith DS asymp 06 (Scheme 3) [63]

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

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Analytical ChemistryInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

ISRN Organic Chemistry 7

OOHO OH

O

OH

OOHO OH

O

OTr

Scheme 1

231 Trityl Ethers The trityl group reacts with cellulose pref-erentially at the primary hydroxyl O-6 on steric grounds(Scheme 1) Trityl ethers may be installed by heating cellulose(rayon) with pyridine and trityl chloride (ie under initiallyheterogeneous conditions with dissolution occurring as thereaction proceeds) and DS values close to 1 with little substi-tution of the secondary positions are obtainable [26 51] Cel-lulose has also been tritylated under homogeneous condi-tions to give products with DS values of 10 [6] The solventsused were DMSON

2O4 DMALiCl or DMSOSO

2DEA

6-O-Trityl derivatives of some other polysaccharides havebeen prepared directly or indirectly Amylose underwent tri-tylation regioselectively at O-6 uneventfully [52] Chitin wasalso tritylated regioselectivity with reaction at O-6 [21] 120573-Chitin was suspended in pyridine and heated at 90∘C for72 h with trityl chloride (10 equiv) and DMAP (3ndash6 equiv)Products with DS values of 075ndash10 were obtained by purifi-cation by precipitation frommethanol A 6-O-trityl derivativeof chitosan was prepared by a three-step sequence First thenitrogen was protected as a phthalimide derivative then O-6 was tritylated and finally N-deprotection gave the 6-O-tritylchitosan with DS = 1 [53]

232 Silyl Ethers Thexyldimethylsilyl chloride (TMDSCl)has been shown to react with cellulose with very good regio-selectivity and different regioselectivities O-6 only or forboth O-2 and O-6 are seen under different reaction condi-tions (Scheme 2) Treatment of cellulose (undissolved ieunder initially heterogeneous conditions) with TMDSC1 inDMF saturated with ammonia at ndash15∘C resulted in the intro-duction of TMDS groups at C-6 only with a DS of 099 [54]When the reaction was carried out under homogeneous con-ditions in DMALiCl and with imidazole as base 26-di-O-thexyldimethylsilylcellulose was formed with a DS of 20 [5556] Moreover this 26-protected derivative can be used forthe regiospecific introduction of substituents at O-3 of cellu-lose 3-O-Methylcellulose and 3-O-allylcellulose have beensynthesised in this way The silyl ethers can be removed bytreatment with TBAF (tetrabutylammonium fluoride) Liq-uid ammonia has also been used as an effective solvent forsilylation reactions of cellulose [57]

233 Carboxylate Esters Regioselectivities (forO-6) are gen-erally lower for carboxylate esterification reactions of cellu-lose than those seen for the formation of trityl ethers or silylethers [45] An investigation of various sterically hinderedacylating agents including pivaloyl chloride adamantoylchloride and 246-trimethylbenzyl chloride in solventsincluding DMALiCl DMSOTBAF and the ionic liquid[amim]Cl failed to give satisfactory regioselectivity [58] But

OOHO OH

O

OHO

OHO OH

O

OTDMS

OOHO OTDMS

O

OTDMSOr

Scheme 2

having said that in a different study excellent regioselectivityfor O-6 of cellulose was observed in an esterification reactionusing benzyl chloride in [amim]Cl without any added base[59]

It is relevant in this context to note that silyl ether protec-tion may be regiospecifically replaced by carboxylate protec-tion [60] When a cellulose derivative bearing trimethylsilylethers is treated with an acyl chloride in the absence of a basethe silyl ethers are regiospecifically replaced by acyl groups(in the presence of a base the silyl ethers remain and thefree hydroxyl groups are acylated) But while this process iswell known for trimethylsilyl ethers it has apparently [45]not yet been investigated for thexyldimethylsilylethers which(as described above) can be introduced into cellulose withexcellent regioselectivity

234 Sulfonate Esters Cellulose reacts preferentially at O-6in tosylation reactions (see above) but the regioselectivity isnot perfect The esterification of cellulose with various sul-fonic acid chlorides including the 246-trimethylbenzenes-ulfonyl group under homogeneous conditions (in DMALiCl) was investigated in an attempt to improve the regios-electivity for substitution at O-6 [61] but in general theproducts contained mixtures of 2- and 6-tosylation

A very interesting result has been obtained concerningthe regioselectivity of the tosylation of starch When starch(70 amylose) was tosylated in solution in DMALiCl O-2reacted preferentially with very good regioselectivity (overO-3 and O-6) to give a product with a DS asymp 1 with the tosylgroups essentially exclusively at C-2 The regioselectivity wasproved by 1H and 13C NMR spectroscopy (Scheme 3) [62]This regioselectivity is counterintuitive and apparently it isalso solvent-dependent Horton had previously reported thatwhen the tosylation of amylose was carried out in pyridinethe more expected product 6-O-tosyl-amylose was formedwith DS asymp 06 (Scheme 3) [63]

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

8 ISRN Organic Chemistry

O

OHO

HO

OH

O

O

OHO

TsO

OH

O

O

OHO

HO

OTs

O

Or

Scheme 3

Inulin was tosylated by treatment with TsCl and Et3N in

DMFLiCl at 0∘C Purification by precipitation then dialysisgave a polysaccharide product derivatised at O-6 and withsome partial derivatisation at O-4 [64]

24 Enzymatic Reactions Regioselective Esterification andDeesterification In general regioselectivity in chemical reac-tions is controlled by a combination of steric electronic andstereoelectronic factors In enzymatic reactions in contrastthe reaction will occur at the position that is held close to therelevant catalytic amino acid side chains when the substrateis bound in the active site of the enzyme That is true at leastwhen the substrate of the reaction is the same as or close instructure to the natural structure that the enzymehas evolvedto modify for example for galactose-6-oxidase and galactose(see below) Some enzymes though have broad substratetolerance and catalyse reactions on rather generic structuresWhen esterases lipases and proteases are used to catalyse theformation and hydrolysis of esters on polysaccharides in thelaboratory this is not the natural function of the enzyme sothey have not evolved to differentiate the different hydroxylgroups Rather in these enzyme-catalysed reactions theenzyme will tend to act on the hydroxyl group (for esterifica-tion) or ester (for hydrolysis) that is most sterically accessibleie those at the primary positions Hence in principle 6-monoesters may be accessible by enzyme-catalysed regios-elective acylation of an unprotected polysaccharide andin principle 6-mono-unprotected polysaccharides may beaccessible by peracylation followed by regioselective hydrol-ysis of the primary esters

The considerations regarding solvents for enzyme-cata-lysed reactions can be summarised briefly as followsEnzymes normally require at least a trace of water to functionproperly and they may also be structurally unstable innonaqueous media However water is not a good solventfor acylation reactions as the enzyme-catalysed reactions arereversible When water is present in excess (ie as solvent)the equilibriumwould lie towards hydrolysis so theDS valuesof the products would be very low Polar solvents (eg DMFDMSO etc) can strip the essential catalytic water from thesurface of enzymes rendering them inactive Solvents withlower hydrogen-bonding ability will thus be more likely tolead to higher enzyme activity but those with a better hydro-gen-bonding ability would better dissolve the polysaccharidesubstrates Thus in choosing a solvent a balance must be

struck between dissolving the substrate and maintaining theactivity of the enzyme [4 65]

Nonpolar solvents are not ideal as the enzyme andthe substrate are insoluble and insoluble enzymes cannotcatalyse reactions on insoluble substrates But enzymes canbe made soluble in nonpolar solvents by micelle formationor they can bemade accessible by immobilisation in the poresof a solid surface (as in Novozyme ie immobilised Candidaantarctica lipase B)

241 In Nonpolar Solvents In a pioneering approach to theenzymatic modification of solvent-insoluble polysaccharidesin organic solvents [66] a method was developed to usesurfactants to solubilise enzymes in organic solvents Inthis way insoluble amylose could be acylated with a pro-tease from Bacillus subtilis (Subtilisin Carlsberg) using vinylcaprate as acyl donor in isooctane as solvent As the startingpolysaccharide is completely insoluble in the very nonpolarsolvent only surface-accessible hydroxyls could be acylatedand the authors estimated thatgt90 of the surface-accessibleprimary hydroxyls were esterified This corresponded toDS values of ca 015 and 030 respectively for a thinamylose film and a milled amylose powder Subsequentlythe enzymatic esterification of various solid celluloses wasaddressed including cloth thread paper andmilled particles[67] The cellulose samples failed to react in isooctanebut esterification did occur in pyridine when the SubtilisinCarlsberg (protease) was transferred into that more polarsolvent presumably due to better preswelling of the cellulose

In a related approach the enzymatic acylation of starchin toluene was achieved by coating polysaccharide nanopar-ticles in surfactant [68] ldquoReverse-micellesrdquo were formed withthe starch particles and the surfactant in octane and then theoctane was removed These surfactant-coated particles thenunderwent acylation in toluene at 60∘C with immobilised Cantarctica lipase B (ie Novozyme 435) using vinyl estersor acid anhydrides as acyl donors A DS of up to 09 wasobtained with acylation occurring regioselectively at O-6Nanoparticles have a high surface areavolume ratio whichallows efficient derivatisation of a heterogeneous system

242 InWater Enzyme-catalysed esterification reactions arereversible so in water the DS values of the products will tendto be very low The esterification of starch in water usingdecanoic acid as acyl donor catalysed by a lipase from

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

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Carbohydrate Chemistry

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Chromatography Research International

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CatalystsJournal of

ISRN Organic Chemistry 9

Thermomyces lanuginosus was reported Only very low DS(=0018) was obtained [69] The authors compared differentmethods of measuring the DS including the classic titri-metric method (saponification followed by back titration)and NMR and FT-IR based methods and proposed a newmethod based on ester hydrolysis followed by GC analysisThe acetylation of (insoluble) cellulose in water using vinylacetate as the acyl donor catalysed by a lipase fromAspergillusniger was reported But here again only very low DS valueswere seen (quoted as 016 by weight) [70 71]

243 In Polar Aprotic Solvents A series of papers describethe lipase-catalysed esterification of starch with fatty acidseither in polar aprotic solvents (DMSO or DMF) or undersolvent-free conditions with microwave heating The esteri-fication of starch was investigated using lipases from Ther-momyces lanuginosus [72] Burkholderia cepacia [73] andCandida rugosa [74] Carboxylic acids obtained by the hydro-lysis of coconut oil were used as acyl donors Both neat (DS =10ndash15) and solution (DS = 10ndash145) methods resulted insignificant esterifcation of the starch except for whenT lanu-ginosus was used in solution in DMSO when only a low DS(008) was obtained

The free hydroxyl groups of cellulose acetate were acy-lated using Novozyme (immobilised Candida anctarcticalipase B) in acetonitrile [75]

244 In Ionic Liquids Ionic liquidsmight seem to be a prom-ising candidate for this transformation as they can dissolvepolysaccharides and they are good solvents for the regiose-lective enzymatic acylation of unprotected monosaccharidesWhen conventional organic solvents are used for the enzy-matic acylation of unprotected monosaccharides the initialreaction products (typically 6-O-acyl derivatives) will tendto be more soluble than the starting material in the reactionsolvent and so are more available for further reaction Thiscan result in overacylation (to give eg 36-di-O-acyl deriva-tives) and mixtures of products But ionic liquids dissolvethe starting monosaccharides so the reaction mixtures arehomogeneous and good regioselectivity results [9] Howeverthe regioselective enzymatic acylation of polysaccharides inionic liquids does not appear to have been investigated

245 Enzymatic Deesterification of Polysaccharides Anexample of the cleavage of esters from6-O-acyl-cellulose (ieonly O-6 acylated) using a protease is reported in the liter-ature [67] Partial hydrolysis occurred in water and theauthors concluded that the more accessible surface esterswere cleaved from the heterogeneous (insoluble solid)substrate

A very interesting development concerns esterases thathave naturally evolved to hydrolyse the esters of polysac-charides Xylan in hemicellulose can be partially substitutedby glucuronic acid residues and by acetates Acetyl xylanesterases are enzymes that hydrolyse these acetates at the 2-and 3-positions of xylopyranose in xylan Several of theseenzymes were screened for cleavage activity of ester groupsin partially acetylated celluloses (DS = 07 or 14) and some

of the enzymes showed regioselective behaviour as shownby 13C NMR spectroscopy [76] The xylan esterase fromAspergillus oryzae cleanly cleaved the O-2 and O-3 acetatesleaving the O-6 acetate Other xylan esterases (eg fromSchizophyllum commune orAspergillus niger) cleaved the O-2acetate leaving the O-3 and O-6 acetates (albeit less cleanly)

3 Saccharide Carbon as Electrophile

The replacement of a saccharide oxygen by a heteroatomicnucleophile in a nucleophilic substitution (SN) reaction typ-ically requires at least two steps First a saccharide hydroxylgroup must be transformed into a good leaving group whichresults in the attached carbon becoming susceptible to nucle-ophilic attack Second treatment with a nucleophile results inattack at the electrophilic carbon of the polysaccharide anddisplacement of the leaving group

Saccharide electrophiles are much less reactive towardsnucleophilic displacement than their more typical hydrocar-bon-derived counterparts In considering the reactions ofpolysaccharides we consider nucleophilic substitution reac-tions at the primary and secondary positions (but not theanomeric position) of the constituent monosaccharides Incontrast to typical hydrocarbon substrates saccharides willalmost certainly never undergo nucleophilic substitution byan SN1 mechanism at the secondary positions nor at theprimary positions This is because an intermediate carboca-tion would be strongly destabilised by the multiple electron-withdrawing hydroxyl groups Hence all nucleophilic substi-tution at the primary and secondary positions in a polysac-charide will occur by SN2 processes

Even SN2 reactions are disfavoured in saccharides at theprimary positions and very much so at the secondary posi-tions The empirical effect sometimes called the 120573-oxygeneffect or Oldham and Rutherfordrsquos rule [43 77 78] has elec-tronic and steric explanations which I summarise very brieflyhere In an SN2 reaction electrons must be relocalised ontothe departing leaving group and this aspect of themechanismis disfavoured by having electron-withdrawing groups in thevicinal positions [79] Also the bulk of neighbouring alkoxyor acyloxy groups makes saccharide-derived electrophilesless reactive in SN2 reactions (cf the neopentyl effect in SN2reactions of hydrocarbons) A further factor that disfavoursSN2 reactions at the secondary positions of pyranoses (butnot furanoses) derives from thewell-known high stability of asix-membered ring in the chair conformation especially onebearingmultiple equatorial substituents At the SN2 transitionstate a ring-conformational change occurs to accommodatethe nucleophile and leaving group in the coordination sphereof the central carbonThis ring-conformational change is lessfavourable in a six-membered ring due to the loss in thestability of the molecule in moving away from a very stableto a less stable ring-conformation

Thus SN2 reactions at the secondary positions of polysac-charides are almost unknown but the fact that they can beachieved in high yields in monosaccharide systems usinggood nucleophiles and good leaving groups means thatthis could be a possible avenue for future exploration in

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

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Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Theoretical ChemistryJournal of

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Analytical ChemistryInternational Journal of

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Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

10 ISRN Organic Chemistry

OOHO OH

O

BrO

OHO OH

O

OTs

OOHO OH

O

OHOr

Two-stepvia sulfonate

One-step

phosphane-based

SOCl 2 etc or

Scheme 4 Introduction of halides illustrated for the bromination of cellulose

the synthesis of polysaccharide derivativesThe derivatisationof cellulose by nucleophilic substitution (saccharide elec-trophile) has been reviewed [80]

31 Installation of Leaving Groups Leaving groups that areuseful at the primary positions include bromide iodide lessreactive sulfonates or phosphonium leaving groups gener-ated in situ (in Mitsunobu and related reactions) Leavinggroups that are useful at the secondary positions of monosac-charides are triflates and epoxides but nucleophilic displace-ment at the secondary positions has hardly been exploited inthe polysaccharide series with only a rare example of a well-defined epoxide-opening reaction by an oxygen nucleophile(see below) Thus almost all of the nucleophilic substitutionchemistry of polysaccharide electrophiles that has beenreported to date has taken place at the primary positions

311 Sulfonates Hydroxyl groups react with sulfonatingagents to generate sulfonate esters It may be possible toactivate the primary alcohol (OH-6) regioselectively butfor more details on this process see the section above onnucleophilic reactions of polysaccharide hydroxyl groupsThe sulfonate group has a general structure RS(O)

2Ondash and

the R group can be varied to tune the electronic propertiesand thus the reactivity of the sulfonate ester Despite thealmost unlimited possibilities for structural variation hereonly a few sulfonates have been in common usage in thenucleophilic displacement reactions of polysaccharides

Mesylate (methanesulfonate R = Me) and tosylate (119901-tolunesulfonate R = 119901-MeC

6H4) have broadly similar reac-

tivities and will normally undergo nucleophilic displacementat the primary positions but not at the secondary positionsof pyranosides When there are free hydroxyl groups at thevicinal positions to tosylates or mesylates at the secondarypositions of partially protected monosaccharides or polysac-charides nucleophilic substitution may take place Presum-ably though this process goes via epoxide intermediates aswhen there is no vicinal alcohol group there is no substitutionreaction Triflate (trifluoromethanesulfonate R = CF

3) has a

strongly electron-withdrawing R group Consequently it isa better leaving group and it can be used in nucleophilicsubstitution reactions at the secondary positions ofmonosac-charides but examples on polysaccharide substrates do notappear to be known

312 Halides Halides are the classic leaving groups innucleophilic substitution reactions and the displacement ofhalides from the primary positions (eg C-6 of celluloseamylose etc) of polysaccharides has been used to introducenucleophilic groups (Scheme 4)

One method that has been used for the introductionof the halide leaving groups at C-6 of polysaccharides isthe treatment of C-6 sulfonates (including tosylates andmesylates) with halide salts using acetone as solvent (ieFinkelstein conditions) [43] An obvious disadvantage of thisapproach though is that if the halide is to be used as a leavinggroup in a nucleophilic substitution reaction it can seempointless to add an extra step to a reaction sequence when theC-6 sulfonate in the startingmaterial can itself act as a leavinggroup in substitution reactions with the same nucleophiles

Thus methods for the preparation of polysaccharidehalides directly in one step from the native polysaccharideswould appear to be advantageous

In themonosaccharide series several sets ofmild reactionconditions based on treatment with PPh

3together with a

halide source that can be reduced (eg CBr4in the Appel

reaction I2in the Garegg reaction etc) have been developed

for the regioselective preparation of bromides or iodidesfrom the unprotected glycosides Under these mild reactionconditions the primary alcohol reacts regioselectively andthe secondary alcohols remain untouched [81]

Polysaccharides may also be halogenated directly andregioselectively under related phosphane-based conditionsor using classical halogenating agents such as SOCl

2 without

initial protecting-group manipulations In cellulose C-6 ishalogenated first and C-3 may also be halogenated undercertain conditions while C-2 does not normally react [80]In chitin C-6 may be halogenated while C-3 does not reactThus chitin may be transformed into a polysaccharide con-taining three different functional groups halogen alcoholand amide in a single step

Cellulose could be chlorinated with the classical chlori-nating agents thionyl chloride and mesyl chloride (MsCl) togive polysaccharideswithDS values of up to 28meaning thatalmost complete chlorination had occurred at both primaryand secondary positions [80] However significant depoly-merisation was also observed under these conditions Thereagent system of N-chlorosuccinimide (NCS)PPh

3LiCl

in DMA was more regioselective for the chlorination ofcellulose

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

ISRN Organic Chemistry 11

OOHO

OHO

OH

OOHO

OHO

OTr

OO O

OTr

OOHO

OTsO

OTr

O

Scheme 5 Synthesis of a cellulose epoxide (DS 03)

Several other polysaccharides were chlorinatedwith goodregioselectivity for the primary positions usingMsCl includ-ing amylose (in DMFLiCl) [82] inulin (in DMF 70∘C 16 h)[64] and pullulan (in DMF) [83]

The chlorination of chitin using sulfuryl chloride wasinvestigated [84] With this reagent reaction at C-6 was seenat low temperatures and at higher temperatures C-3 was alsochlorinated Chitin could be chlorinated regioselectively atC-6 using NCSPPh

3in DMALiCl to give a product with a

DS of 10 but some depolymerisation was seen under theseconditions [85]

The bromination of cellulose could be carried outwith thetribromoimidazolePPh

3imidazole reagent system in DMA

LiBr to give bromocelluloses with DS values of up to 16 [86]Here bromination had occurred at C-6 and C-3 and the bro-minated C-3 carbons were found to have a mixture of glucoand allo configurations

An essentially completely regioselective bromination ofcellulose (at C-6) was achieved using N-bromosuccinimide(NBS)PPh

3in DMALiBr giving a 6-bromo-6-deoxycellu-

lose with DS = 09 [87 88] The regioselectivity of this bro-mination reaction can be better than that of a tosylationreaction This makes phosphane-mediated bromination anattractive method for the very regioselective modification ofcellulose (at C-6) [45] the analogous direct iodination ofunprotected polysaccharides does not appear to be knownhowever

Similar bromination reactions of other polysaccharideswith the NBSPPh

3reagent system gave similarly excellent

regioselectivity and high degrees of substitution When amy-lose was treated with NBSPPh

3in DMF only derivatisation

of the primary positions was observed [82] and it waspossible to monitor the progress of this reaction by followingthe development of the NMR spectra The analogous bromi-nation of chitin was achieved with NBSPPh

3in DMALiBr

to give a product with a DS of 094 but here some loss in DPwas seen [89] It is possibly relevant that while chitin is solublein DMALiCl it is not soluble in DMALiBr so this reactionwas heterogeneous

The bromination of curdlan was achieved with a differentphosphane-based reagent system CBr

4PPh3in DMFLiCl

[90] The reaction proceeded essentially to completion andwith complete selectivity for the primary position (C-6) [90]

313 Epoxides To date polysaccharide epoxides do notappear to have been widely investigated but the synthesis ofa 23-anhydro derivative of cellulose (ie a 23-epoxide) hasbeen reported (Scheme 5) [91] First O-6 was protected asa trityl ether then O-2 was converted regioselectively intoa tosylate Treatment of this compound with base resultedin attack of O-3 onto C-2 displacement of the tosylateand closure of the epoxide ring to give a 23-anhydro-6-O-tritylcellulose The DS of this polysaccharide was ca 03 asdetermined from the incorporation of methyl groups afterring-opening by methoxide

Cyclodextrin (per) epoxides are also known [92] andthey have been synthesised by a similar but possibly moreregioselective sequence of 6-O-silylation 2-O-sulfonationand base treatment for epoxide closure

32 Nucleophilic Displacement

321 OxygenNucleophiles Normally esters or ethers of poly-saccharides (or indeed of monosaccharides) would be pre-pared by the reaction of a saccharide oxygen nucleophile withan alkylating agent or acylating agent (see above) The com-plementary approach where the saccharide acts as an elec-trophile and is attacked by an alcohol (for ether formation)or a carboxylate (for ester formation) is much less commonbut examples of this type of derivatisation do exist for poly-saccharide substrates

A situation where the more usual approach of nucle-ophilic attack by a saccharide oxygen nucleophile would beimpossible would be in the synthesis of phenyl ethers Andindeed a 6-O-phenyl ether derivative of cellulose was synthe-sised by displacement of a 6-tosylate by phenoxide [93 94]Nucleophilic substitution reactions at the secondary posi-tions of polysaccharides are extremely rare but a 23-epoxidederivative of cellulose underwent ring-opening bymethoxidein a reaction that was assumed to be quantitative [91]

Intramolecular O-nucleophilic displacement to givecyclic derivatives is also known For example starch wasconverted into a 36-anhydro derivative with a DS of 085using the following sequence tritylation of O-6 acetylationof O-2 and O-3 detritylation of O-6 tosylation of O-6and finally deacetylation of O-2 and O-3 which also

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

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Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

12 ISRN Organic Chemistry

OOHO OH

O

X

OOHO OH

O

OOHO OH

O

NHR

OOHO OH

O

Reduce

NaN3

N3

NH2

X = Br OTs etcRNH2

Scheme 6 Introduction of nitrogen as alkylamines or azide

resulted in intramolecular nucleophilic attack of O-3 ontoC-6 displacing the tosylate and cyclisation to form the36-anhydrosugar [95]

Esterification by this concept has also been reported Car-boxylate salts have been used in nucleophilic displacementreactions with primary amylose halides to give C-6 esters[82]

Finally esterification is possible under the conditions oftheMitsunobu reaction an overall formal condensation reac-tion between an (unactivated) alcohol and a carboxylic acidnucleophile The basis of the Mitsunobu reaction is a redoxreaction between stoichiometric amounts of an oxidisingagent [normally DEAD (diethyl azodicarboxylate which isreduced to DEAD-H

2)] and a reducing agent [normally PPh

3

(which is oxidised to Ph3P=O)] that require amole equivalent

of water to allow their reaction Hence anhydrous conditionsare a prerequisite for this chemistryThemechanism involvesthe in situ activation of an alcohol by the generation of aphosphonium leaving group and its subsequent displacementby a nucleophile to give the product The reaction is relatedto the phosphane-based halogenation reactions describedabove

Mitsunobu reactions at the primary positions of carbo-hydrates are well known The reactions are normally high-yielding and regioselective so it is often possible to refunc-tionalise the primary position of an unprotected monosac-charide [96] However a limited number of reactions of sec-ondary carbohydrate alcohols are known

Very little has been published on the Mitsunobu chem-istry of polysaccharides However the reactivity of amyloseunder the conditions of Mitsunobu esterification has beeninvestigated [82] Initially esterification occurred regioselec-tively at C-6 but as the reaction proceeded above DS = 05some esterification of the secondary positions started to beobserved

322 Nitrogen Nucleophiles The introduction of differenttypes of nitrogen-containing groups at the primary positionsof polysaccharides by nucleophilic displacement has beenfairly extensively investigated Two broad classes of nucle-ophile can be considered (Scheme 6) Amines will be neutralnucleophiles and will carry one or more alkyl chains that willbe retained in the final product Alternatively a negativelycharged nucleophile such as azide could be usedThe azide in

the polysaccharide product could then be reduced to revealan amine that could be further functionalised if desiredThe monovalent nature of an azide nucleophile can have theadvantage of avoiding possiblemultiple substitution of aminenucleophiles that would lead to cross-linking and complexproduct mixtures [97]

A synthesis of 6-amino-6-deoxycellulose (DS = 10) bythe essentially uniform introduction of nitrogen at C-6 ofcellulose has been described [98] Tosylation of celluloseresulted in complete derivatisation of O-6 but the reactionwas not completely regioselective and significant tosylationof O-2 and O-3 also occurred This polysaccharide wasthen treated with azide The C-6 tosylates were substitutedbut the secondary tosylates did not react Treatment withLiAlH

4reduced the C-6 azides to give C-6 amines and at

the same time reductively cleaved the 2- and 3-tosylates togive the final product The displacement of the C-6 tosylateby azide was carried out in DMSO at 50∘C When highertemperatures (100∘C) or an acetonewater solvent were usedsome introduction of azide at C-2 or C-3 was also seen(possibly via epoxide intermediates see above)

An alternative approach to 6-amino-6-deoxycellulosegoing via the C-6 bromide which can be formed fromcellulose more regioselectively than the C-6 tosylate hasbeen published [99] Thus bromination of cellulose fol-lowed by azide displacement and reduction gave 6-amino-6-deoxycellulose with very clean 13C NMR spectra (DS =096) in only three steps However some depolymerisationoccurred (the Avicel microcrystalline cellulose startingmate-rial had DP = 114 product DP = 66) But when microwaveirradiation was used for heating the reaction times could beshortened and the degradationminimised (startingDP= 114product DP = 106) [100]

Primary halides or tosylates of several other polysaccha-rides have been shown to undergo nucleophilic displacementby azide 6-Azido-6-deoxyamylose was prepared from thecorresponding amylose bromide (sodium azide DMSO50∘C 6 h) or chloride (sodium azide DMSO 70∘C 65 h [82])As expected the bromide was much more reactive than thechloride Similarly a starch tosylate reacted with sodiumazide (DMF 100∘C 24 h) to give a starch azide with a DS of096 [101]

Treatment of 6-bromo-6-deoxycurdlan (DS asymp 1) withazide gave complete substitution as judged by the very clean

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

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Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

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Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ElectrochemistryInternational Journal of

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CatalystsJournal of

ISRN Organic Chemistry 13

O

OHO HO

OH

O

O

OHO HO O

PPh3 CBr4NaN3 DMF

N3

Scheme 7 Azide formation from the hydroxyl group under Appel-like conditions

13C NMR spectrum of the product [90] The introduction ofazide into phthalimide-protected chitosan was achieved bydisplacement of both tosylate and bromide leaving groups[102] The reaction of tosylates of lichenan pullulan anddextran with an azide nucleophile was investigated [61]Heating with sodium azide in DMF (24 h 100∘C) resulted inhigher degrees of substitution of tosylate by azide (67ndash75)for the tosylates of lichenan and pullulan than for the tosylateof dextran (45) probably because the number of primarytosylates in dextran [predominantly a (1ndash6)-linked polymer]is lower Azide substitution of a 6-chloro-6-deoxypullulan(NaN

3 water 100∘C) [83] and of tosyl or chloride derivatives

of inulin (NaN3in DMSO) [64] has also been reported

The direct introduction of azide into unprotected poly-saccharides in a phosphane-based process related to theAppel Garegg and Mitsunobu reactions discussed aboveoffers an advantageous straightforward one-step route to 6-azido-6-deoxy derivatives of some polysaccharides(Scheme 7) [103] Amylose or pullulan could be treated withPPh3 CBr

4in DMFLiN

3under homogeneous conditions

at room temperature to readily give the C-6 azides regio-selectively This procedure was extended to starches replac-ing LiN

3by the more easily available NaN

3 and using either

DMF or DMA as solvent [104] Native starches failed to reactunless their granular structures were disrupted in whichcase full conversion was seen With amylose or amylopectinstarches whenNaN

3(2 equiv) was used and the reaction was

run at 100∘C for 1 h essentially homogeneous incorporationof azide at C-6 (DS = 1) was observed no evidence ofsubstitution at C-2 or C-3 could be seen

The functionalisation of cellulose derivatives (but notother polysaccharides) using amine nucleophiles has alsobeen investigated The reaction of tosylated cellulose withmethylamine was studied in detail [typical conditions DMAMeNH

2(aq ca 40 equiv) 60∘C 48 h purification by precipi-

tation] [105]The nucleophilic substitution reaction occurredonly at C-6 and conditions were found that allowed the prep-aration of a polysaccharide with DSN of ca 1 but presumablysome unreacted tosylate groups remained at the secondarypositions of this product

Similarly the reaction of tosylated cellulose (DStotal asymp2 DSC-6 = 10) with butylamine was studied under differentconditions [106]The reaction proceeded muchmore quickly(and regioselectively for C-6) in neat butylamine (neatBuNH

2 50∘C 24 h) than it did in DMSO solution (DMSO

BuNH2(ca 5 equiv) 75∘C 24 h) It has also been shown that

bromide can be an effective leaving group in such reactionsas 6-bromo-6-deoxycellulose (DS = 092) reacts with amines

in DMSO at 90∘C to give after purification by precipitationand dialysis polysaccharide amine products with DSN asymp 09[107] Finally tertiary amines have been shown to react withtosylated cellulose to give ammonium salts [108]

323 Sulfur Nucleophiles The introduction of sulfur nucle-ophiles into polysaccharides (cellulose and starch) has beenthe subject of some research (Scheme 8) albeit to a muchlesser extent than for nitrogen nucleophiles

Thiols were used as nucleophiles in nucleophilic sub-stitution reactions with 6-bromo-6-deoxycellulose (RSH R= Me Ph CH

2CH2OH CH

2CH2NH2 etc) under hetero-

geneous conditions in aqueous sodium hydroxide givinga maximum conversion of 65 [109] When the pH wastoo basic 56-elimination and 36-cyclisation competed withthe SN reaction A similar reaction between a 6-bromo-6-deoxycellulose and thiols was also carried out under homoge-neous conditions in DMALiBr using triethylamine as basefollowed by purification by precipitation or dialysis [110]A detailed optimisation of the conditions for this reactionwas undertaken 6-O-Tosyl-cellulose has also been used asan electrophile in a thioether-forming reaction with sodiummethanethiolate (DMF 0∘C 8 h) [111]

Other sulfur nucleophiles have been used in reactionswith polysaccharide electrophiles for the indirect synthesisof polysaccharide thiols 6-Bromo-6-deoxycellulose (DS =085) was converted into the thiol in a two-step process Firstsulfur was introduced using a thiourea nucleophile (DMSO70∘C 48 h) [112] The initial product a (poly)thiouroniumsalt then underwent hydrolysis to give the polysaccharidethiol Alternatively 6-bromo-6-deoxycellulose (DS = 092)underwent substitution with potassium thiocyanate (DMF150∘C 2 h) [113] Purification by precipitation and dialysisgave a product with DSSCN = 088 and residual DSBr = 002 A6-deoxy-6-thio derivative of amylose with DS = 08 could beprepared similarly Thus 6-O-tosyl-amylose (or alternatively23-di-O-phenylcarbamoyl-6-O-tosyl-amylose) underwent anucleophilic substitution reaction with KSCN and then thethiocyanate product was reduced (and the 23-protectioncleaved) by treatment with LiAlH

4[114] Xanthates were

used as nucelophiles in reactions with tosylates of starch(DS lt 02) and the products were reduced to give thepolysaccharide thiols [115] Here though the conversion ofthe tosylates in the nucleophilic substitution reaction wasnot complete and some formation of thioether linkages wasobserved

A heterogeneous reaction in which sulfur nucleophileswere bonded to Whatman filter paper was carried out by

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

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International Journal ofPhotoenergy

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Carbohydrate Chemistry

International Journal of

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Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

14 ISRN Organic Chemistry

OOHO OH

O

XO

OHO OH

O

SH

OOHO OH

O

SR

(ii) Deprotect

X = Br OTs etc

(i) NCSminus xanthate etc

RSminus

Scheme 8 Introduction of sulfur with thiolate or other sulfur nucleophiles

initial chlorination followed by nucleophilic substitution bytreatment with thiourea or cysteine in suspension in a DMFwater mixture [116]

It is perhaps worth noting that in monosaccharides theintroduction of thiol nucleophiles at the secondary positionsof pyranosides by triflate displacement is relatively trivial[117] but related work has not been done to date in polysac-charides Also in monosaccharides selenoethers have beenintroduced in a protecting-group-minimised approach sim-ilar to those described here for thioethers [118] But again norelatedworkwith seleniumnucleophiles appears to have beendone to date in the polysaccharide series

4 Oxidation

Polysaccharides may be oxidised in different ways to producestructures of different types (Scheme 9) Where there is afree primary alcohol (eg at C-6 in cellulose or amylose)this may be oxidised simply to give the aldehyde or furtherto the carboxylic acid level Oxidation to the carboxylicacid level would result in a polysaccharide based on uronicacids which would then resemble the structure of naturalpolyuronic acids such as pectin or alginates Chemical andenzymatic methods have both been used for oxidation of theprimary alcohols of polysaccharides An alternative mode ofoxidation would be the oxidative cleavage of 12-diols Wherethis structural motif occurs in a polysaccharide (eg at C-2and C-3 in cellulose amylose or xylose) it may be possibleto undergo a ring-opening oxidative CndashC bond cleavage togive dicarbonyl compounds With these different possibleoxidation modes come issues of selectivitymdashwhen carryingout an oxidative derivatisation of a native (unprotected)polysaccharide it would be desirable to have either oneof these oxidation modes operating but not both Whenoxidising primary alcohols it may also be desirable to avoidpotential simple oxidation of unprotected secondary alcoholsto give ketones and also to be able to choose conditions thatresult in either oxidation to the aldehyde or the carboxylicacid levels The periodate oxidation of polysaccharides [119]and the oxidation of cellulose have recently been reviewed[120]

41 Oxidation of Primary Alcohols A method that has beenused for the oxidation of C-6 of monosaccharide glycosides

OOHO OH

O

OHO

OHO OH

O

OH

OOHO

O

OH

(b)

(a)

O

OOH

O

Scheme 9 Different modes of chemical oxidation illustrated forcellulose (a) Oxidation of a primary alcohol (b) oxidative cleavageof a diol

to the uronic acid level is treatment with oxygen over aheterogeneous platinum metal surface as a catalyst [121] Inmany respects this is an attractive method since molecularoxygen is used as the oxidising agent water is the sole by-product and in principle heterogeneous catalysts can beeasily recovered and reused However this method has asignificant disadvantage when it comes to the oxidation ofpolysaccharides as the catalyst is heterogeneous the degreeof oxidation (DSox) can be quite low [122] It is generally truethat homogeneous catalysts will give better results for themodification of insoluble polymeric substrates Neverthelessinulin with a DP of ca 30 could be oxidised to the uronic acidlevel at the primary positions (C-6) with a DSox of ca 020under such conditions [123] and C-6 oxidation of a galactanover platinum to the uronic acid level with a DSox of ca 015has also been achieved [121 122 124] Purification was carriedout by precipitation followed by membrane filtration

In the early 1990s Van Bekkum found that a homoge-neous catalyst TEMPO [ie (2266-tetramethyl-piperidin-1-yl) oxyl] could be used for the regioselective oxidation ofthe primary alcohols in polysaccharides (starch and inulinwere included in the initial report) to give the correspondingpolyuronic acids with essentially complete conversion (ieDSox ca 10) [125]

In a typical oxidation procedure [126] the polysaccha-ride (20mmol Glc units) a catalytic amount of TEMPO(065mol-) and NaBr (04 equiv) were dissolved in waterA pH-adjusted solution of the stoichiometric oxidant NaOCl

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

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Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

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Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

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Analytical ChemistryInternational Journal of

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Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

ISRN Organic Chemistry 15

(11 equiv) was added at 0∘C The reaction mixture was keptat 0∘C and the pHwas kept at ca 10 by the addition of NaOHThe reaction was complete after 1-2 h after which EtOH wasadded to quench the reaction and to precipitate the polysac-charide which could then be collected by filtration The pro-ducts were the sodium salts of the polyuronic acids

The method is catalytic in TEMPO and is selective forprimary alcohols with secondary alcohols remaining unaf-fected In the reaction mechanism the persistent radicalTEMPO is initially oxidised to give the active oxidant anoxoammonium species

This species then oxidises the polysaccharide primaryalcohol to the aldehyde being itself reduced to the hydroxy-lamine The polysaccharide aldehyde must then be hydratedand the hydrate is then oxidised to the acid by a secondmolecule of the oxoammonium reagent The stoichiometricoxidant is NaOClNaBr NaOBr or NaOCl and this isresponsible for the initial oxidative activation of TEMPO andthe subsequent reoxidation of the hydroxylamine to the activeoxoammonium species

This method was suitable for the very selective oxidationof C-6 of soluble potato starch and of pullulan [126] Thethree Glc(A) environments of the oxidised pullulan can beclearly seen and distinguished in the 13C NMR spectra ofthe product The selectivity for the primary alcohols wasestimated to be gt95

Amylodextrin which is a short amylose structure witha DP of ca 20 was oxidised selectively at C-6 but someoveroxidation at the reducing ends became significant atthe shorter polymer chain length [125] Dextran whichis basically a (1ndash6)-linked polymer without free primaryhydroxyl groups except for end-groups was oxidised only atthe level of background oxidation of the secondary alcoholsby NaOCl (or NaOBr) which occurred much more slowlythan the TEMPO-catalysed oxidation of the primary alcohols[125] Apparently the selectivity for the primary alcohols wasless good in inulin based on furanoside residues but whenthe reaction was quenched after 20min the a 13C NMRspectrum of the product was clean [125] and gt90 selectivitywas reported

Water-soluble polysaccharides were investigated initiallybut this C-6 oxidation to the carboxylic acid (carboxylate)level greatly increased the water solubility of the polysac-charide products and in fact the method was found tobe broadly applicable The polysaccharides that have beensuccessfully oxidised using the TEMPO method includestarch [125ndash127] amylose [127] amylopectin [127] amy-lodextrin [125] dextran [125] regular comb dextran [127]pullulan [126 127] alternan [127] inulin [125] chitin [127ndash129] chitosan [127 128] and cellulose [127 128] Normallyexcellent selectivity for oxidation of the primary alcohol wasseen and normally DSox values close to 10 (ie completeconversion) were obtained [127] Some reports indicate thatthe selectivity for the primary alcohols was lower in chitinand some oxidation of secondary alcohols also occurred[127] while others found that chitin could be oxidised to givea polyuronic acidwith a quite clean 13CNMR spectrum [128]

The oxidation of cellulose by the TEMPO methodhas been studied in detail [128] Different celluloses were

investigated includingmicrocrystalline cellulose (DP = 200)linters (DP= 800) bleached kraft pulps (DP= 900ndash1200) andamorphous regenerated celluloses The oxidation procedurewas essentially identical to that described above except thatall of the celluloses were of course initially insoluble inthe aqueous reaction medium When the oxidation wascomplete the polysaccharide had dissolved and purificationcould be carried out again by precipitation from EtOH Theregenerated celluloses were completely oxidised at C-6within2 h whereas the native celluloses did not form homogeneoussolutions even after long reaction times presumably due tothe crystallinity and the resulting inaccessibility of some ofthe C-6 hydroxyl groups When the native cellulose sampleshad been mercerised they underwent rapid oxidation Anessentially completely regioselective (C-6) oxidation of theseinsoluble polysaccharides (ie the regenerated or mercerisedcellulose samples) was achieved under these conditions asshown by the 13C NMR spectra of the products

It was found that under these reaction conditions somedepolymerisation occurred presumably by a E1CB elimina-tion mechanism across C-4ndashC-5 the reaction time tempera-ture and amounts of reagents are all important factors to beconsidered if this depolymerisation is to be minimized [128]

A variant of the TEMPO oxidation method in which thesodium bromide is omitted but still using NaOCl as thestoichiometric oxidant has been used for the oxidation ofpotato starch [130]This variantmethod gave similar reactionrates and selectivities when the reaction was carried out atroom temperature and when the pH was kept below 95

TEMPO is a persistent stable radical to the extent thatit is a commercially available solid Related methods forthe oxidation of polysaccharides using shorter-lived NndashOradicals have been investigated briefly An example of such amethod uses catalyticN-hydroxysuccinimide NaOCl as stoi-chiometric oxidant and NaBr [120] Another related reactionis the oxidation with N

2O4[122 124 131 132] This reagent

oxidises the primary position of carbohydrates regioselec-tively to give the uronic acids but the regioselectivity isnot perfect and some oxidation of the secondary positionscan take place Normally then it is necessary to include aborohydride reduction step after the oxidation to reduce anyketones back to the alcohol level (clearly this would introduceissues of diastereoselectivity and inhomogeneity in the prod-ucts) Depolymerisation can also occur (by E1CB eliminationresulting in chain cleavage at C-4 see above) under thebasic conditions of this reaction The side-reactions that arefound with this reagent mean that it is less suitable for thepreparation of pure polyglucuronic acid polysaccharides thanthe other methods discussed here

42 Enzymatic Oxidation The enzyme galactose-6-oxidase(EC 1139) catalyses the C-6 oxidation of galactose to thealdehyde level using oxygen as the oxidant and generatinghydrogen peroxide as the reduced by-product (3) The reac-tions are carried out in aqueous solutionThus the reaction iscomplementary to the TEMPO oxidation where the productof C-6 oxidation is the carboxylic acid rather than thealdehyde

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

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Journal of

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Medicinal ChemistryInternational Journal of

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Chromatography Research International

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ElectrochemistryInternational Journal of

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CatalystsJournal of

16 ISRN Organic Chemistry

O

HOO

HO

O

HO HO

OHHO

OO

OHO

OHOHO

O

HOO

HO

O

HO HO

OHO

OO

OHO

OHOHO

Galactose-6-oxidaseCatalase

horseradish-peroxidase

Scheme 10 Enzymatic oxidation of guar gum

O

HO HO

OHHO

O

HO HO

OHO

OH OH

Galactose-6-oxidase+ O2 + H2O2

(3)

The enzyme is highly selective for C-6 of galactosealthough it does tolerate substituents at the anomeric positionof the galactose (ie the formation of glycosides) Possiblegalactose-derived by-products include the uronic acid (fromoveroxidation) or the 120572120573-unsaturated aldehyde (from E1CBelimination across C-4ndashC-5)

The oxidation of polysaccharides with galactose-6-oxidase has been investigated but first an optimisation ofthe reaction conditions was carried out on a monosaccharidemodel system methyl 120572-d-galactopyranoside [133] The bestresults were obtained using a combination of three enzymes(viz galactose-6-oxidase catalase and horseradish peroxi-dase) in water rather than buffer Catalase (EC 11116) wasadded to catalyse the decomposition of the H

2O2formed in

the reaction as otherwise H2O2can poison the activity of

the galactose-6-oxidase Horseradish peroxidase was addedto activate the oxidase enzyme by oxidising it to its activeform

The same group went on to investigate the oxidationof polysaccharides using galactose-6-oxidase in some detail[134] The general oxidation procedure was as follows thepolysaccharide was stirred in water at 4∘C or RT for 1ndash12 huntil it had dissolved Then the enzymes were added andthe mixture was stirred for 48 h The oxidation of severalgalactose-containing polysaccharides was investigated usingthe same three-enzyme systemThese included spruce galac-toglucomannan [a 120573(1ndash4)-linked backbone of glucose andmannose residues with pendant galactose residues linked120572(1ndash6)] guar gum [a 120573(1ndash4)-mannan backbone with pendantgalactose residues linked 120572(1ndash6)] larch arabinogalactan [a120573(1ndash3)-linked galactan backbone with pendant arabinofu-ranose units linked 120572(1ndash6) and galactose and galactobioseunits linked to the backbone by 120573(1ndash6)-linkages] corn ara-binoxylan [a 120573(1ndash4)-linked xylan with various appendagesmostly arabinofuranose] and xyloglucan from tamarindseeds [a 120573(1ndash4)-linked glucan with pendant 120572(1ndash6)-linkedxylose units about half of the xylose residues are galacto-sylated] Hence the polysaccharides had different galactosecontents and different presentations of the galactose units

due to branching and the efficiency of the oxidation reactionvaried between the different polysaccharides Xyloglucan wasthe most efficiently oxidised (up to DSox 08 based on thegalactose residues) followed by galactoglucomannan (DSoxca 065) and guar gum (DSox ca 04 Scheme 10)

There are also some further earlier reports on the oxida-tion of polysaccharides by galactose-6-oxidase in the litera-ture The galactose residues in guar gum were converted intothe corresponding uronic acids in a two-step process consist-ing of enzymatic oxidation at C-6 with galactose-6-oxidasefollowed by chemical oxidation (with I

2KI) [135] A synthetic

polysaccharide consisting of chitosan to which lactose hadbeen attached by reductive amination was also a substrate forgalactose-6-oxidase and the appended galactose units couldbe oxidised enzymatically at C-6 [136] The (1-deoxy-lactit-1-yl) chitosan was dispersed in phosphate buffer to give asoft glassy gel which was purged with O

2for 1min Catalase

and galactose-6-oxidase solutions were added and a viscousmaterial formed after a few hours After 2 d the mixture wasdiluted with water and the polysaccharide was precipitatedfrom absolute ethanol to give a product with a DSox of ca 07

43 Oxidative Cleavage of 12-Diols Periodate may be usedas an oxidising agent to achieve the ring-opening cleavage ofthe 12-diols at C-2 and C-3 of polysaccharides very efficientlyand selectively The initial product is the dialdehyde and isthen usually oxidised further to give the dicarboxylate

The C-2ndashC-3 oxidation mode was tested on starch andmaltodextrin using different oxidants [121] TungstateH

2O2

and hypochlorite both resulted in chain degradationThe bestresults were obtained using a two-step procedure of periodateoxidation-cleavage (to the dialdehyde) followed by chloriteoxidation (to the dicarboxylate) Under the same conditionsthe polysaccharides tested were essentially quantitativelyring-opened to give the polycarboxylate derivatives It wasalso confirmed that (as expected) the ring-opened polymersare more susceptible than the parent unoxidised polysac-charides to acid-catalysed depolymerisation (ie acetalhydrolysis)

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

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Carbohydrate Chemistry

International Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

ISRN Organic Chemistry 17

OOHO

O

OHO

OH

O

OH

OH

O

OO

OO O

OH

NHR

O

OH Periodateoxidation

Reductive

amination

RHN

Scheme 11

For cellulose the efficiency of this oxidation reactionmay be improved by the addition of metal salts to disruptintermolecular hydrogen bonding and improve the solubility[137] Alginates have been subjected to C-2ndashC-3 oxidativecleavage using periodate [138] Initially formed aldehyde pro-ducts were subjected to reductive amination with long-chainalkylamines to give hydrophobically modified derivatives(Scheme 11)

5 Reactions of Carboxylic Acids

Several natural polysaccharides including alginates andpectins use uronic acid residues as structural componentsIn a uronic acid derivative the C-6 position is oxidised tothe carboxylic acid level This section covers the reactionsof these carboxylic acids (Scheme 12) both electrophilicand nucleophilic reactions including esterification amideformation and multicomponent reactions As well as naturaluronic-acid-containing polysaccharides this chemistry maybe applicable to synthetic C-6 oxidised polysaccharides (seeabove) The modification of the carboxylic acid (uronic acid)functionality of alginates has been reviewed [138 139]

51 Esterification Carboxylic acids can react either as elec-trophiles or nucleophiles to form esters In the first scenariothe acid must first be activated which may happen prior tothe esterification (eg by formation of an acid chloride) orin situ by using a coupling reagent such as DCCI or by usinga strong-acid catalyst (Fischer esterification) The activatedacid should then be attacked by an alcohol nucleophile to givethe ester However this approach has some disadvantages thatmean it does not appear to have been widely used for themodification of polysaccharide uronic acids (i) in aqueoussolution the water can effectively compete with the intendedalcohol nucleophile hydrolysing the activated acid interme-diates and restoring the carboxylic acid starting material(ii) where the other hydroxyl groups of the polysaccharideare unprotected they too could compete as nucleophileswith the added alcohol and possible cyclised products couldresult (iii) in a Fischer (acid-catalysed) esterification thereis significant risk of depolymerisation of a polysaccharidesubstrate

In the second approach the carboxylic acid can be depro-tonated by a weak base to generate a carboxylate This canthen react as a nucleophile with alkylating agents to generate

the estersThe hydroxyl groups of the polysaccharide will notnormally react under these conditions and so this approachhas been more widely used for the preparation of esters ofpolysaccharide uronates [140 141]

Treatment of the TBA salt of (completely demethylated)pectin with benzyl bromide and TBAI in DMSO at RT gavethe benzyl ester with a DS of up to 073 [141] The decyl estercould be prepared similarly with a DS of up to 044The samemethod has been used for the preparation of esters of pectinwith lower DS (gt01) [142] and of alginates and hyaluronatesagain with lower DS (gt01) [140]

52 Amide Formation Uronic acids must be activated toreact as electrophiles with amine nucleophiles to generateamides Classically this can be achieved using a coupling(dehydrating) agent such asDCCI or thewater-soluble EDCIbut even esters can be used as electrophilic carboxylic acidderivatives in amide-forming reactions

The conversion of the uronic acids of alginate into amideshas been achieved by reaction with amines in water usingEDCI a water-soluble coupling agent [139] Alginate amideswithDS of 01ndash03were synthesised in this way by the reactionof sodium alginate with octylamine and EDCI in water [143]Purification was achieved by precipitation from EtOH Alter-natively the reactions could be carried out in an organic sol-ventThus alginate amideswithDS of up to 02were preparedby the reaction of an alginate TBA salt with decylamine andCMPI (2-chloro-1-methylpyridinium iodide the couplingagent) in DMF [144] Purification was achieved by ionexchange followed by precipitation from water

Esters react directly with amines to form amides in a reac-tion termed aminolysis In a polysaccharide context highlymethylated pectin (methyl esters DSmethyl = 073) was treatedwith various alkylamines (n-butyl up to n-octadecyl) in DMFunder heterogeneous conditions (8 25 or 45∘C) and theamide products were formed with DSamide = 04ndash055 [145ndash147]

53 Other Reactions Other reactions of carboxylic acidsmayalso be applicable to polysaccharide uronic acids A conceptthat has been used to rapidly generate molecular diversity isthat of multicomponent reactions [148ndash151] in which con-densationaddition products are generated from three ormore starting materials in a single reaction Carboxylic acidsare often found as components in such reactions

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

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Medicinal ChemistryInternational Journal of

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Chromatography Research International

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Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

18 ISRN Organic Chemistry

OOHO

O

OHO

OHO

O

OR

OOHO

O

NHR

Ester formationOH

OH

OH

O

O

O

Amide formation

Scheme 12

O

HOO

OHO

O

OH

O

H

H

NC

O

HOO

OHO

O

HNO

H2N(CH2)7CH3

N(CH2)7CH3

Scheme 13 Ugi reaction of a polysaccharide

One example is the Ugi four-component reaction bet-ween an aldehyde (or ketone) an amine an isocyanideand a carboxylic acid to form a diamide [152 153] It hasbeen shown that the uronic acids of alginate can undergotheUgi reaction (Scheme 13) [154]Thus an aqueous solutionof alginate was treated with formaldehyde octylamine andcyclohexyl isocyanide for 24 h Purification was achieved bydialysis

6 Saccharide Nitrogen as Nucleophile

This section concerns the reactions of polysaccharide aminessuch as chitosan which carries a free basic nitrogen at C-2

but the methods should also be applicable to other syntheticaminated polysaccharides for example C-6 aminated cellu-lose

Amines can react with electrophiles to give amides (ieacylation) higher order amines or ammonium salts (iealkylation) or imines (Schiff bases) The different reactivityof nitrogen and oxygen nucleophiles means that it is oftenpossible to carry out these derivatisations in aqueous solu-tion and without protection of any free hydroxyl groups inthe saccharide derivative Of course O-alkylation and O-acylation may take place under some conditions but with anappropriate choice it should be possible to find conditionsthat favour chemoselective derivatisation at nitrogen

X+ + base NHAlkylationNH2

R998400

R998400

+ base middot H+ + Xminus (4)

O

H+ N

HImine

formation R998400 R998400NH2

+ H2O(5)

O

H+

NHReductiveamination

(alkylation)

NH2

R998400 R998400

+ NaBHX3 + NaB(OH)X3 (6)

O

X+ + base NH

OAmide

formationNH2

R998400 R998400 + base middot H+ + Xminus (7)

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

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Advances in

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Analytical ChemistryInternational Journal of

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ElectrochemistryInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

ISRN Organic Chemistry 19

OOHO

O

OH

OOHO NH

O

OH

H

ONH2 R998400

R998400

NaBHX3

R998400 can be alkylaromatic carbohydrate

Scheme 14

The alkylation of amines can be complex in that the initialproducts which are also amines can react further to formhigher order amines or under direct alkylation conditionseventually ammonium salts This can be particularly prob-lematic in direct alkylation reactions with very reactive elec-trophiles (sterically eg methyl electronically eg benzylor with special reactivity eg allyl) and with reactive nucle-ophiles As a result direct alkylation is not normally used forthe preparation of amines even though when the reactantsare more sterically hindered as is the case with saccharideamine nucleophiles and moderately hindered electrophilesthe barrier to oversubstitution increases

The reductive amination reaction is widely regarded asthe alkylation method of choice for amines In this methodthe amine first condenses with a carbonyl compound (nor-mally an aldehyde) to give an imine A reducing agent nor-mallyNaBH

4 NaCNBH

3 orNa(OAc)

3BH reduces the imine

to give the amine product The reaction is best carried outunder mildly acidic conditions Overalkylation can be mini-mised by this method but in fact it is still often seen to agreater or lesser extent (see below) But quaternisation toform ammonium salts cannot occur under these conditionsand neither can O-alkylation to form ethers and these aredefinite advantages over a direct alkylation method

61 Reductive Amination A standard procedure for the pre-paration of N-alkylated derivatives of chitosan by reductiveamination has been widely used over the years (Scheme 14)[136]

Even here though overalkylation occurs and prod-ucts with homogeneous structures are often not obtainedDepending on the ratio of GlcNaldehyde used the polysac-charide products were composed of mixtures of mainlymonoalkylated and unalkylated glucosamines ormainly dial-kylated and monoalkylated glucosamines according to the1HNMR spectra of the products [155]The general procedureis as follows chitosan was dissolved (ie reactions arehomogeneous) in either a mixture (1 1 pH 55) of an alcohol(normally methanol or ethanol) and 1 aq acetic acid or in1 aq acetic acid alone A solution containing the carbonylcompound andNaCNBH

3(7 equiv) was added and the reac-

tion mixture was stirred at room temperature usually untilgel formation was observed (ca 1ndash24 h) The reaction may bestopped by adjustment of the pH to 10 The solid productis then obtained by filtration and washing with methanoland Et

2O Further purification by Soxhlet extraction into

EtOHEt2O (1 1) has also been done in some cases [156 157]

OOHO

O

OH

OOHO N

O

OH

H

ONH2 R998400

R998400

Scheme 15

When no alcohol cosolvent is added the reaction takes placein essentially aqueous solution The role of the alcohol is tosolubilise the aldehyde component which can often behydrophobic

This procedure has been used with many different car-bonyl components including reducing monosaccharidesdisaccharides ketosugars other oxidised sugars and noncar-bohydrate carbonyls [136] Aldehydes bearing straight-chainalkyl groups with chain lengths from C

3ndashC12have been used

[155] Chitosan underwent N-alkylation under reductiveamination conditions with benzylic (heterocyclic) aldehydesfurfural methylfurfural pyridine-3-carboxaldehyde and soforth The DS of the products was between 030 and 043and the broad 1H NMR spectra showed two sets of signalspresumably due to the monoalkylated and the unalkylatedglucosamines [156] Chitosan underwent N-alkylation byreductive amination with aliphatic aldehydes C

2ndashC12

(01 to1 equiv) to give products with DS between 003 and 03and with twelve substituted benzaldehydes (1 equiv) to giveproducts with DS between 02 and 05 [157] A fluorescencelabel was installed into chitosan by the reductive aminationmethod with 9-anthraldehyde as the carbonyl componentaiming for very low DS (values between 000001 and 001)[158]

62 Imine Formation Imines the C=N intermediates in thereductive amination procedure are liable to hydrolysemdashtheirformation is reversible This is clearly a disadvantage whendesigning a stable product but in cases where the reversibleformation of semistable covalent compounds is beneficial insupramolecular chemistry for example imines can be usefulcompoundsThe conversion of chitosan into imines (withoutreduction Scheme 15) has been investigated in solution (togive products with DS of ca 09) and under heterogeneousconditions on prespun polysaccharide fibres (to give productswith DS of 09ndash10) [159] Typical conditions for imine forma-tion under homogeneous conditions are as follows chitosan

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

20 ISRN Organic Chemistry

OOHO

O

OH

OOHO

O

OH

NH2+N

Scheme 16

was dissolved in a mixture of 2 aq AcOH and methanoland a solution of the aldehyde in methanol was added Thismixture was left overnight and then the imine (a solidgel)was then purified by filtration and washing with methanolImine formation on prespun chitosan fibres was simplycarried out by suspending the fibres in methanol and addingthe aldehydes and after the mixture had been left overnightthe derivatised fibres were washed with methanol

63 Formation of Quaternary Ammonium Salts Repeatedalkylation of the free amine base of chitosan eventually givesquaternary salts (Scheme 16) According to a very recentreview covering the formation of quaternary salts (quaterni-sation) of chitosan [160] better synthetic routes that do notrequire the use of dangerous alkylating agents still need to bedeveloped

Much research into the quaternisation of chitosan hasfocussed on trimethyl derivatives [161] In this transforma-tion the chitosan nitrogen must act as a nucleophile attack-ing an alkylating agent (methylating agent) three times Theoxygen nucleophiles in chitosan (ie OH-3 and OH-6) couldalso be alkylated in a potential undesired side processThe pHof the reaction mixture can affect the rate and outcome ofthe reaction When no base is added the basic nitrogens inthe starting material and partially alkylated products will beprotonated decreasing their nucleophilicity and resulting inproducts with low DS But under basic conditions O-alkylation could become problematic

The methylation of chitosan with the aim of tri-N-meth-ylation to form the quaternary ammonium salt without con-comitantO-methylation has been investigated in some detail[162] and errors in a published method [163] were foundThus when alkylation was carried out with MeI and NaOHin 1-methyl-2-pyrrolidinone at 60∘C the major product wasfound to be the dialkylated product (ie the tertiary amine)and significant quaternisation did not occur A polysaccha-ride with a DSquat of 07 was obtained in a two-step procedurein which the initial product (containing the NN-dialkylatedmaterial as its major component) was isolated and thenresubjected to the same reaction conditions But for higherDSquat values looking towards complete quaternisation con-comitant O-alkylation started to become significant

A recent paper describes how a change of solvent can sup-press O-methylation enabling a one-pot synthesis of essen-tially uniform (DS ca 09) quaternised trimethyl chitosan[161] In this approach DMFH

2O (1 1) was used as solvent

and several separate additions of NaOH andMeI were neces-sary for complete quaternisation to be achieved Purification

OOHO

O

OH

OOHO NH

O

OH

O

NH2

R998400

Scheme 17

of the products was achieved by precipitation ion exchangeand dialysis

A two-step approach to the synthesis of quaternised chi-tosan using reductive amination followed by alkylation opensthe possibility of installing two different R groups onto thenitrogen atoms [164] The reductive amination procedurewas carried out essentially as described above Subsequentlyalkylation was carried out with MeI and NaOH in NMP assolvent and purification was by precipitation from acetoneThe chitosan derivatives obtained by this method were foundelectrochemically to have DSquat values between 08 and 09

64 Acylation (Amide Formation) Theacylation of amines togive amides (Scheme 17) is a very well investigated reactiondue to its importance in peptide synthesis Here I am cover-ing the reaction of polysaccharide amines with nonpolysac-charide acylating agents to give amides [165 166] the relatedamide-forming reactions between polysaccharide carboxylicacid (uronic acid) derivatives and nonpolysaccharide aminesfollowing similar principles are covered above The reactionmay be carried out (in water or alcohol solvents) usingacylating agents such as acyl chlorides or acid anhydridesor using carboxylic acids and dehydrating agents It can bebeneficial to use a reactive O-nucleophile such as watermethanol or ethanol as solvent or cosolvent so as to suppressO-acylation of the polysaccharide a possible side-reactionthat can occur when a polar aprotic solvent (such as DMFNMP) is used

ChitosanwasN-acylated under homogeneous conditionsin solution in 1 aqAcOHandmethanol (1 1) using differentcarboxylic anhydrides as acylating agents [167] A solution ofthe anhydride in methanol was added to the chitosan solu-tion and the reaction was quenched after 15min by pouringinto ammonia solution (7 3 vv) The precipitated polysac-charides were filtered and washed with methanol and etherThe DS values of the products were determined by titrationto be lt05

Chitosan was also shown to undergo N-acylation underheterogeneous conditions Fibres of the polysaccharide weresuspended in methanol and a carboxylic acid anhydride (5equiv acetic propionic butyric or hexanoic anhydride) wasadded The mixture was shaken at 40∘C for 24 h and thenthe derivatised fibres were washed with methanol The DS ofthe products were between 065 and 085 as determined byelemental analysis [168]

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

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Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ElectrochemistryInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

ISRN Organic Chemistry 21

O

O

OH

OH

O

(a)

O

O

O

OH

(b)

O

O

O

(c)

Figure 4 Unsaturated derivatives (a) 56-Unsaturated (enol ether) (b) 23-unsaturated (alkene) (c) 23-unsaturated pentose derivative

OO

AcO OAc

O

I

OOHO OH

O(i) Elimination (DBU)

(ii) Deacetylation (NaOMe)

Scheme 18

7 Unsaturated Derivatives

Polysaccharide derivatives inwhich themonosaccharide con-stituents contain C=C double bonds have been preparedThese C=C double bonds represent unusual types of func-tional groups in polysaccharides

Cellulose derivatives of this type have been termed cellu-losenes [5] and they should be classified as one of two types-enol ethers or alkenesmdashdepending onwhether one of the car-bons of the C=C double bond is directly bonded to an oxygenor not (Figure 4) The enol ether and alkene types of unsat-urated polysaccharides may be expected to have differentproperties and reactivities 56-Cellulosene is unsaturatedbetween C-5 and C-6 it is formed by simple elimination(ie a formal elimination of water from cellulose) and theC=C double bond is part of an enol ether In 23-celluloseneunsaturated between C-2 and C-3 the C=C double bondrepresents an alkene (olefin) functionality and must beformed by a reductive elimination from cellulose

Some similar unsaturated derivatives of other polysaccha-rides have been synthesised Xylan and amylose two morecommon (1ndash4)-linked polysaccharides have both been trans-formed into their 23-unsaturated olefinic derivatives The56-unsaturated (enol ether) derivative of amylose has alsobeen investigatedmdashof course as xylose is built up of pentosemonomers a corresponding 56-unsaturated derivative ofthis polysaccharide cannot exist

Further possibilities for both the enol ether and alkenetypes of unsaturated polysaccharide can be envisaged For (1ndash6)-linked structures olefinic unsaturation in the ring couldbe located either between C-2 and C-3 or between C-3 and C-4 although the regioselective synthesis of such compoundsmay not be straightforward In (1ndash3)-linked pyranose-basedpolysaccharides an alkene structure is impossible as all ofC-1 C-3 and C-5 must bear an oxygen atom (1ndash2)-Linkedpyranose-based polysaccharides are not common

For both simple elimination and reductive eliminationreactions stereoelectronic factors are important It will nor-mally be necessary for the two groups that will undergothe elimination reaction to adopt an antiperiplanar or syn-periplanar relationship Free rotation about the exocyclic

C-5ndashC-6 bond should allow a favourable conformation to bereached in the synthesis of 56-unsaturated polysaccharidesFor the synthesis of compounds with endocyclic unsatura-tion though the stereochemistry of the hydroxyl groups inthe pyranose ring can be important

71 56-Unsaturated Derivatives As stated above the formaloverall process for the synthesis of an enol-ether-basedunsaturated derivative of a polysaccharide is elimination ofwater For 56-unsaturated derivatives this means eliminationof water across C-5 and C-6 In a two-step process OH-6 isconverted into a good leaving group and then treatment witha basewill promote the elimination reaction Processes for theregioselective conversion of OH-6 into a good leaving groupare quite well described (see the section on nucleophilicsubstitution above) It is well known that nucleophilic sub-stitution reactions can compete with basic eliminations Suchcompeting processes are typically minimised by using a non-nucleophilic (eg sterically hindered) baseHowever in poly-saccharide systems when the polysaccharide is unprotectedany base could deprotonate the free hydroxyl groups in thepyranose rings to generate intramolecular nucleophiles thatcould attack the carbon bearing the leaving group to forma new ring The undesired intramolecular cyclisation of O-3 onto C-6 in particular has been a problem in the synthesisof 56-cellulosene

A solution to this problem has been reported in a synthe-sis of 56-cellulosene that gave aDS as high as 07 (Scheme 18)HI was eliminated from 23-di-O-acetyl-6-deoxy-6-iodocel-lulose by treatment with DBU [169] DBU is a strong non-nucleophilic base that is able to induce elimination withoutacting as a nucleophile on C-6 or removing the acetate pro-tection from O-2 or O-3 The acetates were subsequentlycleaved by methoxide treatment to give the unprotectedpolysaccharide derivative

72 23-Unsaturated Derivatives 23-Unsaturated derivativesof the (1ndash4)-linked polysaccharides cellulose [5] amylose[170] and xylan [170] have all been mentioned in theliterature The stereochemistry at C-2 and C-3 of all these

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

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Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

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Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

22 ISRN Organic Chemistry

OO

OTr

OO O

OOTsO TsO

OTr

OOTsO OTs

O

OO

Zn NaI DMF

Zn NaI DMF

Scheme 19

polysaccharides is the same ie trans diequatorial whichmeans that they may be expected to form 23-unsaturatedpolysaccharides under similar conditions (Scheme 19)

The conversion of amylose into its 23-unsaturated deriva-tive was achieved by the following reaction sequence [170]protection of O-6 as a trityl ether conversion of O-2 andO-3 into tosylates reductive elimination with zinc andsodium iodide Xylan was converted into the correspondingunsaturated polysaccharide following a similar sequenceThereactivity of the alkene functionality was also briefly investi-gated undergoing dibromination or hydrogenation [170]

The number of published methods for the synthesisof alkene-containing polysaccharides by reductive elimina-tion is limited but studies of similar reactions on simplermonosaccharide systems can be relevant for the furtherdevelopment of this chemistry A one-step procedure [171] toconvert pyranoside 23-diols into alkenes seems particularlyrelevant Treatment of the diols with chlorodiphenylphos-phine iodine and imidazole (reflux 1 h) gave 23-unsaturatedderivatives in 75ndash89 yields starting from glucose (23-trans) derivatives and in 52 yield from a mannose (23-cis)derivative Alternatively vic-diols were first converted intovic-halocarboxylates which were then treated with a reduc-ing agent such as zinc [172 173] or NaSH [174] to give thealkenes The reductive elimination step can be easier forfuranoside than pyranoside substrates [174]

8 Concluding Remarks

Aswell as summarising the achievements in this field also thegaps are highlighted and this will hopefully inspire furtherdevelopments Many of the methods that have been devel-oped for the modification of polysaccharides are inefficientand wasteful as stoichiometric amounts of waste productsmay be formed and several stepsmay be requiredTheuse of arenewable resource loses a lot of its meaning and significanceif it must undergo many manipulations with nonrenewablematerials before reaching its final goal Thus future researchin this area would do well to focus on catalytic transforma-tions

References

[1] M Yalpani ldquoA survey of recent advances in selective chemicaland enzymic polysaccharide modificationsrdquo Tetrahedron vol41 no 15 pp 2957ndash3020 1985

[2] A Corma S Iborra and A Velty ldquoChemical routes for thetransformation of biomass into chemicalsrdquo Chemical Reviewsvol 107 no 6 pp 2411ndash2502 2007

[3] S Van de Vyver J Geboers P A Jacobs and B F Sels ldquoRecentadvances in the catalytic conversion of celluloserdquo Chem-CatChem vol 3 no 1 pp 82ndash94 2011

[4] A G Cunha and A Gandini ldquoTurning polysaccharides intohydrophobic materials a critical review Part 2 Hemicelluloseschitinchitosan starch pectin and alginatesrdquo Cellulose vol 17no 6 pp 1045ndash1065 2010

[5] T L Vigo and N Sachinvala ldquoDeoxycelluloses and relatedstructuresrdquo Polymers for Advanced Technologies vol 10 no 6pp 311ndash320 1999

[6] T Heinze and T Liebert ldquoUnconventional methods in cellulosefunctionalizationrdquo Progress in Polymer Science vol 26 no 9 pp1689ndash1762 2001

[7] T Liebert and T Heinze ldquoInteraction of ionic liquids wlth poly-saccharides 5 Solvents and reaction media for the modificationof celluloserdquo BioResources vol 3 no 2 pp 576ndash601 2008

[8] M Gericke P Fardim and T Heinze ldquoIonic liquids-promisingbut challenging solvents for homogeneous derivatization of cel-luloserdquoMolecules vol 17 no 6 pp 7458ndash7502 2012

[9] S Murugesana and R J Linhardt ldquoIonic liquids in carbohy-drate chemistry-current trends and future directionsrdquo CurrentOrganic Synthesis vol 2 no 4 pp 437ndash451 2005

[10] A W T King J Asikkala I Mutikainen P Jarvi and I Kilpe-lainen ldquoDistillable acid-base conjugate ionic liquids for cellu-lose dissolution and processingrdquo Angewandte Chemie Interna-tional Edition vol 50 no 28 pp 6301ndash6305 2011

[11] A Takaragi M Minoda T Miyamoto H Q Liu and L NZhang ldquoReaction characteristics of cellulose in the LiCl13-dimethyl-2-imidazolidinone solvent systemrdquo Cellulose vol 6no 2 pp 93ndash102 1999

[12] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-ben-zylcellulose by the use of nonaqueous cellulose solventsrdquo Jour-nal of Applied Polymer Science vol 29 no 6 pp 2097ndash21091984

[13] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-sub-stituted cellulose ethers by the use of a nonaqueous cellulosesolventrdquo Journal of Applied Polymer Science vol 29 no 12 pp3873ndash3882 1984

[14] A Isogai A Ishizu and J Nakano ldquoPreparation of tri-O-alkyl-celluloses by the use of a nonaqueous cellulose solvent and theirphysical characteristicsrdquo Journal of Applied Polymer Science vol31 no 2 pp 341ndash352 1986

[15] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[16] L Petrus D G Gray and J N BeMiller ldquoHomogeneous alkyla-tion of cellulose in lithium chloridedimethyl sulfoxide solventwith dimsyl sodium activation A proposal for the mechanismof cellulose dissolution in LiClMe

2SOrdquoCarbohydrate Research

vol 268 no 2 pp 319ndash323 1995[17] J Asikkala Acta Universitatis Ouluensis 502 2008[18] M Soderqvist Lindblad and A-C Albertsson ldquoChemical mod-

ification of hemicelluloses and gumsrdquo in Polysaccharides Struc-tural Diversity and Function S Dumitriu Ed p 491 CRCPressNew York NY USA

[19] J N BeMiller and R E Wing ldquoMethyl terminal-4-O-methyl-malto-oligosaccharidesrdquo Carbohydrate Research vol 6 no 2pp 197ndash206 1968

ISRN Organic Chemistry 23

[20] R Pieters R A De Graaf and L P B M Janssen ldquoThe kineticsof the homogeneous benzylation of potato starch in aqueoussolutionsrdquo Carbohydrate Polymers vol 51 no 4 pp 375ndash3812003

[21] T Umemura M Hirakawa Y Yoshida and K Kurita ldquoQuanti-tative protection of chitin by one-step tritylation and benzy-lation to synthesize precursors for chemical modificationsrdquoPolymer Bulletin vol 69 no 3 pp 303ndash312 2012

[22] O Somorin N Nishi S Tokura and J Noguchi ldquoStudies onchitin-2 Preparation of benzyl and benzoylchitinsrdquo PolymerJournal vol 11 no 5 pp 391ndash396 1979

[23] N Teramoto T Motoyama R Yosomiya andM Shibata ldquoSyn-thesis and properties of thermoplastic propyl-etherified amy-loserdquo European Polymer Journal vol 38 no 7 pp 1365ndash13692002

[24] M Shibata R Nozawa N Teramoto and R Yosomiya ldquoSyn-thesis and properties of etherified pullulansrdquo European PolymerJournal vol 38 no 3 pp 497ndash501 2002

[25] K Petzold K Schwikal and T Heinze ldquoCarboxymethyl xylan-synthesis and detailed structure characterizationrdquoCarbohydratePolymers vol 64 no 2 pp 292ndash298 2006

[26] L J Tanghe L B Genung and JWMensch ldquoCellulose acetaterdquoin Methods in Carbohydrate Chemistry Vol III Cellulose R LWhistler Ed pp 193ndash212 Academic Press NewYorkNYUSA1963

[27] C L McCormick and P A Callais ldquoDerivatization of cellulosein lithium chloride and NN-dimethylacetamide solutionsrdquoPolymer vol 28 no 13 pp 2317ndash2323 1987

[28] C Grote and T Heinze ldquoStarch derivatives of high degree offunctionalization 11 studies on alternative acylation of starchwith long-chain fatty acids homogeneously in NN-dimethylacetamideLiClrdquo Cellulose vol 12 no 4 pp 435ndash444 2005

[29] F Belmokaddem C Pinel P Huber M Petit-Conil and DDa Silva Perez ldquoGreen synthesis of xylan hemicellulose estersrdquoCarbohydrate Research vol 346 no 18 pp 2896ndash2904 2011

[30] M Grondahl A Teleman and P Gatenholm ldquoEffect of acety-lation on the material properties of glucuronoxylan from aspenwoodrdquoCarbohydrate Polymers vol 52 no 4 pp 359ndash366 2003

[31] R C Sun J M Fang J Tomkinson and C A S Hill ldquoEster-ification of hemicelluloses from poplar chips in homogenoussolution ofN N-dimethylformamidelithium chloriderdquo Journalof Wood Chemistry and Technology vol 19 no 4 pp 287ndash3061999

[32] T Heinze T F Liebert K S Pfeiffer and M A HussainldquoUnconventional cellulose esters synthesis characterizationand structure-property relationsrdquo Cellulose vol 10 no 3 pp283ndash296 2003

[33] J Wu J Zhang H Zhang J He Q Ren and M Guo ldquoHomo-geneous acetylation of cellulose in a new ionic liquidrdquo Bioma-cromolecules vol 5 no 2 pp 266ndash268 2004

[34] T Heinze K Schwikal and S Barthel ldquoIonic liquids as reactionmedium in cellulose functionalizationrdquo Macromolecular Bio-science vol 5 no 6 pp 520ndash525 2005

[35] J E Sealey G Samaranayake J G Todd and W G GlasserldquoNovel cellulose derivatives IV Preparation and thermal analy-sis of waxy esters of celluloserdquo Journal of Polymer Science B vol34 no 9 pp 1613ndash1620 1996

[36] S N Pawar and K J Edgar ldquoChemical modification of alginatesin organic solvent systemsrdquo Biomacromolecules vol 12 no 11pp 4095ndash4103 2011

[37] M E I Badawy E I Rabea T M Rogge et al ldquoFungicidal andinsecticidal activity of O-acyl chitosan derivativesrdquo PolymerBulletin vol 54 no 4-5 pp 279ndash289 2005

[38] S R Labafzadeh J S Kavakka K Sievanen J Asikkala and IKilpelainen ldquoReactive dissolution of cellulose and pulp throughacylation in pyridinerdquo Cellulose vol 19 no 4 pp 1295ndash13042012

[39] KArai S Sano andH Satoh ldquoPreparation of cellulose stilbene-4-carboxylate and its application to thin-layer chromatogra-phyrdquo Journal ofMaterials Chemistry vol 2 no 12 pp 1257ndash12601992

[40] K Arai and S Sano ldquoPreparation of cellulose 2-methylstilbene-5-carboxylate and photoregulation of its propertiesrdquo Journal ofMaterials Chemistry vol 4 no 2 pp 275ndash278 1994

[41] C M Buchanan N L Buchanan J S Debenham et al ldquoPrep-aration and characterization of arabinoxylan estersrdquo ACS Sym-posium Series vol 864 pp 326ndash346 2004

[42] T Iwata A Fukushima K Okamura and J Azuma ldquoDSC studyon regioselectively substituted cellulose heteroestersrdquo Journal ofApplied Polymer Science vol 65 no 8 pp 1511ndash1515 1997

[43] E Pascu ldquoHalogenationrdquo in Methods in Carbohydrate Chem-istry Vol III Cellulose R L Whistler Ed p 259 AcademicPress New York NY USA 1963

[44] K Rahn M Diamantoglou D Klemm H Berghmans andT Heinze ldquoHomogeneous synthesis of cellulose p-toluenesul-fonates in NN-dimethylacetamideLiCl solvent systemrdquo Ange-wandte Makromolekulare Chemie vol 238 pp 143ndash163 1996

[45] S C Fox B Li D Xu and K J Edgar ldquoRegioselective ester-ification and etherification of cellulose a reviewrdquo Biomacro-molecules vol 12 no 6 pp 1956ndash1972 2011

[46] Y Morita Y Sugahara A Takahashi and M Ibonai ldquoPrepa-ration of chitin-p-toluenesulfonate and deoxy(thiocyanato)chitinrdquo European Polymer Journal vol 30 no 11 pp 1231ndash12361994

[47] A F Kolova V P Komar I V Skornyakov A D Virnik R GZhbanov and Z A Rogovin Cellulose Chemistry and Tech-nology vol 12 p 553 1978

[48] GMocanuM Constantin andA Carpov ldquoChemical reactionson polysaccharides 5 Reaction of mesyl chloride with pullu-lanrdquo Die Angewandte Makromolekulare Chemie vol 241 no 1pp 1ndash10 1996

[49] D Klemm T Helme B Philipp and W Wagenbiecht ldquoNewapproaches to advanced polymers by selective cellulose func-tionalizationrdquo Acta Polymerica vol 48 no 8 pp 277ndash297 1997

[50] A Koschella D Fenn N Illy and T Heinze ldquoRegioselectivelyfunctionalized cellulose derivatives a mini reviewrdquo Macro-molecular Symposia vol 244 pp 59ndash73 2006

[51] J W Green ldquoTriphenylmethyl ethersrdquo in Methods in Carbohy-drate Chemistry Vol III Cellulose R L Whistler Ed p 327Academic Press New York NY USA 1963

[52] R LWhistler and S Hirase ldquoIntroduction of 36-anhydro ringsinto amylose and characterization of the productsrdquo Journal ofOrganic Chemistry vol 26 no 11 pp 4600ndash4605 1961

[53] J Holappa T Nevalainen P Soininen et al ldquoN-chloroacyl-6-O-triphenylmethylchitosans useful intermediates for syntheticmodifications of chitosanrdquo Biomacromolecules vol 6 no 2 pp858ndash863 2005

[54] D Klemm and A J Stein ldquoSilylated cellulose materials indesign of supramolecular structures of ultrathin cellulose filmsrdquoJournal ofMacromolecular Science A vol 32 no 4 pp 899ndash9041995

24 ISRN Organic Chemistry

[55] A Koschella and D Klemm ldquoSilylation of cellulose regiocon-trolled by bulky reagents and dispersity in the reaction mediardquoMacromolecular Symposia vol 120 pp 115ndash125 1997

[56] A Koschella T Heinze and D Klemm ldquoFirst synthesis of 3-O-functionalized cellulose ethers via 26-di-O-protected silylcelluloserdquo Macromolecular Bioscience vol 1 no 1 pp 49ndash542001

[57] D Klemm B Heublein H Fink and A Bohn ldquoCellulose fas-cinating biopolymer and sustainable rawmaterialrdquoAngewandteChemie International Edition vol 44 no 22 pp 3358ndash33932005

[58] D Xu B Li C Tate and K J Edgar ldquoStudies on regioselectiveacylation of cellulose with bulky acid chloridesrdquo Cellulose vol18 no 2 pp 405ndash419 2011

[59] J Zhang JWu Y Cao S Sang J Zhang and J He ldquoSynthesis ofcellulose benzoates under homogeneous conditions in an ionicliquidrdquo Cellulose vol 16 no 2 pp 299ndash308 2009

[60] A Stein and D Klemm ldquoSyntheses of cellulose derivativesvia O-triorganosilyl celluloses 1 Effective synthesis of organiccellulose esters by acylation of trimethylsilyl cellulosesrdquo DieMakromolekulare Chemie Rapid Communications vol 9 no 8pp 569ndash573 1988

[61] A Koschella T Leermann M Brackhagen and T HeinzeldquoStudy of sulfonic acid esters from 1rarr 4- 1rarr 3- and 1rarr 6-linked polysaccharidesrdquo Journal of Applied Polymer Science vol100 no 3 pp 2142ndash2150 2006

[62] R Dicke K Rahn V Haack and T Heinze ldquoStarch derivativesof high degree of functionalization Part 2 Determination ofthe functionalization pattern of p-toluenesulfonyl starch byperacylation and NMR spectroscopyrdquo Carbohydrate Polymersvol 45 no 1 pp 43ndash51 2001

[63] D M Clode and D Horton ldquoPreparation and characterizationof the 6-aldehydo derivatives of amylose and whole starchrdquoCarbohydrate Research vol 17 no 2 pp 365ndash373 1971

[64] J Ren P Wang F Dong Y Feng D Peng and Z GuoldquoSynthesis and antifungal properties of 6-amino-6-deoxyinulina kind of precursors for facile chemical modifications of inulinrdquoCarbohydrate Polymers vol 87 no 2 pp 1744ndash1748 2012

[65] H N Cheng and Q M Gu ldquoEnzyme-catalyzed modificationsof polysaccharides and poly(ethylene glycol)rdquo Polymers vol 4no 2 pp 1311ndash1330 2012

[66] F F Bruno J A Akkara M Ayyagari et al ldquoEnzymatic mod-ification of insoluble amylose in organic solventsrdquo Macromole-cules vol 28 no 26 pp 8881ndash8883 1995

[67] J Xie and Y Hsieh ldquoEnzyme-catalyzed transesterification ofvinyl esters on cellulose solidsrdquo Journal of Polymer Science Avol 39 no 11 pp 1931ndash1939 2001

[68] S Chakraborty B Sahoo I Teraoka L M Miller and R AGross ldquoEnzyme-catalyzed regioselective modification of starchnanoparticlesrdquoMacromolecules vol 38 no 1 pp 61ndash68 2005

[69] A Alissandratos N Baudendistel S L Flitsch B Hauer andP J Halling ldquoLipase-catalysed acylation of starch and determi-nation of the degree of substitution by methanolysis and GCrdquoBMC Biotechnology vol 10 p 82 2010

[70] K Yang and Y J Wang ldquoLipase-catalyzed cellulose acetylationin aqueous and organic mediardquo Biotechnology Progress vol 19no 6 pp 1664ndash1671 2003

[71] K Yang Y J Wang and M I Kuo ldquoEffects of substrate pre-treatment and water activity on lipase-catalyzed cellulose acety-lation in organic mediardquo Biotechnology Progress vol 20 no 4pp 1053ndash1061 2004

[72] A Rajan V S Prasad andT E Abraham ldquoEnzymatic esterifica-tion of starch using recovered coconut oilrdquo International Journalof BiologicalMacromolecules vol 39 no 4-5 pp 265ndash272 2006

[73] A Rajan and T E Abraham ldquoEnzymatic modification of cas-sava starch by bacterial lipaserdquo Bioprocess and Biosystems Engi-neering vol 29 no 1 pp 65ndash71 2006

[74] A Rajan J D Sudha and T E Abraham ldquoEnzymatic modifi-cation of cassava starch by fungal lipaserdquo Industrial Crops andProducts vol 27 no 1 pp 50ndash59 2008

[75] V Sereti H Stamatis E Koukios and F N Kolisis ldquoEnzymaticacylation of cellulose acetate in organic mediardquo Journal of Bio-technology vol 66 no 2-3 pp 219ndash223 1998

[76] C Altaner B Saake M Tenkanen et al ldquoRegioselective deacet-ylation of cellulose acetates by acetyl xylan esterases of differentCE-familiesrdquo Journal of Biotechnology vol 105 no 1-2 pp 95ndash104 2003

[77] R S Tipson ldquoSulfonic esters of carbohydratesrdquo Advances inCarbohydrate Chemistry vol 8 pp 180ndash215 1953

[78] JW H Oldham and J K Rutherford ldquoThe alkylation of aminesas catalyzed bynickelrdquo Journal of theAmericanChemical Societyvol 54 no 1 pp 306ndash312 1932

[79] S S Shaik ldquoThe 120572- and 120573-carbon substituent effect on SN2reactivity A valence-bond approachrdquo Journal of the AmericanChemical Society vol 105 no 13 pp 4359ndash4367 1983

[80] K Petzold-Welcke N Michaelis and T Heinze ldquoUnconven-tional cellulose products through nucleophilic displacementreactionsrdquoMacromolecular Symposia vol 280 no 1 pp 72ndash852009

[81] P R Skaanderup C S Poulsen L Hyldtoft M R Joslashrgensenand R Madsen ldquoRegioselective conversion of primary alcoholsinto iodides in unprotected methyl furanosides and pyrano-sidesrdquo Synthesis no 12 pp 1721ndash1727 2002

[82] A L Cimecioglu D H Ball D L Kaplan and S H HuangldquoPreparation of 6-O-acyl amylose derivativesrdquo in Proceedings ofthe MRS Symposium pp 7ndash12 December 1993

[83] D H Ball B J Wiley and E T Reese ldquoEffect of substitution atC-6 on the susceptibility of pullulan to pullulanases Enzymaticdegradation of modified pullulansrdquo Canadian Journal of Micro-biology vol 38 no 4 pp 324ndash327 1992

[84] H Tseng K Takechi and K Furuhata ldquoChlorination of chitinwith sulfuryl chloride under homogeneous conditionsrdquo Carbo-hydrate Polymers vol 33 no 1 pp 13ndash18 1997

[85] M Sakamoto H Tseng and K Furuhata ldquoRegioselective chlo-rination of chitin with N-chlorosuccinimide-triphenylphos-phine under homogeneous conditions in lithium chloride-NN-dimethylacetamiderdquo Carbohydrate Research vol 265 no 2 pp271ndash280 1994

[86] K Furuhata N Aoki S SuzukiM Sakamoto Y Saegusa and SNakamura ldquoBromination of cellulose with tribromoimidazoletriphenylphosphine and imidazole under homogeneous condi-tions in LiBr-dimethylacetamiderdquo Carbohydrate Polymers vol26 no 1 pp 25ndash29 1995

[87] K-I Furuhata K Koganei H-S Chang N Aoki andM Saka-moto ldquoDissolution of cellulose in lithium bromide-organic sol-vent systems and homogeneous bromination of cellulose withN-bromosuccinimide-triphenylphosphine in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 230 no1 pp 165ndash177 1992

[88] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

ISRN Organic Chemistry 25

[89] H Tseng K Furuhata and M Sakamoto ldquoBromination ofregenerated chitin with N-bromosuccinimide and triphenyl-phospine under homogeneous conditions in lithium bromide-NN-dimethylacetamiderdquo Carbohydrate Research vol 270 no2 pp 149ndash161 1995

[90] T Hasegawa M Umeda M Numata et al ldquolsquoClick chemistryrsquoon polysaccharides a convenient general and monitorableapproach to develop (1rarr 3)-120573-d-glucans with various func-tional appendagesrdquo Carbohydrate Research vol 341 no 1 pp35ndash40 2006

[91] G N Smirnova L S Golrsquobraikh A I Polyakov and Z ARogovin ldquoSynthesis of 2 3-anhydro-6-O-tritylcelluloserdquoChem-istry of Natural Compounds vol 2 no 1 pp 1ndash3 1966

[92] S Immel K Fujita H J Lindner Y Nogami and F W Licht-enthaler ldquoStructure and lipophilicity profile of 23-anhydro-120572-cyclomannin and its ethanol inclusion complexrdquo Chemistry Avol 6 no 13 pp 2327ndash2333 2000

[93] Z A Rogovin and T V Vladimirov Chimiceskaja Nauka i Pro-myslennost vol 2 p 527 1957

[94] Z A Rogovin and T V Vladimirov Chemical Abstracts vol 52p 4167 1958

[95] T R Ingle and R L Whistler ldquo36-anhydroamylose by nucle-ophilic displacementrdquo in Methods in Carbohydrate ChemistryVol 5 General Polysaccharides R L Whistler Ed p 411 Aca-demic Press New York NY USA 1963

[96] I Cumpstey J Frigell E Pershagen et al ldquoAmine-linkeddiglycosides synthesis facilitated by the enhanced reactivity ofallylic electrophiles and glycosidase inhibition assaysrdquo BeilsteinJournal of Organic Chemistry vol 7 pp 1115ndash1123 2011

[97] T Heinze A Koschella M Brackhagen J Engelhardt and KNachtkamp ldquoStudies on non-natural deoxyammonium cellu-loserdquoMacromolecular Symposia vol 244 pp 74ndash82 2006

[98] C Liu and H Baumann ldquoExclusive and complete introductionof amino groups and their N-sulfo and N-carboxymethylgroups into the 6-position of cellulose without the use of pro-tecting groupsrdquoCarbohydrate Research vol 337 no 14 pp 1297ndash1307 2002

[99] Y Matsui J Ishikawa H Kamitakahara T Takano and F Nak-atsubo ldquoFacile synthesis of 6-amino-6-deoxycelluloserdquo Carbo-hydrate Research vol 340 no 7 pp 1403ndash1406 2005

[100] T Takano J IshikawaHKamitakahara and FNakatsubo ldquoTheapplication of microwave heating to the synthesis of 6-amino-6-deoxycelluloserdquo Carbohydrate Research vol 342 no 16 pp2456ndash2460 2007

[101] C Xiao D Lu S Xu and L Huang ldquoTunable synthesis ofstarch-poly(vinyl acetate) bioconjugaterdquo Starch-Starke vol 63no 4 pp 209ndash216 2011

[102] G Zampano M Bertoldo and F Ciardelli ldquoDefined chitosan-based networks by C-6-azide-alkyne ldquoclickrdquo reactionrdquo Reactiveand Functional Polymers vol 70 no 5 pp 272ndash281 2010

[103] A L Cimecioglu D H Ball S H Huang and D L Kaplan ldquoAdirect regioselective route to 6-azido-6-deoxy polysaccharidesundermild and homogeneous conditionsrdquoMacromolecules vol30 no 1 pp 155ndash156 1997

[104] J Shey K M Holtman R Y Wong et al ldquoThe azidation ofstarchrdquoCarbohydrate Polymers vol 65 no 4 pp 529ndash534 2006

[105] S Knaus U Mais and W H Binder ldquoSynthesis characteriza-tion and properties of methylaminocelluloserdquo Cellulose vol 10no 2 pp 139ndash150 2003

[106] C Liu and H Baumann ldquoNew 6-butylamino-6-deoxycelluloseand 6-deoxy-6-pyridiniumcellulose derivatives with highest

regioselectivity and completeness of reactionrdquo CarbohydrateResearch vol 340 no 14 pp 2229ndash2235 2005

[107] G R Saad and K-I Furuhata ldquoDielectric study of 120573-relaxationin some cellulosic substancesrdquoPolymer International vol 41 no3 pp 293ndash299 1996

[108] A Koschella and T Heinze ldquoNovel regioselectively 6-function-alized cationic cellulose polyelectrolytes prepared via cellulosesulfonatesrdquoMacromolecular Bioscience vol 1 no 5 pp 178ndash1842001

[109] N Aoki K Koganei H Chang K Furuhata andM SakamotoldquoGas chromatographic-mass spectrometric study of reactions ofhalodeoxycelluloses with thiols in aqueous solutionsrdquo Carbohy-drate Polymers vol 27 no 1 pp 13ndash21 1995

[110] N Aoki K Furuhata Y Saegusa S Nakamura and M Saka-moto ldquoReaction of 6-bromo-6-deoxycellulose with thiols inlithium bromide-NN-dimethylacetamiderdquo Journal of AppliedPolymer Science vol 61 no 7 pp 1173ndash1185 1996

[111] G Wenz P Liepold and N Bordeanu ldquoSynthesis and SAMformation of water soluble functional carboxymethylcellulosesthiosulfates and thioethersrdquo Cellulose vol 12 no 1 pp 85ndash962005

[112] N Aoki K Fukushima H Kurakata M Sakamoto and KFuruhata ldquo6-Deoxy-6-mercaptocellulose and its S-substitutedderivatives as sorbents for metal ionsrdquo Reactive and FunctionalPolymers vol 42 no 3 pp 223ndash233 1999

[113] G R Saad and K Furuhata ldquoEffect of substituents on dielectric120573-relaxation in celluloserdquo Polymer International vol 42 no 4pp 356ndash362 1997

[114] D Horton and D H Hutson ldquoDevelopments in the chemistryof thio sugarsrdquo Advances in Carbohydrate Chemistry C vol 18pp 123ndash199 1963

[115] D Trimnell E I Stout W M Doane and C R Russel ldquoPrepa-ration of starch 2-hydroxy-3-mercaptopropyl ethers and theiruse in graft polymerizationsrdquo Journal of Applied Polymer Sci-ence vol 22 no 12 pp 3579ndash3586 1978

[116] EMentasti C SarzaniniM C Gennaro andV Porta ldquoNitrilo-triacetic acid thiourea and cysteine ligands immobilized oncellulose for the uptake of trace metal ionsrdquo Polyhedron vol 6no 6 pp 1197ndash1202 1987

[117] I Cumpstey ldquoNeodisaccharide diglycosyl compounds ethersthioethers and selenoethers A survey of their synthesis andbiological activityrdquo Comptes Rendus Chimie vol 14 no 2-3 pp274ndash285 2011

[118] V Fourniere and I Cumpstey ldquoSynthesis of non-glycosidicallylinked selenoether pseudodisaccharidesrdquo Tetrahedron Lettersvol 51 no 16 pp 2127ndash2129 2010

[119] K A Kristiansen A Potthast and B E Christensen ldquoPeriodateoxidation of polysaccharides for modification of chemical andphysical propertiesrdquo Carbohydrate Research vol 345 no 10 pp1264ndash1271 2010

[120] S Coseri G Biliuta B C Simionescu K Stana-Kleinschek VRibitsch and V Harabagiu ldquoOxidized cellulose-Survey of themost recent achievementsrdquo Carbohydrate Polymers 2012

[121] Van Bekkum ldquoStudies on selective carbohydrate oxidationrdquo inCarbohydrates as Organic Raw Materials F Lichtenthaler Edp 289 VCH Weinheim Germany 1990

[122] G O Aspinall and A Nicolson ldquoPaper 505 The catalyticoxidation of European larch 120576-galactanrdquo Journal of the ChemicalSociety pp 2503ndash2507 1960

[123] D L Verraest J A Peters and H Van Bekkum ldquoThe platinum-catalyzed oxidation of inulinrdquo Carbohydrate Research vol 306no 1-2 pp 197ndash203 1998

26 ISRN Organic Chemistry

[124] G O Aspinall ldquoReduction of uronic acids in polysaccharidesrdquoin Methods in Carbohydrate Chemistry Vol 5 General Polysac-charides R L Whistler Ed p 397 Academic Press New YorkNY USA 1963

[125] A E J de Nooy A C Besemer and H van Bekkum ldquoHighlyselective tempo mediated oxidation of primary alcohol groupsin polysaccharidesrdquo Recueil des Travaux Chimiques des Pays-Bas vol 113 no 3 pp 165ndash166 1994

[126] A E J De Nooy A C Besemer and H Van Bekkum ldquoHighlyselective nitroxyl radical-mediated oxidation of primary alco-hol groups in water-soluble glucansrdquo Carbohydrate Researchvol 269 no 1 pp 89ndash98 1995

[127] P S Chang and J F Robyt ldquoOxidation of primary alcoholgroups of naturally occurring polysaccharides with 2266-tetramethyl-1-piperidine oxoammonium ionrdquo Journal of Carbo-hydrate Chemistry vol 15 no 7 pp 819ndash830 1996

[128] A Isogai and Y Kato ldquoPreparation of polyuronic acid from cel-lulose by TEMPO-mediated oxidationrdquo Cellulose vol 5 no 3pp 153ndash164 1998

[129] R A A Muzzarelli C Muzzarelli A Cosani and M Terbo-jevich ldquo6-Oxychitins novel hyaluronan-like regiospecificallycarboxylated chitinsrdquo Carbohydrate Polymers vol 39 no 4 pp361ndash367 1999

[130] P L Bragd A C Besemer and H Van Bekkum ldquoBromide-free TEMPO-mediated oxidation of primary alcohol groupsin starch and methyl 120572-d-glucopyranosiderdquo CarbohydrateResearch vol 328 no 3 pp 355ndash363 2000

[131] K Maurer and G Drefahl ldquoOxydationen mit stickstoffdioxydI Mitteil die Darstellung von glyoxylsaure glucuronsaureund galakturonsaurerdquo Berichte der Deutschen ChemischenGesellschaft vol 75 no 12 pp 1489ndash1491 1942

[132] E C Yackel and W O Kenyon ldquoThe oxidation of cellulose bynitrogen dioxiderdquo Journal of the American Chemical Society vol64 no 1 pp 121ndash127 1942

[133] K Parikka and M Tenkanen ldquoOxidation of methyl 120572-d-gal-actopyranoside by galactose oxidase products formed and opti-mization of reaction conditions for production of aldehyderdquoCarbohydrate Research vol 344 no 1 pp 14ndash20 2009

[134] K Parikka A -S Leppanen L Piktanen M Reunanen SWill-for and M Tenkanen ldquoOxidation of polysaccharides by galac-tose oxidaserdquo Journal of Agricultural and Food Chemistry vol58 no 1 pp 262ndash271 2010

[135] E Frollini W F Reed M Milas and M Rinaudo ldquoPolyelec-trolytes from polysaccharides selective oxidation of guar gum-a revisited reactionrdquo Carbohydrate Polymers vol 27 no 2 pp129ndash135 1995

[136] M Yalpani and L D Hall ldquoSome chemical and analyti-cal aspects of polysaccharide modifications 3 Formation ofbranched-chain soluble chitosan derivativesrdquo Macromoleculesvol 17 no 3 pp 272ndash281 1984

[137] S Dumitriu Polysaccharides Structural Diversity and Func-tional Versatility Marcel Dekker New York NY USA 2005

[138] J Yang Y Xie andWHe ldquoResearch progress on chemicalmod-ification of alginate a reviewrdquo Carbohydrate Polymers vol 84no 1 pp 33ndash39 2011

[139] M D Cathell J C Szewczyk and C L Schauer ldquoOrganicmodification of the polysaccharide alginaterdquo Mini-Reviews inOrganic Chemistry vol 7 no 1 pp 61ndash67 2010

[140] S Pelletier P Hubert F Lapicque E Payan and E DellacherieldquoAmphiphilic derivatives of sodium alginate and hyaluronatesynthesis and physico-chemical properties of aqueous dilute

solutionsrdquo Carbohydrate Polymers vol 43 no 4 pp 343ndash3492000

[141] C S Pappas AMalovikova Z Hromadkova P A Tarantilis AEbringerova andM G Polissiou ldquoDetermination of the degreeof esterification of pectinates with decyl and benzyl ester groupsby diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS) and curve-fitting deconvolution methodrdquo Carbohy-drate Polymers vol 56 no 4 pp 465ndash469 2004

[142] G A Morris Z Hromadkova A Ebringerova A MalovikovaJ Alfoldi and S E Harding ldquoModification of pectin with UV-absorbing substitutents and its effect on the structural andhydrodynamic properties of the water-soluble derivativesrdquoCarbohydrate Polymers vol 48 no 4 pp 351ndash359 2002

[143] J S Yang H B Ren and Y J Xie ldquoSynthesis of amidic alginatederivatives and their application in microencapsulation of 120582-cyhalothrinrdquo Biomacromolecules vol 12 no 8 pp 2982ndash29872011

[144] F Vallee C Muller A Durand et al ldquoSynthesis and rheologicalproperties of hydrogels based on amphiphilic alginate-amidederivativesrdquoCarbohydrate Research vol 344 no 2 pp 223ndash2282009

[145] A Synytsya J CopikovaMMarounek et al ldquoPreparation ofN-alkylamides of highly methylated (HM) citrus pectinrdquo CzechJournal of Food Sciences vol 21 pp 162ndash166 2003

[146] A Sinitsya J Copikova V Prutyanov S Skoblya andVMacho-vic ldquoAmidation of highly methoxylated citrus pectin with pri-mary aminesrdquo Carbohydrate Polymers vol 42 no 4 pp 359ndash368 2000

[147] A Synytsya J Copikova M Marounek et al ldquoN-octadecyl-pectinamide a hydrophobic sorbent based on modification ofhighly methoxylated citrus pectinrdquo Carbohydrate Polymers vol56 no 2 pp 169ndash179 2004

[148] I Ugi ldquoRecent progress in the chemistry of multicomponentreactionsrdquo Pure and Applied Chemistry vol 73 no 1 pp 187ndash191 2001

[149] J P Zhu ldquoRecent developments in the isonitrile-based multi-component synthesis of heterocyclesrdquo European Journal ofOrganic Chemistry no 7 pp 1133ndash1144 2003

[150] P Slobbe E Ruijter and R V A Orru ldquoRecent applications ofmulticomponent reactions in medicinal chemistry rdquoMedicinalChemistry Communications vol 3 pp 1189ndash1218 2012

[151] R V A Orru and E Ruijter Synthesis of Heterocycles via Multi-component Reactions Springer Berlin Germany 2010

[152] I Ugi R Meyr U Fetzer and C Steinbruckner ldquoVersuche mitIsonitrilenrdquo Angewandte Chemie vol 71 no 11 pp 386ndash3881959

[153] I Ugi and C Steinbruckner ldquoUber ein neues Kondensations-PrinziprdquoAngewandte Chemie vol 72 no 7-8 pp 267ndash268 1960

[154] H Bu A L Kjoslashniksen K D Knudsen and B Nystrom ldquoRhe-ological and structural properties of aqueous alginate duringgelation via the Ugi multicomponent condensation reactionrdquoBiomacromolecules vol 5 no 4 pp 1470ndash1479 2004

[155] J Desbrieres C Martinez and M Rinaudo ldquoHydrophobicderivatives of chitosan characterization and rheological behav-iourrdquo International Journal of Biological Macromolecules vol 19no 1 pp 21ndash28 1996

[156] M E I Badawy ldquoChemical modification of chitosan synthesisand biological activity of new heterocyclic chitosan derivativesrdquoPolymer International vol 57 no 2 pp 254ndash261 2000

[157] E I Rabea M E I Badawy T M Rogge et al ldquoEnhancemen offungicidal and insecticidal activity by reductive alkylation of

ISRN Organic Chemistry 27

chitosanrdquo Pest Management Science vol 62 no 9 pp 890ndash8972006

[158] K Toslashmmeraas S P Strand W Tian L Kenne and K MVaruma ldquoPreparation and characterisation of fluorescent chi-tosans using 9-anthraldehyde as fluorophorerdquo CarbohydrateResearch vol 336 no 4 pp 291ndash296 2001

[159] S Hirano K Nagamura M Zhang et al ldquoChitosan staplefibers and their chemical modification with some aldehydesrdquoCarbohydrate Polymers vol 38 no 4 pp 293ndash298 1999

[160] D de Britto R C Goy S P C Filho and O B G Assis ldquoQua-ternary salts of chitosan history antimicrobial features andprospectsrdquo International Journal of Carbohydrate Chemistryvol 2011 Article ID 312539 12 pages 2011

[161] V O Runarsson J Holappa S Jonsdottir H Steinsson andM Masson ldquoN-selective ldquoone potrdquo synthesis of highly N-sub-stituted trimethyl chitosan (TMC)rdquoCarbohydrate Polymers vol74 no 3 pp 740ndash744 2008

[162] A B Sieval M Thanou A F Kotze J C Verhoef J Brusseeand H E Junginger ldquoPreparation and NMR characterizationof highly substituted N-trimethyl chitosan chloriderdquo Carbohy-drate Polymers vol 36 no 2-3 pp 157ndash165 1998

[163] P L DungMMilas M Rinaudo and J Desbrieres ldquoWater sol-uble derivatives obtained by controlled chemical modificationsof chitosanrdquo Carbohydrate Polymers vol 24 no 3 pp 209ndash2141994

[164] Z Jia D Shen and W Xu ldquoSynthesis and antibacterial activ-ities of quaternary ammonium salt of chitosanrdquo CarbohydrateResearch vol 333 no 1 pp 1ndash6 2001

[165] S Hirano and Y Yagi ldquoThe effects ofN-substitution of chitosanand the physical form of the products on the rate of hydrolysisby chitinase from Streptomyces griseusrdquo Carbohydrate Researchvol 83 no 1 pp 103ndash108 1980

[166] S Hirano Y Ohe and H Ono ldquoSelective N-acylation ofchitosanrdquo Carbohydrate Research vol 47 no 2 pp 314ndash3201976

[167] K Y Lee W S Ha and W H Park ldquoBlood compatibility andbiodegradability of partially N-acylated chitosan derivativesrdquoBiomaterials vol 16 no 16 pp 1211ndash1216 1995

[168] C Y Choi S B Kim P K PakD I Yoo andY S Chung ldquoEffectof N-acylation on structure and properties of chitosan fibersrdquoCarbohydrate Polymers vol 68 no 1 pp 122ndash127 2007

[169] T Ishii ldquoFacile preparation of deoxyiodocellulose and its con-version into 56-cellulosenerdquo Carbohydrate Research vol 154no 1 pp 63ndash70 1986

[170] D Horton and M H Meshreki ldquoSynthesis of 23-unsaturatedpolysaccharides from amylose and xylanrdquo CarbohydrateResearch vol 40 no 2 pp 345ndash352 1975

[171] Z Liu B Classon and B Samuelsson ldquoA novel route to olefinsfrom vicinal diolsrdquo Journal of Organic Chemistry vol 55 no 14pp 4273ndash4275 1990

[172] B Classon P J Garegg andB Samuelsson ldquoA facile preparationof 2101584031015840-unsaturated nucleosides and hexopyranosides fromacetylated halohydrins by reductive eliminationrdquoActa ChemicaScandinavica B vol 36 p 251 1982

[173] M J Robins J S Wilson D Madej N H Low F Hansskeand S F Wnuk ldquoNucleic acid-related compounds 88 Effi-cient conversions of ribonucleosides into their 2101584031015840-anhydro21015840(and 31015840)-deoxy 2101584031015840-didehydro-2101584031015840-dideoxy and 2101584031015840-dide-oxynucleoside analogsrdquo Journal of Organic Chemistry vol 60no 24 pp 7902ndash7908 1995

[174] L Alvarez de Cienfuegos A J Mota C Rodriguez and R Rob-les ldquoHighly efficient synthesis of 2101584031015840-didehydro-2101584031015840-dide-oxy-120573-nucleosides through a sulfur-mediated reductive 2101584031015840-trans-elimination From iodomethylcyclopropanes to thiiraneanalogsrdquo Tetrahedron Letters vol 46 no 3 pp 469ndash473 2005

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

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