Green Synthesis of Bioactive Phenolics Employing Ionic ...shodhganga.inflibnet.ac.in/.../6/06_introduction.pdf · C-C bond involves styrenes as one of its coupling partner (S cheme

Green Synthesis of…… General Introduction

1

Green Synthesis of Bioactive Phenolics Employing Ionic Liquids and

Microwave Assisted Approaches

“Only when I saw the earth from space, in all its ineffable beauty and fragility, did I realize that

humankind's most urgent task is to cherish and preserve it for future

generations”................................................. Sigmund Jahn, German Cosmonaut

1.1 Introduction:

Nature is a phenomenal repository of an amazing array of structurally and functionally

diverse organic compounds which are useful as drugs, fine chemicals, fragrances, flavors

and biologically active dietary constituents. [Treben (1986); Harborne and Dey (1989);

Albert (1996); Clardy and Walsh (2004)]. For example, compounds like artemisinin,

podophyllotoxin, atropine (Figure 1) etc obtained from different plant parts are reported to

possess various bioactivities such as antimalarial, anticancer and anticholinergic activities.

Among the various natural products, phenolic compounds or more specifically ‘phenolics’

are one of the most ubiquitous groups possessing plethora of biological activities [Harborne

and Dey (1989); Chadwick and Marsh (1990); Ahmad et al. (2006); Crozier et al. (2009)].

For instance, various phenolics like resveratrol (trans-3,4',5-trihydroxystilbene) and DMU-

212 (trans-3,4,4',5-tetramethoxystilbene) have shown potential as therapeutic agents against

various cancer cell lines [Shen et al. (2009)]. Similarly, α-asarone (trans-2,4,5-trimethoxy-

1-phenylpropene) has been recognized as a cardioprotective agent due to its hypolipidemic

activity [Popławski et al. (2000)]. Recently, phenolic derivatives (e.g. chalcones) have been

O

O

H

H

H

O

O

O

Artemisinin(Antimalarial)

OO

O

OHH

H O

H3COOCH3

OCH3

Podophyllotoxin(Anticancer)

Figure 1

O

O

OHN

Atropine(Anticholinergic)


2

reported as appropriate partner in artemisinin based combination therapies (ACTs) against

malaria [Bhattacharya et al. (2009)].

Owing to the immense importance of phenolics, interest in accessing these molecules has

further intensified the research [Ahmad et al. (2006); Sinha et al. (2010)]. However, these

compounds are often present in only feeble concentration in their natural sources.

Consequently, development of newer methodologies for their synthesis or chemical

modification into various bioactive molecules is gaining ample momentum. However, the

deleterious environmental impact of some of the current chemical practices [Gartner et al.

(2003)] such as use of toxic reagents/solvents, multistep reactions, wastage of energy etc for

the synthesis of above compounds has shifted the attention of scientific community towards

“Sustainable or Green Chemistry” [Anastas and Warner (1998); Li and Trost (2008)]. The

present study aimed to address some of the above challenges using ionic liquids (ILs) and

microwave (MW) as tools of green chemistry by focusing on two important classes of

phenolic compounds viz phenylethanoids and phenylpropanoids.

1.2 Brief description and significance of phenolics:

1.2.1 Phenolics:

The term, phenolics [Harborne and Dey (1989); Harborne et al. (1999)] refers to the

compounds having one or more hydroxyl group attached to the aromatic ring. Phenolics are

widely distributed in the plant kingdom ranging from simple phenol to complex compounds

known as polyphenols. In general, according to the number of carbon atoms in conjunction

with the basic skeleton, phenolics are conveniently classified into various sub-classes like

phenols (C6), phenolic acids (C6-C1), styrenes (C6-C2), cinnamic acids (C6-C3),

naphthaquinones (C6-C4), xanthones (C6-C1-C6), stilbenes (C6-C2-C6), flavonoids (C6-C3-

C6), lignans (C6-C3)2 and lignins (C6-C3)n etc (Table 1) [Harborne et al. (1999)]. In addition,

methylation of hydroxyl functional group or substitution at the phenyl ring further enriches

the phytochemical diversity.

It is evident from Table 1 that phenolic compounds may also bear alkyl side chains to their

core aromatic structure. Further, the functional groups such as -COOH, -CHO, -C=C,

halogen and NO2 etc may be attached either to phenyl ring or to the alkyl side chain.


3

OH

COOH

HO

O

O

COOH

O

O

O

O

O

O

O

O

O

O

OOH

Carboskeleton Class Basic Structure Examples

C6

C6-C1

C6-C2

C6-C3

C6-C4

C6-C1-C6

C6-C2-C6

C6-C3-C6

Simple phenols

Phenolic acids

Styrenes

Acetophenones

Phenylpropenes

Propiophenones

Cinnamic acids

Naphthaquinones

Xanthones

Stilbenes

Chalcones

Flavones

Anthraquinones

Catechol, Resorcinol

Gallic acid

4-Vinylguaiacol, Canolol

Eugenol, Asarone

Juglone, Plumbagin

Mangostin, Mangiferin

Resveratrol, Combretastatin

Emodin

Lichochalcone A

Sinensetin

Flavanols Catechin

Ferulic acid, Caffeic acid

Table 1. Classification of phenolic compounds along with some examples

Lignans, neolignans(C6-C3)2

(C6-C3)n Lignins Highly crosslinked aromaticpolymer

Pinoresinol, Eusiderin

CHO

HOPhenolic aldehydes

Gallacetophenone

Isoacoramone

Anisaldehyde, Vanillin


4

In fact, a number of abundantly available bioactive phenolics possessing two to three carbon

side chain are found in nature and have been characterized as phenylethanoids and

phenylpropanoids respectively [Dixon and Paiva (1995); Harborne et al. (1999)]. These

compounds are biosynthetically produced in plants either by the shikimate pathway (which

starts from carbohydrates) or the polyketide pathway (which starts from acetyl and malonyl

coenzyme A) [Dewick (1994)].

A brief description of some of the phenolics (phenylethanoids and phenylpropanoids) taken

up in the present study is given below:

1.2.1.1 Phenylethanoids:

The term “phenylethanoids” represents the organic compounds having C6-C2 skeleton

[Harborne et al. (1999)]. These constitute a large number of compounds such as

phenylethenes (styrenes, stilbenes), phenylethanols, phenyl acetic acids etc (Figure 2), out

of which this study will be mainly focused on synthesis of substituted styrenes and

stilbenes.

R

R'

OH

COOH

RRR

Figure 2. Examples of some phenylethanoids

1.2.1.1.1 Styrenes:

Styrenes, also known as vinyl benzenes, constitute one of the simplest classes of

phenylethanoids.

Significance of styrenes:

As Bioactive and Flavoring agents

Styrenes (Figure 3) are obtained from various natural sources and have immense importance

in flavor and pharmaceutical

industries [Crouzet et al. (1997);

Lasekan et al. (2001)]. For

example, 4-hydroxy-3-

methoxystyrene (4-

vinylguaiacol, Figure 3), is

isolated from a variety of plants

such as Hibiscus esculentus (okra), Feijoa sellowiana (feijoa fruit) etc, which is a FEMA

OHOCH3

OH OHOCH3

Figure 3. Examples of some natural styrenes

4-Vinylguaiacol

H3CO

4-Vinylphenol Canolol


5

GRAS (Flavour and Extract Manufacturers Association Generally Regarded As Safe)

approved compound [Crouzet et al. (1997)]. On the other hand, 4-hydroxy-3,5-

dimethoxyphenylethene (canolol, Figure 3) is a constituent of rapeseed oil and is reported to

possess potent antioxidant and anticancer activities [(Kuwahara et al. (2004)].

Styrenes as synthons in organic chemistry

One of the most significant applications of styrenes in organic synthesis lies in their use for

the production of fine chemicals through transition metal catalysis. For instance, the

classical Heck reaction which is a Pd-catalyzed cross coupling reaction for the formation of

C-C bond involves styrenes as one of its coupling partner (Scheme 1) [Alonso et al. (2005)].

This transformation is a prominent route towards synthesis of biologically active stilbenes

such as resveratrol and pterostilbene etc.

+X

Pd(OAc)2, PPh3

R R' R

R'

X = Br, I, Cl, OTf etc.R = R' = H, CH3, OCH3 etc.

Et3N, DMF

Scheme 1

Similarly, styrenes via epoxidation and hydroformylation approaches can be converted into

synthetically important compounds such as -arylaldehydes [Kim and Alper (2005);

Sharma (2010)]. In addition, styrenes also act as precursors for the synthesis of various

polymers like styrene-butadiene rubber and styrene-divinylbenzene etc [Atsushi et al.

(1998)].

1.2.1.1.2 Stilbenoids:

Stilbene, (also known as biphenylethene), can be considered

to arise from a core C6-C2 skeleton of styrene by replacement

of H atom from side chain with a C6H5 moiety (Figure 4).

Stilbenes and their derivatives including dihydrostilbenes are

commonly known as stilbenoids and are widely present in

nature [Jang et al. (1997); Xiao et al. (2008)]. As such these are known as phytoalexins, a

class of defense compounds synthesized by plants in response to pathogens and abiotic

stress.

Figure 4. Stilbene


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Significance of stilbenoids:

As bioactive agents

Stilbenes are known to have a number of biological activities. For example, various

stilbenes such as resveratrol, pterostilbene, DMU-212 and combretastatin A-4 (Figure 5)

have been explored as chemotherapeutic agents against various cancer cell lines [Rimando

et al. (1994); Jang et al. (1997); Sale et al. (2005); Delmas et al. (2006)]. The biological

potential of various stilbenes has further been discussed in details in chapter 4.

OH

HO

OH

Resveratrol Pterostilbene

Figure 5. Some anticancer stilbenoids

DMU-212

OCH3

H3CO

OCH3

H3CO

H3CO

OCH3H3CO

OCH3

OHOCH3

H3CO

OH

Combretastatin A4

Stilbenes as precursors

Aslam et al. reported the synthesis of cicerfuran, an antifungal benzofuran, by epoxidation

and cyclization of corresponding 2-hydroxy-substituted stilbene (Scheme 2) [Aslam et al.

(2006)].

O

O

TBDMSO OTBDMS

OMe

O

O

HO OH

OMeO

O

O OMe

O

m-CPBA

OH

Scheme 2

DCM CHCl3PTS A

Similarly, biological active moracins, norlignans and phenanthrene alkaloids have been

synthesized from corresponding stilbenes [Kumar (2007)]. In addition, use of

polyaromatic/conjugated stilbenes in organic light emitting diodes, laser dyes,

photochemically crosslinked polymers and nonlinear optical devices etc is a subject of

prime interest [Wei and Chen (2007); Kalanoor et al. (2009)].

1.2.1.2 Phenylpropanoids:

The phenylpropanoids are the compounds possessing one or more C6-C3 skeleton [Dixon

and Paiva (1995); Vogt (2010)]. Thus, this is a diverse family comprising of compounds

such as phenylpropenes, propiophenones, chalcones, cinnamaldehydes, coumarins etc, out

of which this study is mainly focused with phenylpropenes, propiophenones and chalcones.


7

1.2.1.2.1 Phenylpropenes:

Phenylpropenes are compounds having a phenyl ring and a three carbon side chain with at

least one double bond (Figure 6). Various phenylpropenes including anethole,

methylisoeugenol, α-asarone and safrole etc are produced by a majority of plants for various

roles such as a part of chemical defense mechanisms and for biosynthesis of other plant

derivatives like flavonols, lignans and lignins etc [Risch and Chi-Tang (1997); Vogt

(2010)].

OCH 3 OCH3

H3CO

OCH 3OCH 3

H3CO

OCH 3H3CO

OCH3

Anethole Methylisoeugenol Asarone -Asarone

Figure 6. Examples of some natural phenylpropenes

Significance of phenylpropenes

Biological importance

Phenylpropenes have been found to possess hypolipidemic, antiatherogenic, anti-

inflammatory, anticholeretic, antifungal and antiplatelet activities [Risch and Chi-Tang

(1997); Harborne et al. (1999); Popławski et al. (2000)]. However, the biological activity of

phenylpropenes obtained from plants is highly influenced by the variation in their isomeric

forms (, β and γ). For example, α-asarone (trans-2,4,5-trimethoxy-1-phenylpropene, Figure

6,) has been recognized as a cardioprotective agent due to its hypolipidemic activity

[Popławski et al. (2000)], whereas, β-asarone (cis-2,4,5-trimethoxy-1-phenylpropene,

Figure 6) is toxic in nature. Similarly, trans-anethole stimulates hepatic regeneration in rats

and also shows spasmolytic activity.

Synthons in organic chemistry

One of the major synthetic utilities of phenylpropenes lies in their use as abundantly

available hydrocarbon feedstocks for synthesis of value added compounds. The peculiar

presence of benzylic double bond allows their easy functionalization into a wide array of

biologically and industrially important products such as cinnamaldehydes, neolignans and

benzaldehydes etc [Sinha et al. (2002); Leite et al. (2004); Freire et al. (2005); Joshi et al.

(2005, 2006)]. Recently, Sharma et al. developed a green route for the conversion of various

phenylpropenes into synthetically important -arylaldehydes [Sharma et al. (2009)].


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1.2.1.2.2 Propiophenones:

Propiophenones are a class of phenolic compounds containing a ketonic group in the propyl

side chain. A large number of substituted propiophenones containing hydroxy,

methylenedioxy and methoxy groups at the aromatic ring have been found in nature

[Harborne et al. (1999)]. Some of the propiophenones are listed in Figure 7.

OMe

MeO

OM eMeOO

O

OO O

O

1-propiophenone 4-methoxy-propiophenone

3,4-methylenedioxy-propiophenone

2,4,5-trimethoxy-propiophenone

Figure 7. Examples of some propiophenones

Propiophenones possess a wide range of biological activities such as anti-PAF, H3-receptor

antagonist, antifungal and hypolipidemic activities [Zacchino et al. (1999)]. For instance,

isoacoramone (2,4,5-trimethoxypropiophenone) found in Piper marginatum (Piperaceae)

and Acorus tararinowii (Araceae) is a potential hypolipidemic compound.

1.2.1.2.3 Chalcones:

Chalcones or 1,3-diaryl-2-propene-1-ones are prominent

plant secondary metabolites and represent another

important subclass of phenolics [Patil et al. (2009)]. The

two aryl rings of chalcone are linked by a three carbon

α,β-unsaturated carbonyl system (Figure 8). Substitution

on both rings (A & B) of chalcone can be easily achieved by their synthesis through

Claisen-Schmidt condensation of substituted benzaldehyde with acetophenones using acid

or base catalysis [Nowakowska (2007); Patil et al. (2009)].

1.2.1.2.3.1 Chalcones as bioactive agents:

Chalcones have been found to possess a wide range of biological properties such as

antioxidant, antileishmanial, antimalarial, pesticidal, antitumor and antibacterial activity

[Modzelewska et al. (2006); Nowakowska (2007)]. Despite a large number of biological

activities, the present work is mainly focused on to see the effect of various substituents on

ring A as well as on ring B of chalcone for antimalarial and pesticidal activity and thereafter

to find out structure-activity relationship.

o

A B

Figure 8. Chalcone


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1.2.1.2.3.2 Chalcones as antimalarial agents:

The antimalarial activity of chalcones was first noted when licochalcone A (1,1,-dimethyl

allylated natural product, Figure 9), an oxygenated chalcone isolated from Chinese liquorice

roots, was reported to exhibit potent in vivo and in vitro antimalarial activity against both

chloroquine-susceptible and chloroquine-resistant P. falciparum strain [Chen et al. (1997)].

Similarly, crotaorixin (Figure 9) isolated from the aerial parts of the Crotalaria and

diprenylated chalcone, medicagenin (Figure 9) isolated from the roots of Crotalaria

medicagenia have been found to show good antimalarial activity [Narender et al. (2005);

Nowakowska (2007)].

HO

OH

OH

OCH 3

O

HO

OH

OH

O

OH

OCH 3

HO

O

Crotaorixin MedicageninLicochalcone A

Figure 9. Some natural antimalarial chalcones

Also, various chalcones and their derivatives have been investigated for their pesticidal

activity against Culex quinquefasciatus [Das et al. (2010)] and Periplaneta americana etc

[Gautam and Chourasia (2010)].

1.3 Current challenges in context of phenolics compounds:

Owing to such a huge importance of phenolic compounds, various protocols are available in

the literature for their synthesis or chemical modification into other bioactive molecules.

Although some of these methodologies are beneficial in their own right, however, majority

of the available methods continue to be afflicted with challenges like use of toxic

reagents/solvents, multi-step reaction, delicate reaction conditions, prolonged reaction time

besides use of energy intensive processes. In particular, excessive use of the halogenated

solvents in organic synthesis is associated with grave perils like ozone layer depletion and

environment change [Gartner et al. (2003)]. Moreover, these solvents have been proven to

be human carcinogen. Hence, there is a growing concern in the society towards sustainable

development using environmental benign processes. In the above context, the concept of

Green Chemistry assumes paramount importance as it seeks to provide a platform for

sustainable chemical practices.


10

1.4 Green Chemistry:

Green chemistry is the design of chemical products and processes aimed at eliminating the

use and generation of hazardous substances. Chemical products can be manufactured using

a wide variety of synthetic routes. Green chemistry enhances the safety of a process by

employing inherently safer substances throughout the process designing including the

selection of substrate, catalysts, solvents and designing the final product so that it too is

innocuous. Green chemistry also promotes the use of agricultural based renewable starting

materials instead of depleting petroleum based feedstock. The essential features of the

concept of Green Chemistry have been enunciated in the form of a set of twelve principles

by Prof. Paul Anastas of the United States Environmental Protection Agency and Prof. John

C. Warner [Anastas and Werner (1998)] as mentioned below:

1.4.1 Principles of Green Chemistry:

(1) Prevention: It is better to prevent waste than to treat or clean up waste after it has been

created.

(2) Atom economy: Synthetic methods should be designed to maximize the incorporation

of all materials used in the process into the final product.

(3) Less hazardous chemical syntheses: Wherever practicable, synthetic methods should

be designed to use and generate substances that possess little or no toxicity to human health

and the environment.

(4) Designing safer chemicals: Chemical products should be designed to effect their

desired function while minimizing their toxicity.

(5) Safer solvents and auxiliaries: The use of auxiliary substances (e.g., solvents,

separation agents, etc) should be made unnecessary wherever possible and innocuous when

used.

(6) Design for energy efficiency: Energy requirements of chemical processes should be

recognized for their environmental and economic impacts and should be minimized. If

possible, synthetic methods should be conducted at ambient temperature and pressure.

(7) Use of renewable feedstocks: A raw material or feedstock should be renewable rather

than depleting whenever technically and economically practicable.

(8) Reduce derivatives: Unnecessary derivatization (use of blocking groups, protection/

deprotection, temporary modification of physical/chemical processes) should be minimized

or avoided if possible, because such steps require additional reagents and can generate

waste.


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(9) Catalysis: Catalytic reagents (as selective as possible) are superior to stoichiometric

reagents.

(10) Design for degradation: Chemical products should be designed so that at the end of

their function they break down into innocuous degradation products and do not persist in the

environment.

(11) Real-time analysis for pollution prevention: Analytical methodologies need to be

further developed to allow for real-time, in-process monitoring and control prior to the

formation of hazardous substances.

(12) Inherently safer chemistry for accident prevention: Substances and the form of a

substance used in a chemical process should be chosen to minimize the potential for

chemical accidents, including releases, explosions and fires.

The above principles can be incorporated into any chemical process by using some enabling

tools. However it is not possible to achieve these entire goals simultaneously in a chemical

process. In this context, the present studies especially involve the application of the

following tools of Green Chemistry:

Tandem reactions

Use of renewable starting materials

Use of environmentally benign solvents: Ionic liquids

Energy conservation: Microwave-assisted organic synthesis

1.4.2 Tandem reactions:

One of the classical strategies for the synthesis of organic compounds utilizes linear and

stepwise processes involving isolation and purification of each intermediate and often lead to

reduced yields. The situation becomes even more problematic when the intermediates are

unstable and therefore difficult to isolate. In this context, tandem (or domino) synthesis

allows the formation of several bonds in one operation without isolating the intermediates or

changing the reaction conditions thus saving lot of solvent, energy and time [Parsons et al.

(1996); Tietze (1996)]. The term tandem, domino, cascade, and sequential are often used

indistinguishably from one another [Nicolaou et al. (2006)], although some efforts for the

classification of above reaction terminologies have been made in literature. As defined by

Tietze [Tietze (1996)], “A tandem reaction is a process involving two or more bond-forming

transformations which take place under the same reaction conditions without adding


12

additional reagents and catalysts, and in which the subsequent reactions result as a

consequence of the functionality formed in the previous step. Tandem reactions not only

increase the yield of a synthetic route but also provide chemo- and regioselective control in

an efficient and atom-economical manner. For instance, Angelin et al. reported a tandem

reaction for the synthesis of 3-substituted isoindolinones using 2-cyanobenzaldehyde and

primary nitroalkanes [Angelin et al. (2010)]. The reaction proceeds via formation of

nitroaldol (Henry reaction), followed by a subsequent cyclization and rearrangement as

mentioned in Scheme 3.

CN

H

OR NO2

Et3NNH

O

NO2

R

OHN

NO2

R

Rearrangement

Scheme 3

R = CH3, C2H5, Ph, etc.

However, designing of a new tandem processes is highly dependent on the judicious

selection of catalyst and reaction conditions so that any interference or cross contamination

between the reagents in concurrent steps could be avoided [Baidossi et al. (2005); Kumar et

al. (2010)].

1.4.3 Use of renewable starting materials:

Ideally, a chemical synthesis should utilize readily available or more preferably renewable

source of starting materials [Bjørsvik and Liguori (2002); Meier et al. (2007)] instead of

depleting petroleum based feedstock. In this context, the use of abundantly available plant

derived raw materials as synthons is highly advantageous as these often provide convenient

templates to efficiently build up a wide array of value added compounds.

For instance, Acorus calamus (family: Araceae) is a rich source of various phenylpropenes

with -asarone as its major component (upto 96%). Recently, -asarone (cis isomer) of

Acorus calamus oil is proved to be toxic and carcinogenic whereas its trans isomer i.e –

asarone is an active hypolipidemic agent. The above problem has highly affected the

economic prospects of this crop for industries as well as farmers. In this context, Sinha and

co-workers have developed various green methodologies utilizing this inexpensive starting

materials for the synthesis of a wide range of commercially important bioactive phenolics

including hypolipidemic active -asarone (Figure 10) [Sinha et al. (2002); Joshi et al.

(2005); Sharma et al. (2009); Sharma et al. (2010)].


13

Similarly, dihydrotagetone (2,6-dimethyl-7-octen-4-one) is an abundantly available

terpenoid isolated from several plants including Tagetes minuta [Baser and Malyer (1996)].

This compound has proved to be an efficient substrate for semi-synthesis of 5-isobutyl-3-

methyl-4,5-dihydro-2(3H)-furanone which is an analogue of a commercially important

naturally occurring flavoring agent whisky lactone [Sinha et al. (2007a)]. In addition, ferulic

acid rich fractions isolated from the maize, corn or rice bran are used as renewable

feedstock for the synthesis of flavoring compounds such as vinyl phenols, vanillin etc

[Lesage-Meessen et al. (1999); Gioia et al. (2009)].

1.4.4 Selection of solvent in a chemical reaction:

Solvents are one of the auxiliary materials used in chemical synthesis to facilitate mass

transfer. However, excessive use of organic solvents like benzene, toluene, dichloromethane

and chloroform etc for various reactions is a major concern in today’s chemical processing

industries due to their deleterious impact on environment and human health. In view of the

above concern there is a need to minimize the amount of solvents during a chemical

synthesis or to find an alternate for halogenated toxic solvents which is one of the key areas

of green chemistry. Some of the strategies include reactions on solid support (heterogeneous

catalysis), use of water or supercritical fluids as solvents etc. Recently, ILs have attracted

much attention [Anastas and Warner (1998); Earle et al. (2000)] as ecofriendly solvents for

chemical synthesis.

OMe

MeO

OMe

CHO

OMe

MeO

OMe

CHO

OMe

MeO

OMe

OMe

MeO

OMe

OMe

OMe

OMe

OMe

MeO

OMe

OMe

MeO

OMe

O

Figure 10. Synthesis of value added products from natural-asarone of Acorus calamus oil

OMe

MeO

OMe


14

1.4.4.1 Ionic liquids:

The term ILs generally refers to those salts, which have melting points below 100oC

[Welton (1999); Plechkova and Seddon (2008)]. Particularly, the salts that melt at room

temperature are known as “room temperature ionic liquids” (RTILs). This temperature limit

does not have any physical or chemical significance and is just an indicator to distinguish

the ILs from high-temperature molten salts. ILs generally consists of relatively large organic

cation such as imidazolium or pyridinium based cation, whereas anion can be

organic/inorganic such as Cl-, Br-, BF4-, PF6

-, NO3-, [AcO]-, [N(CF3SO2)2]-, [CF3CO2]-,

[CF3SO3]- and [SCN]- etc [Chowdhury et al. (2007); Plechkova and Seddon (2008); Palou

(2010)]. Some of the commonly used cations and anions used for the synthesis of ILs are

depicted in Figure 11.

N NR1H3C N

R

R1

N

R3

R2

R4

R1

P

R3

R2

R4

1-alkyl-3-methyl-imidazolium

[Cnmim]+

1-alkyl-pyridinium

[CnPy]+

NR1 R2

1,1-dialkyl-pyrrolidinium

[CmCnpyr]+

tetraalkyl-ammonium

[Nijkl]+

tetraalkyl-phosphonium

[Pijkl]+

Some common cations:

Some common anions:Water-immiscible Water-miscible

PF6-

[(CF3SO2)2N]-

BF4-

[CF3SO3]-

[CH3COO]-, [CF3COO]-

Br-, Cl-, I-, [NO3]-, [Al2Cl7]-

Figure 11. Examples of some commonly used cations and anions of ionic liquids

+ + ++

Where, n = number of carbon atoms in the linear alkyl chainindicies i, j, k and l indicate the length of the corresponding linear alkyl chains

The field of ILs began in 1914 when Pual Waldon studied the electrical conductivity of

organic ammonium salts which have been found to melt nearly upto 100°C. These

anhydrous salts such as ethylammonium nitrate [EtNH3][NO3] were synthesized by the

neutralization reaction of ethylamine with nitric acid. However, the earliest application of

ILs dates back to 1948 when chloroaluminate salts were used as bath solution for

electroplating aluminium [Wasserscheid and Keim (2000)].


15

1.4.4.1.1 Classification of ionic liquids according to their acidity or basicity:

The design and choice of an IL in a particular reaction is greatly determined by various

properties such as water miscibility, viscosity, density etc. On the other side, less attention

has been paid to assess the role of acidity or basicity of ions of ILs. In the year 2006,

MacFarlane and co-workers demonstrated that the nature of the IL (as acidic, neutral or

basic) significantly affects the catalytic properties and applications in various organic

transformations [MacFarlane et al. (2006)]. Some of the cations and anions of ILs

categorized according to their Lewis acid/base properties are given in Figure 12

[MacFarlane et al. (2006); Hakala (2009)].

Acidic HN N R

N N SO3H

N N COOHN N

SCl

O

R

RR

(Protonated cation)

AlCl4 FeCl4

(Lewis acidic)

HSO4 H2PO4

(Bronsted amphoteric)

Neutral

N NR3R1

R2

N

R2

R1 R3

R4

S

R1

R3 R2

NR1

PF6 BF4 NO3

Br Cl R-SO3

S

O

O

S

O

O

CF3F3CN

BasicN

NR

(1-alkyl-4-aza-1-azoniabicyclo-[2.2.2]octane

N

NN

Cations Anions

H3C O

O HO

O

O

Type

R2

Figure 12. Structures and acid/base properties of some common cations and anions of ILs

1.4.4.1.2 Properties of ionic liquids:

ILs as reaction media have several interesting properties such as:

Negligible vapor pressure: ILs have negligible vapor pressure and as a result they can be

used as environmental friendly substitutes for volatile halogenated organic solvents.


16

Recyclability: ILs have been proven to be good solvents for metal catalyzed reactions due to

recyclability of expensive metal complexes besides easy work up of reaction products.

Catalytic properties: ILs can act as a catalyst as well as solvent besides their applications in

asymmetric synthesis and biotransformation studies.

High thermal stability: Most of the ILs have been found to be stable at temperature higher

than 300°C. In addition, ILs are non-flammable and can be handled very easily.

Wide liquid range: ILs have the ability to dissolve a wide variety of organic, inorganic and

organometallic compounds.

Designer property: Most interesting property of ILs is their tunable nature i.e. various

properties of ILs such as miscibility with water and other solvents, dissolving ability,

polarity, viscosity, density etc can be tuned by an appropriate choice of the anion and the

cation, hence these are also called as designer or tunable solvents.

1.4.4.1.3 Preparation and applications of ionic liquids in organic synthesis:

The basic concept for the synthesis of imidazolium based IL containing halide anion (e.g.

Cl, Br, I) involves the quaternization reaction of 1-alkylimidazole with corresponding alkyl

halide (Scheme 4) [Laus et al. (2005); Polshettiwar and Varma (2008)]. The halide anion of

above IL can further be converted into various other anions (such as BF4, PF6 etc) through

metathesis reaction with (i) metal salts or (ii) strong Bronsted acids. On the other hand,

addition of Lewis acid to above halide IL results in the formation of a complex anion e.g.

chloroaluminate ILs. The general procedure for the preparation of 1,3-dialkylimidazolium

based ILs is depicted in Scheme 4.

N NR2R1

X

N NR1

R2X

NaBF 4

NaXN N

R2R1

BF4

N NR2R1

AlCl4

AlCl3

NaPF 6N NR2R1

PF6

NaX

Scheme 4. General procedure for the synthesis of imidazolium based ionic liquids

X = Cl,Br or IR1 = R2 = CnH2n+1


17

For halide free synthesis of ILs, alkyl carbonates in place of alkyl halides have also been

used as alkylating agents.

In synthetic organic chemistry, ILs have successfully been explored for various reactions

such as Diels-Alder, Mannich, Knoevenagel, Heck, Aldol condensation, Friedal-Craft

reaction etc besides their applications in synthesis of pharmaceutical intermediates

[Malhotra (2007); Jain et al. (2005); Kumar et al. (2007a)]. For instance, Earle et al.

achieved the synthesis of NSAID, Pravadoline in ionic liquid [bmim]PF6 without the need

of any Lewis acid [Earle et al. (2000)] (Scheme 5). The use of IL not only eliminates the

waste disposal problems associated with conventional Friedal-Craft reaction but can also be

recycled.

NH

CH 3N

CH3

N

O

NCH3

N

O

O OCH3

NOCl

HC l.

+Base

[bmim]PF6 [bmim]PF6

Cl

O

H3CO

Scheme 5

ILs have also been used for the production of sustainable and alternative sources of energy

like 5-(hydroxymethyl) furfural (HMF), an intermediate for biofuel industry. Yong et al.

utilized ionic liquid [bmim]Cl along with N-heterocyclic carbene complex of chromium

(NHC-Cr) for the dehydration of glucose and fructose into HMF (Scheme 6) [Yong et al.

(2008)].

OHOHO

OHOH

OH

OHO

HMF

Glucose

OHO

OH

OHHOOHNHC-Cr

Imidazolium saltsbasemetal chloride

DMF 80 °C

[bmim]Cl80°C

(-3H2O)

[bmim]Cl100°C

(-3H2O)

O

Scheme 6

Fructose

Since various permutation of cation and anion can lead to at least a million binary and 1018

ternary ILs whereas only approx. 600 molecular solvents are in use today [Plechkova and


18

Seddon (2008)]. Being such a huge diversity, there exist numerous opportunities for the

synthesis of various novel ILs to explore them for a particular task.

1.4.4.1.4 Task-specific ionic liquids or functionalized ionic liquids:

The terms ‘task-specific ionic liquids (TSILs)’ or ‘functionalized ionic liquids’ are used for

those ILs which contain additional functional groups as a part either at anion or at the cation

[Lee (2006); Giernoth (2010)]. Thus, ILs possessing various functional groups such as

amine, nitrile, ether, alcohols, acid, urea etc have shown great promises as a reagent/catalyst

besides their role as a solvent. Some of the examples and applications of imidazolium salts

containing functionality at alkyl side chain are shown below (Figure 13) [Lee (2006)].

XN N

R FunctionalGroup

-NH2

-OH, -OR

-SH-PPh2

-Si(OR)3

-Urea & thiourea

-Metal complex etc.

Catalysis

Organic synthesis

Extraction and dissolution

Nanoparticles

Conductive materials

Figure 13

For instance, Wang et al. designed and synthesized a TSIL which acts as a base, ligand and

recyclable reaction media for Heck reaction (Figure 14) [Wang et al. (2009)]. Similarly,

immobilised metal ion containing ILs have been reported as reusable catalytic systems for

various organic reactions such as Kharasch reaction [Sasaki et al. (2005)]. Recently, the

area of TSILs has been expanded through the development of chiral ionic liquids (Figure

14) [Luo et al. (2006)]. Such ILs are usually designed from precursors such as chiral

amines, alcohols or amino acids etc.

(n-C4H9)3NN

OH

OH

Br

Organic Base

Effectiveanion

Figure 14. Examples of some task-specific ionic liquids

N,O-Ligand

(For Heck reaction)

O OSi

N

N

O OSi

N

N

Cu

SiO 2 SiO 2

Cl

ClCl

Cl

H3CO OCH 3

(For Kharasch reaction)

NH

N

N

Bu

BF4-

(Asymmetricorganocatalysts forMichael addition)


19

In addition, various TSILs have found applications as lubricant, magnetic materials besides

their ability for the absorption of gases such as CO2, SO2 etc [Giernoth (2010)]. Moreover,

ILs having high nitrogen content have been described as “energetic materials” finding

applications in civil as well as for military purposes [Smiglak et al. (2007)].

The first successful example of an industrial process using IL technology was the BASILTM

(Biphasic Acid Scavenging utilising Ionic Liquids) process started in 2002 [Plechkova and

Seddon (2008)]. The use of IL in BASIL process increased the productivity of their

alkoxyphenylphosphine (photoinitiator precursor) formation by a factor of 80000 compared

with the conventional process [Rogers and Seddon (2003)]. Although, research in the field

of IL is booming day by day, however there are certain limitations pertaining to ILs which

need to be resolved.

1.4.4.1.5 Some limitations of ionic liquids:

ILs possessing negligible vapor pressure are rarely flammable or explosive meaning that

they do not contribute to air pollution. However their high solubility in water may pose

environmental risks to aquatic ecosystem [Cho et al. (2008)]. Recent research on ILs in

aquatic system have shown them to be toxic against various organisms including Vibrio

fischeri [Docherty and Kulpa Jr. (2005)], Daphnia magna [Bernot et al. (2005)], algae

[Latala et al. (2005)], Escherichia coli [Lee et al. (2005)] and Danio rerio [Pretti et al.

(2006)] etc.

Another disadvantage is that ILs possessing BF4 or PF6 as counter anions sometimes

produce hydrofluoric acid (HF) as a byproduct due to hydrolysis. The use of such ILs could

be a problem for industry because HF is highly corrosive and dissolves all inorganic metal

and semimetal oxides. However, in positive sense, such ILs can be used to deliver this

corrosive acid (i.e. HF) safely in many applications.

Overall, the research in the field of ILs is still at very early stage and many of their

properties need to be elucidated as yet. However, various permutation of cations and anions

can lead to the design of a variety of novel ILs having useful applications as well as less

toxicity besides biodegradability to microorganisms. In fact, a large number of non-toxic

and biodegradable ILs have been discovered recently [Harjani et al. (2010); Trivedi et al.

(2011)].

After discussion on ILs in organic synthesis, conservation of energy is also an important

principle of green chemistry which is discussed below:


20

1.4.5 Energy conservation:

Traditionally, in the most commonly used heating sources such as Bunsen burner, heater, oil

bath, electric plate heater or heating mantle, the transfer of heat energy into the reaction

system depends on convection currents beside thermal conductivity of various materials of

the reaction pot. Consequently, the temperature of the reaction vessel is always higher than

that of the reaction mixture which in turn can lead to the decomposition of product,

substrate or reagent due to development of temperature gradient. In the above backdrop,

MW as non conventional energy source has become very popular and useful technology in

organic chemistry [Lidstrom et al. (2001); Kappe (2004, 2008); Loupy (2006); Polshettiwar

and Varma (2008)].

1.4.5.1 Microwave:

Microwaves are basically electromagnetic radiations which fall in the frequency range from

300 Hz to 30 GHz that corresponds to the wavelengths of 1m to 1cm. To avoid the

interference with radar and telecommunications, most of the MW appliances operate at

fixed frequency of 2450 MHz. In contrast to traditional heating sources, MW irradiation

couple directly with the component of reaction mixture [Kappe (2008); Loupy (2006)].

1.4.5.1.1 Theory of Microwave:

Heat energy of MW is transferred to the reaction mixture by the following two mechanisms

[Lidstrom et al. (2001); Kappe (2008)].

(i) Dipolar polarization (ii) Ionic conduction

(i) Dipolar polarization:

In the dipolar polarization mechanism,

electric field component of MW

interacts with polar molecules of

reaction mixture. When a molecule

with dipole moment is subjected to

MW it tends to align itself with the

field by rotation (Figure 15). However,

the frequency of the rotating dipole is

not high enough to precisely follow the

alternating electric field of MW. So as the dipole re-orients to align itself with the electric

field, the field is already changing and generates a phase difference between the dipole and

the orientation of the field. As a result lot of friction leads to intense internal heating.

Figure 15. Interaction of the electric field of MW withdipole moment [Gagnon (2008)]

Electric field of MW

Dipole

Figure 15. Interaction of the electric field of MW withdipole moment [Gagnon (2008)]

Electric field of MW

Dipole


21

(ii) Ionic conduction:

In the ionic conduction mechanism, the charged particles of the sample (usually ions)

oscillate back and forth under the influence of electric component of MW irradiation. They

collide with their neighbouring molecules or atoms and these collisions cause agitation or

motion, creating heat. The ionic conduction principle is a much stronger effect than the

dipolar rotation mechanism with regard to the heat-generating capacity. That’s why the

media containing ions are heated more efficiently by MW than just polar solvents.

Since MW energy is directly imparted to the reaction medium rather than through the wall

of reaction vessel, it is an efficient source of energy than conventional steam wherein

heating the entire furnace or oil bath consumes lot of time and energy.

1.4.5.1.2 Microwave-assisted organic synthesis [MAOS]:

MAOS is considered as an important approach towards green chemistry [Basu et al. (2003);

Kappe (2008); Polshettiwar and Varma (2008)]. Since the first report on MAOS in 1986,

the technique has been accepted to reduce the reaction time besides increasing yield of

product compared to conventional synthesis. In addition, MW heating in a pressurized

system rapidly increases temperature far above the boiling point of the solvent and leads to

a uniform energy transfer to the reactants of the chemical reaction.

Some of the examples of microwave-assisted organic reactions and their comparison with

conventional methods are given in Table 2.

Table 2. Some examples of microwave-assisted reactions and their comparison with conventional conditions

Ph

COOH

Ph

Reaction Activation mode Reference

Conventional

MW

Time Yield

CHO

HO HO

6 h

5 min

Kumar etal. (2007b)

Sinha et al.(2007b)

O

Ph

Ph

O Conventional

MW

10h 0%

1 h 73%

Cleary et al.(2011)

O

O

O

O

Conventional

MW

61%

88%

16 h

10 min

Zhou et al.(2006a)

+ CH2(COOH)2

CO2Et

N

NCH2CH2CO2Et

NNH

Conventional

MW 5 minMartin-Arandaet al. (1997)

Conventional

MW

5 min 27%

75 %

12%

61%

AcO HO 20 min 87%

16 h

OCH3 OCH3

62%

+


22

Recent trends in MAOS are the use of environmentally benign ILs. Ionic liquids being salts

(feature polar and ionic character) interact efficiently with MW irradiation through both

polarization and ionic conduction energy transfer mechanisms. Thus, ILs are considered as ideal

solvents for MAOS.

1.4.6 Application of ionic liquids in microwave assisted organic synthesis:

A number of reports on the use of ILs as heating aid, solvents, co-solvents, additives and

catalysts in MAOS has been furnished in literature. Some of the selected applications of ILs

in MAOS are described below:

1.4.6.1 Ionic liquids as heating aid under microwave:

Leadbeater et al. investigated the role of ILs for the MW heating of non polar solvents such

as hexane, toluene, THF and dioxane etc [Leadbeater and Torenius (2002)] and found that

such non polar solvents can be heated far above their boiling points with the aid of small

amount of an IL. Some of the ILs used in the present study and comparison of the

temperature attained in the presence or absence of these ILs is depicted in Table 3.

N N X N N X

1. X = I,2. X = PF6 3. X = Br

THF

Solventused IL added Temperature

attained with IL(°C)

Time(S)

Temperaturewithout IL

(°C)

Boiling point(°C)

Hexane

Toluene

Dioxane

279 20217 10 46 69

228 15195 150 109 111

268 70 112 66

264 90 76 101

Table 3. The microwave heating effects of adding a small quantity of ionic liquids to hexane,toluene, THF and dioxane

234 130280 60

242 60231 60

246 90149 100

1

32

1

32

1

32

1

32


23

1.4.6.2 Ionic liquids as benign reaction media under microwave:

Some of the organic reactions wherein ILs have been used as reaction media are discussed

below:

1.4.6.2.1 For synthesis of 2,4,5-trisubstituted imidazole derivatives:

Xia et al. conducted a three component synthesis of 2,4,5-trisubstituted imidazole

derivatives in a neutral ionic liquid, 1-methyl-3-heptylimidazolium tetrafluoroborate

([hemim]BF4) under MW (Scheme 7) [Xia and Lu (2007)]. The reaction got completed

within 2-6 min of MW irradiation whereas conventional heating (oil bath) took 2 h for its

completion besides providing the product in comparatively low yield.

O

O

CHO

NH

N+

MW (135 W)

NH4OAc[hemim]BF4

R

R

R =H, F, Cl, Br, CF3, CH3, OH etc.

(2-6 min)

Scheme 7

1.4.6.2.2 For Heck reaction:

Heck reaction is a transition metal catalyzed cross coupling arylation of olefins with organic

halides and is an important method for the construction of C-C bond. Heck reaction has

been studied by various groups under ILs [Bellina and Chiappe (2010)] or IL-MW

conditions. For instance, Vallin et al. studied the Heck coupling of aryl halides with n-butyl

acrylate using PdCl2 along with ligand P(o-tol)3 and base Et3N in [bmim]PF6 under MW

condition (Scheme 8) [Vallin et al. (2002)]. Similarly, Heck coupling of aryl halides with

styrenes or n-butyl acrylate using Pd/C and (n-Bu)3N without any ligand has been carried

out in [omim]BF4 under MW irradiation [Xie et al. (2004)]. The reaction time was reduced

significantly using IL-MW combination

X R'

+R

PdCl2, [bmim]PF6, Et3NP(o-tol)3 (5-20 min)

MicrowaveR

Pd/C, [omim]BF4, (n-Bu)3N (1.5-2.0 min)

R'

R = H, OCH3 etc.X = Br, I

R' = COOBu

R' = COOBu or Ph

Scheme 8


24

1.4.6.2.3 For oxidation of alcohols:

Development of cost-effective and environmentally benign oxidation process, particularly

using H2O2 holds a prominent place among other oxidants [Wahlen et al. (2003); Kumar et

al. (2007a)]. However, oxidation with H2O2 requires prior activation by transition metal

catalysts due to its low activation energy. Consequently, various transition metal complexes

for H2O2 assisted oxidation of alcohols in ILs (such as [bmim]Br, [bmim]BF4) under

conventional heating have been studied by a number of groups [Muzart (2006)]. Also,

combination of IL and MW has been employed for the oxidation of various alcohols using KIO4

as an oxidant (Scheme 9) [Hajipour et al. (2006)].

R1 R2

OH

R1 R2

O

MW

R1 = R2 = H, Ph etc.

KIO4, Et4NBr

Scheme 9

To the best of our knowledge, oxidation of alcohols with green oxidant H2O2 without any

transition metal catalyst using IL-MW combination has not yet been explored.

1.4.6.2.4 For Stetter reaction:

Zhou et al. studied the combination of [bmim]BF4 and MW irradiation for the

intramolecular Stetter reaction for the synthesis of chromanone derivatives [Zhou et al.

(2006b)]. The reactions were also performed under conventional heating using IL as a

solvent (Table 4). The results show that IL-MW condition significantly reduced the reaction

time from 8 h to 20 min besides improvement in the yield of the products.

OO

O

O

O

OO

O

Et3N, [bm im]BF4

N

S

CH3H3C

BrHO

IL-conventional IL-MW

Table 4. Microwave-assisted intramolecular Stetter reaction using ionic liquid as a solvent

Entry

12

Time Yield Time Yield

5 h2.5 h8 h

808874

20 min5 min20 min

919484

RR

R

HClOCH33


25

The use of ILs under MW irradiation for various organic reactions is summarized at the end

i.e. in section 1.4.6.7.

There has been much recent interest in developing ‘catalyst free’ organic transformations in

neat ILs, wherein, the classical necessity of an additional metal or acid/base catalyst stands

removed [Meciarova et al. (2007); Parvulescu and Hardacre (2007)]. Consequently, a

number of reports on the applications of such TSILs, whereby the role of the IL goes

beyond that of a solvent have been furnished in literature.

1.4.6.3 Ionic liquids as solvent cum catalysts under microwave:

1.4.6.3.1 For decarboxylation of aromatic acids:

Sharma et al. have shown that ILs can be used as efficient catalysts cum solvents for

decarboxylation of diverse N-heteroaryl and aryl carboxylic acids under MW irradiation

without using any metal or base quinoline (Scheme 10) [Sharma et al. (2008)]. The

developed methodology offers several inherent advantages like reduction in waste,

recyclability of reagent system, short reaction times besides ease of product recovery.

HOOC

N

R

R=R'= H, CH3, X = H, Cl

R'OR3

R1R2

R4

R1-R4 = OMe, OH etc.R' = H, CH3 etc.

HOR3

R1

R2

R4

R5 R7

R8

R9

R6

R1-R9 = H, OMe, OH etc.

x

Ionic Liquid-WaterMW

R = Indoles, Aryl ethenes andArene derivatives

R

X= OH, NO2, ClR = H, CH3, CH2-C6H5 etc.

R

X

CO2

R'

Scheme 10

1.4.6.3.2 For Michael addition and alkylation of active methylene compounds:

Ranu et al. studied the use of basic ionic liquid [bmim]OH for the Michael addition of

active methylene compounds to conjugated -unsaturated ketones, carboxylic acids,

esters and nitriles besides alkylation of active methylene compounds (Scheme 11) [Ranu et

al. (2007a)]. Thus, it is observed that alkylation reaction of active methylene compounds

with alkyl halides proceed efficiently under MW irradiation within 5 min. The open chain


26

active methylene compounds (such as 1,3-diketones or 1,3-keto carboxylic esters) produced

the monoalkylated products, whereas the cyclic diketones provided the dialkylated products.

On the other side, conventional heating (80-100°C) for more than 12 h provided the

products in inferior yields.

R1

R2W

R1

R2

R1

R2

W

W

R1

R2

R3XR1

R2

R3R1

R2

COOMe

R1 = R2 = COOMe, COOEt, CN, NO2R3 = alkyl, benzyl, allyl, propargylX = Br, I

R3

R3

+ or[bmim]OH

+

W = COR

W = CN

[bmim]OH

MW (100°C)

W

Scheme 11

The same group has also investigated the stereoselective debromination of vicinal

dibromides [Ranu and Jana (2005)] and -bromoketones [Ranu et al. (2007b)] using ionic

liquid [pmim]BF4 under MW irradiation. In both cases [pmim]BF4 was found to be an

efficient catalyst cum solvent.

1.4.6.3.3 For Pechmann reaction:

The Pechmann reaction (condensation of phenols with β-ketoesters) for the synthesis of

coumarins generally involves acid catalysts such as H2SO4, P2O5, AlCl3 etc. In this context,

ionic liquid [bmim]HSO4 has been effectively utilized for the synthesis of coumarins under

MW (Scheme 12) [Singh et al. (2005)]. A comparison of MW and conventional heating was

also carried out, wherein, MW proved better in terms of yields and reaction times.

O OOH

O

OR'

OR R+

M.W (140 W)(2-10 min)

[bmim]HSO4

R = OH, CH3 etc.R' = CH3, C2H5

Scheme 12


27

1.4.6.4 Ionic liquids and microwave in biocatalysis:

ILs are promising as media for enzymatic transformations, allowing high levels of

efficiency and good solubility [Sheldon et al. (2002); Jain et al. (2005); Sunitha et al.

(2007)]. Major et al. investigated the enzymatic esterification of lactic acid with ethanol in

IL medium under MW conditions (Scheme 13) [Major et al. (2009)]. MW irradiations were

found to cause hydrolysis of lactoyllactic acid (the linear dimer of lactic acid) and as a

result, more lactic acid was found available as substrate for enzyme (CALB) enabling better

yield of product.

H3C

OH

OH

O

H3C OH H3CCH

OH

O

O

CH3

MW (10W, 40°C)

Scheme 13

Lipase, ionic liquid+

Recently, IL-MW combination has been successfully explored for the pretreatment of

cellulosic biomass to make it more accessible to enzymatic hydrolysis [Ha et al. (2011)].

1.4.6.5 Deuterolabeling of polyphenols using ionic liquid and microwave:

Deuterolabeling of biologically active compounds is highly desired because such labeled

analogues are used as internal standards for quantitation of biological samples, screening of

biological activities besides determining the biosynthetic and metabolic pathways. In this

context, IL-MW combination has been effectively employed for postsynthetic regioselective

aromatic ring H/D exchanges (using DCl/D2O) in bioactive polyphenolic compounds

(Scheme 14) [Hakala and Wahala (2007)].

Unlabled compound[bmim]Cl + DCl/D2O(MW, 15-40 min)

e.g.O

O

D

D

HOD

D

DD OH

Scheme 14


28

1.4.6.6 Ionic liquid and microwave for nanoparticles synthesis:

The low surface tension of many ILs leads to high nucleation rates and thus offers

outstanding properties as media for the synthesis of nanoparticles. In this context an

efficient microwave-assisted preparation of magnetite nanoparticles is described in ionic

liquid [bmim]BF4 (Scheme 15) [Hu et al. (2010)]. The use of IL was found to be an

efficient aid for MW heating of non-polar dibenzyl ether in high temperature solution-phase

synthesis of monodisperse magnetite nanoparticles. The developed IL-MW technology

provided lot of advantages over conventional protocols which usually proceed via co-

precipitation of Fe2+ and Fe3+ ions by a base (e.g. NaOH, NH3.H2O etc) for which careful

adjustment of pH is required.

O

O

N NBF4

Fe3O4

Fe(acac)3

RCOOH

ROH

Microwave

Good microwave absorption(Efficient synthesis of nanoparticles)

Poor microwave absorption(inefficient synthesis of nanoparticles)

Scheme 15

1.4.6.7 Applications of ionic liquids and microwave combination for some of the organic

name reactions:

The application of IL-MW technology for various name reactions is summarised in Table 5

[Palou (2010)].


29

Name of the reaction Catalyst/IL-MW conditions Reference

Diels-Alder cycloaddition

S.No.

1

Mannich condensation

Knoevenagel condensation

Biginelli

Pictet–Spengler

Friedel–Craft (acylation)

Beckmann Rearrangement

Heck coupling

Morita–Baylis–Hillman

Pechmann

[bmim]Cl–AlCl3

[bmim]HSO4

Bis{(trifluoromethyl)sulfonyl}amine(HNTf2) or BF3-Et2O/[bmim]BF4

[bmim]HSO4

Tsuji–Trost Pd(OAc)2/[emim]BF4/H2O

[bmim]BF4

CuCl/[i-ProMIM]PF6

Organotungsten catalyst/[bmim]PF6Mineral supports/[hmim]BF4

In(OTf)/[bdmim]PF6

H2O/DABCO/[bmim]PF6

Pd/C/[omim]BF4

2

3

4

5

6

7

8

9

10

11

12

Leadbeater et al. (2003)

Arfan et al. (2007)

Liao et al. (2005)

Srinivasan and Ganesan(2003)

Singh et al. (2005)

Hakala and Wahala(2006)

de Souza et al. (2008)

Xie et al. (2004)

Sugamoto et al. (2011)

Ma et al. (2006)

Chen et al. (2004)López et al. (2007)

Fisher esterification [bmim]HSO4Arfan and Bazureau(2005)

Table 5. Applications of ionic liquids and microwave for some selected organic reactions

1.5 Objectives of present studies:

In view of the above discussion, it is evident that synergistic combination of ILs with MW

is a useful concept for the designing of environmentally benign chemical processes. The

thesis entitled “Green Synthesis of Bioactive Phenolics Employing Ionic Liquids and

Microwave Assisted Approaches” is mainly concerned with the development of alternative

environmental benign strategies for the synthesis of phenolic compounds or their chemical

modification into other value added products either using ILs or MW irradiation. ILs have

been used as solvent, co-solvent besides exploring their dual role as solvent-cum catalyst.

Moreover, use of ILs in conjunction with MAOS has led to the expeditious synthesis of

biologically important phenolics such as arylalkenes, arylalkanones, stilbenoids and


30

chalcones etc. Also, various synthesized chalcone derivatives have been evaluated for their

antimalarial and pesticidal potential.

For the sake of convenience, the studies undertaken in this thesis have been divided into

four chapters as mentioned below:

Chapter 1 Ionic liquid and microwave assisted dehydration of arylalkanols into (E)-

arylalkenes under neutral condition

Chapter 2 Synergism of ionic liquid and microwave towards metal-free activation of

H2O2 for oxidation of benzyl alcohols

Chapter 3 Structure-activity relationship of chalcones and their derivatives for

antimalarial and pesticidal activity

Chapter 4 Microwave promoted tandem C-C bond formation strategy in ionic liquid for

synthesis of stilbenoids

I.6 References:

Ahmad, I., Aqil, F. and Owais, M. (2006). Modern Phytomedicine: Turning Medicinal

Plants into Drugs. John Wiley & Sons, New York.

Albert, Y. L. (1996). Encyclopaedia of Common Natural Ingredient Used in Food, Drugs

and Cosmetics. John Wiley & Sons, New York.

Alonso, F., Beletskaya, I. P. and Yus, M. (2005). Non-conventional methodologies for

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