Meta Selective C-H Bond Functional is at Ion

8/3/2019 Meta Selective C-H Bond Functional is at Ion

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A Meta Selective CopperCatalyzed C-H Bond Arylation

Robert J. Phipps and Matthew J. Gaunt

Critical Review Report submitted in Partial Fulfillment

of the Requirements for the Award of the Degree of

Master of green Technology

by

Jayendra Ahire

Institute of Chemical Technology, Mumbai

2010


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CONTENTS

Sr.No. Title Page

No.

1. Introduction 3

2. Transition metal catalysed Reaction 4

3. Coupling and Cross Coupling Reaction 6

4 C-H bond activation and Transition

Metal catalysed reaction

8

5 C-H bond functionalisation 8

6 Need of Research on C-H bond

Acttivation

11

7 Need Of Research 11

8 Importance Of Paper 12

9 Theme of Papaer 13

10 Title And Abstract 13

11 Actual Experiment 14

12 Green Chemistry Aspect 17

13 Current Research 18

14 References 19


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Introduction:

The general ideology that we use for predicting the formation of reaction product is that electron

donating group (electrophilic) introduce substituents at ortho and para position while electron

withdrawing group introduce substituents at meta position of aromatic compound is now require

to improve.

Mathew Gaunt and Robert Phipps carried out copper catalyzed reaction involving electron

donating groups on the aromatic ring which allow the substituent to be introduced at meta

position instead of ortho and para positions in aromatic compounds. They carried out the reaction

under mild condition. Interesting part in is research is therefore the meta selective Cu (II)

catalyzed reaction leading to different chemistry than the conventional way of synthesis under

green conditions. Basic aspect of this research paper start from Cu (II) which is the transition

metal used for the reaction.

The Transition metals Cu, Ag, Pd, Pt show their catalytic properties due to the presence of

incompletely filled d-orbitals. They show similar properties of group I&II metals because ofadditional electrons added to inner atomic orbital. They are coloured because they absorb the

radiations from visible region in the electromagnetic spectra. Cu (II) has been used as the metal

of choice because it is easy to get and not expensive. There are different types of reaction which

are catalyzed by transition metal such as oxidation, hydrogenation, hydroformylation.


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The basic mechanism of transition-metal catalyzed reactions involves following three

processes

1. Oxidative addition

The addition of a metal into a covalent bond leads to an overall two-electron loss on one metal or

a one-electron loss on each of two metals. Oxidative addition is catalyzed by metals that are

basic or easily oxidized. Metals with a relatively low oxidation states are used, but even high

oxidation state metals undergo oxidative addition,

Example the oxidation of Pt(II) with chlorine:

[PtCl4]2- + Cl2 [PtCl6]

2-

Reaction mechanism


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2 .Reductive elimination

Reductive elimination involves the elimination of a molecule from a transition metal complex. In

this process the metal oxidation state is reduced by two electrons. In the example shown below

the metal goes from thex+2 to thex oxidation state and a coordinatively unsaturated metal

center is obtained. Equation 2 is binuclear reductive elimination reaction

Reductive elimination is reverse of oxidative addition.

3. Insertion reaction

Insertion reactions contain the insertion of one ligand onto another metal-ligand bond on the

same complex. The generic reaction is shown below, where U = unsaturated ligand:

Beta hydride elimination and alpha hydride elimination are mechanism responsible for formation

of side product.


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Coupling and cross coupling reaction

A coupling reactions are the reactions in which two hydrocarbon fragments are coupled with the

help of a metal catalyst. RM (R = organic fragment, M = main group centre) reacts with an

organic halide of the type R'X with formation of a new carbon-carbon bond in the product R-R' .

The most popular metal catalyst is palladium, but some processes use nickel and copper. A

common catalyst is tetrakis (triphenylphosphine) palladium (0).

The reaction mechanism starts with oxidative addition of one organic halide to the catalyst.then

the second partner undergoes transmetallation, which places both coupling partners on the same

metal centre. The final step is reductive elimination of the two coupling fragments to regenerate

the catalyst and give the organic product. Unsaturated organic groups couple more easily in part

because they add readily.

Example:

Suzuki-Miyaura reaction

The Suzuki-Miyaura reaction is a palladium-catalyzed coupling of a vinyl or aryl halide (R'X)

with organoborane (RBY2) to form a product (RR') with a new CC bond.

Pd (PPh3)4

is the typical palladium catalyst.

The reaction is carried out in the presence of a base such as NaOH or NaOCH2CH3.

The halogen is usually Br or I.

The Suzuki reaction is completely stereo specific.


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Buchwald-Hartwig Cross Coupling Reaction

Palladium-catalyzed synthesis of aryl amines. Starting materials are aryl halides or pseudo

halides (for example triflates) and primary or secondary amines.

Stille, Buchwald- Hartwig, Tsuji- Trost and Heck, Suzuki reactions are all well known cross-

coupling reactions. Although, they shows very impressive applications use of organometallic

reagents in stochiometric amounts with the requirement of functional group makes these

processes environmentally hazardous. While in the C-H bond functionalisation the

organometallic reagent used is avoided completely and the direct focus on C-H bond activation

eliminate the need of functional group for the reaction. Hence it leads us to the development of

greener process in terms of C-H bond activation.

Advantage of C-H bond functionalisation over transition metal catalyzed reaction

Transition metal catalysed reactions use of one of the starting materials (organometallic reagent)

in reaction in stoichiometric amounts where as C-H bond functionalisation uses an arene. There

are very few transition-metal catalysed reactions for converting alkanes, or saturated

hydrocarbons directly to more valuable products. Inertness arises from the constituent atoms of

alkanes together by strong CC and CH bonds. CH bond functionalisation research and

development can reduce waste of energy and resources with reducing reaction steps required for

the production of complex valuable products in pharmaceutical, petroleum industries etc.


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There are several mechanisms under the direct arylation in C-H bond functionalisation.

1. Aromatic electrophillic substitution reaction.

The elements of the reagent (HBr or Br2) are simply added to the starting reactant. This is called

an addition reaction.

Aromatic compounds do not react in this way and requires a catalyst to start reaction with

halogens, e.g. in this case to substitute a bromine atom for a hydrogen atom. Hence the reaction

is termed an aromatic substitution. Because the benzene ring is electron-rich, it always behaves

as the nucleophile in a reaction - which means that the substitution on benzene occurs by the

addition of an electrophile to benzene; thus, the reactions are termed electrophilic aromatic

substitution:

There is basically one simple mechanism for all electrophilic aromatic substitutions:

The benzene acts as a nucleophile, attacking the electrophile with a pair of its -electrons. This

initial step destroys the aromaticity of the molecule. The resulting positive charge is delocalized

over the ortho and para positions. The conjugate base of the initial electrophile then work for in

removing the now extraneous proton, and restores aromaticity.

Because all electrophilic aromatic substitutions proceed in this way, the only thing that matters is

the preparation of a reactive electrophile. Why areactive electrophile? because, the first step

of the reaction involves destroying aromaticity. In order to do this, there must be a significant

energetic driving force. This driving force comes in the form of a very reactive (unhappy)

electrophile. Which suppose to be in halogenations ,friedel crafts reaction.


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2. -bond metathesis.

A sigma-bonded ligand is replaced in reaction with the sigma bond of an incoming ligand. This

mechanism does not involve a change in oxidation state. Sigma-bond metathesis is a common

reaction with alkyl halide ofearly transition metals hydroxide that are in their highest oxidationstate with d0 electronic transition state.

Such complexes cannot undergo an exchange of ligand by a pathway involving an oxidative

addition followed by a reductive elimination. This makes sigma bond metathesis a common

reaction in lanthanide complexes as the lanthanides generally have only one common oxidation

state (3+).

3. Oxidative addition

Oxidative addition reactions are typical for electron-rich, low-valent complexes of the 'late'

transition metals found towards the right side of the periodic tableRe, Fe, Ru, Os, Rh, Ir, Pt.the reactive species [LnM

x] is coordinative unsaturated and hence almost always unstable; it is

therefore generated in situ by thermal or photochemical decomposition of a suitable precursor.

Source :Reference (1)

4. Heck Reaction

The reaction of an unsaturated halide (or triflate) with an alkene and a base and palladium

catalyst to form a substituted alkene. Together with the other palladium-catalyzed cross-coupling

reactions, this reaction is of great importance, as it allows one to do substitution reactions on


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planar centers. Heck was awarded the 2010 Nobel Prize in Chemistry for the discovery and

development of this reaction.

The reactive position for aromatic electrophilic substitution reaction that are ortho or para for

electron donating groups and meta position for electron withdrawing groups.

The general mechanism of aromatic substitution reaction is give conventional site reactivity but

if the reaction which give the different reactivity than conventional then it will be very useful for

complex molecule synthesis.

Need for research

The research paper presented in this report shows how it is possible to inverse the specific

position reactivity generally associated with aromatic electrophilic substitution reactions. Thislead us to new approach with minimization of side product formation and waste production.

The Cu (II) catalyzed reaction of indole shows the inverse site selectivity such that electron

donating group introduces the incoming electrophile at meta position rather than the usual ortho,

para positions. The synthesis of product which have functional group at meta position is

normally difficult to synthesise. It requires lot of steps and material which is eliminated by using

this reaction.

The synthesis of drugs which include complex molecule is affected and improve which reduced

its cost and reaction time.

Source: Original Research paper


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Importance of paper

This paper is published in second highly rated research publication Science journal which

mainly focuses on fundamental research which change conventional way of thinking in all field

of science.

This paper was voted as one of the top 12 papers of 2009 by Chemical and Engineering

News ChemicalYear in Review 2009.

There are numerous research publications on C-H bond activation by Gaunt group of which

some are highlighted below

a) Recent development in natural product synthesis using metal-catalysed C-H bond

functionalisation in Chem. Soc. Rev., 2011,

b) Copper(II)-Catalyzed meta-Selective Direct Arylation of -Aryl Carbonyl Compounds in

Angew. Chem. Int. Ed., 2011.

c) Perspectives in Science: Copper Puts Arenes in a Hard Position

d) RSC Chemistry World:Copper catalysts give meta aromatics

e) Research Highlights in Nature Chemistry:Electrophilic arylation: Substitution success

f) Chemical and Engineering News:Dodging The Substitution Laws

The Mathew gaunt who is the author of this research paper and has done extensive work on the

C-H bond functionalisation. The research group mainly focuses on area such as enantoselective

organocatalysis, transition-metal catalyzed C-H bond activation, cascade reaction of natural

product synthesis, chemical biology.
http://www.sciencemag.org/cgi/content/full/sci;323/5921/1572http://www.rsc.org/chemistryworld/News/2009/March/19030902.asphttp://www.rsc.org/chemistryworld/News/2009/March/19030902.asphttp://www.rsc.org/chemistryworld/News/2009/March/19030902.asphttp://www.nature.com/nchem/reshigh/2009/0409/full/nchem.203.htmlhttp://www.nature.com/nchem/reshigh/2009/0409/full/nchem.203.htmlhttp://www.nature.com/nchem/reshigh/2009/0409/full/nchem.203.htmlhttp://pubs.acs.org/cen/news/87/i12/8712notw1.htmlhttp://pubs.acs.org/cen/news/87/i12/8712notw1.htmlhttp://pubs.acs.org/cen/news/87/i12/8712notw1.htmlhttp://pubs.acs.org/cen/news/87/i12/8712notw1.htmlhttp://www.nature.com/nchem/reshigh/2009/0409/full/nchem.203.htmlhttp://www.rsc.org/chemistryworld/News/2009/March/19030902.asphttp://www.sciencemag.org/cgi/content/full/sci;323/5921/1572


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Theme of Paper

The research of C-H bond arylation with Cu catalyzed condition of Mathew gaunt is with

mechanism of aromatic electrophilic substitution reaction. Reversal in the site selectivity

difference of product formation under catalyzed condition of Cu (II) and Pd(II) has beenpresented in the paper.

In order to control site selectivity of reaction which is useful for medicines, natural product

synthesis or complex molecule synthesis the following experiments have been planned. The first

experiment involves electophillic substitution reaction on indoles as substrates under Cu(II) to

give meta site selective isomer while Pd(II) give ortho site selective isomer. This result gave

encouragement for further research to be carried out.

Title And Abstract

Title gives complete idea about paper but does not give the conditions where actually paper has

success to get meta selective arylation. The abstract shows importane of paper by comparing

with chemistry we use in general case. It does not give any idea about research and method of

synthesis.

Actual Experiment

The first reaction of indole skeleton under catalyzed condition of Pd (II) gives C2 position

isomer, which is the predictable conventional result but under Cu (II) catalyzed condition it

shoes C3 position isomers. The reason for the change in product is due to the highly electrophilic

Cu catalyst somehow reverse the selectivity of reaction.

Source: original research paper


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The Cu(II) catalysed reaction undergo oxidized to Cu(III) with high electronic config d8 for

electrphilicity. To get more standard proof the experiment on acetanilide because of property to

change readily into other functionalities and after that with 2-methyl acetanilide. Reaction with

acetanilide with phenyl triflate resulted into meta selective product with low yield of about 14%

with no successive formation of other product. Research with 2-methyl acetanilide yield 43% of

the product. With changing (acyl) group the results are far better for benzamides (yield 73%)

and pivanilides (yield 79%).

Source : Orignal Research paper

The reaction under Cu(II) catalysed conditions give selectivity which also gives by steric effects

under borylation at certain parameter of reaction. The scope for substrate has tremendous

capacity for achieving meta selectivity with the group SO2Me introduced at meta position

illustrate reaction not occurring due to any error or partial reaction stage. The mechanism duringreaction involves several steps a) meta position is blocked by weak bond between oxygen and

hydrogen and aromaticity is lost b) at the same time highly electrophillic Cu(OTf)2 ,Ph2OTf

attacks on meta position. The dearomatization is possible through oxy-cupration at meta position.

source: Original Rsearchpaper


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They research on ortho substituted pivanilides where arylation is take place at meta position to amido

group and form 1,2,5-trisubstituted arene. But with nitro group it shows slow rate of reaction and form

incomple conversion.it also give lower yield. It shows that the depending upon functional group or

substitute group the reaction output changes drastically. This point in research paper not aplly for all

fumctional groups it is limitation. The research on aryl transformation is controlled by give acess to otherisomeric product is one of the most intresitng part.

3-Oxygeneted pivanlide under straight forward manipulation give 1,3,5- or 1,3,6-trisubstituted arene

product.When use 3-oxygen tosylate which give 1,3,5- functionalize pattern where 3-oxygen tosylate is

electron withdrawing group.the same reaction replacing 3OTs to 3-OMe give control over arylation to 6-

position.author is very optimistic about future abot this controllable swith which control selectivity.

Behalf of that this method show very impressive work on electon donating groups at amide ring but not

Same for electron withdrawing group.Even reaction is not suit for electon withdrawing group but it give

beautiful selectivity. Some time selectivity is not attainable under strong electron donating groups the

research paper work on many substitution group some are has high potential for selectivity and reactivity

and some are not at that stage. The research paper even has not completely at stage of providing

promising method to Industries but it create the base for start to thinking in new way for reaction. it has

vital key in synthesis of complex compounds that can change synthesis methods in future. Majorly all

compound show high selectivity although they has substituent on ortho position.some comound like 6th

molecular structure has low yield which is highly substituted.

79 % yield 86% yield 62% yield 61% yield

31% yield 44% yield 77% yield

Source : Orignal Research paper


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Green Chemistry Aspect

1. Prevention of waste: C-H bond functionalisation is enormously useful to prevent production of

waste, side products accordingly obeying the first principle of green chemistry.

2. Atom economy: As C-H bond functionalisation reduces the requirement of functional group and

stoichiometric amount of organometallic reagent it drastically increases the atom economy of

process as the only byproduct possibly formed is HX.

3. Safer chemical synthesis: The requirement of toxic or hazardous chemicals, functional groups

which are used in synthesising meta selective complex molecules in conventional process is

omitted by C-H bond fuctionalisation as it acts directly on unreactive C-H bond .

4. Safer Solvents and Auxiliaries The C-H bond fuctionalisation reduce the use of toxic

solvent and reduce the energy requirement of process as temperature it ultimately achieve

green chemistry aspect of safer chemicals and Auxillaries.5. Design for Energy Efficiency: As we reduce prerequisite conditions such as tempreture

and pressure it suit for use .

6. Reduce derivitives: The C-H bond functionalization reduces the formation of side

product, derivitives.

7. Catalyst: C-H bond functionalisation omit use of stochiometric reagent and use catalytic

reagents.

Current Research

Research on Microwave-Promoted Three-Component Coupling of Aldehyde, Alkyne,and

Aminevia C-H Activation Catalyzed by Copper in Water by Prof essor Tu is now vey impressive

due to Although several methods for construction of such units in water were reported, some

required expensive Au or Ag as catalyst, while some were limited to only one kind of aldehyde or

the aromatic. it not get meta selectivity but it activate C-H bond purely.

Key points in research

a. Microwave (MW)-promoted, in water---Green chemistry.

b. It requireed only the cheaper Cu (I) as catalyst without Au, Ag


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or other additives.

c. It was applicable to a broader substrate scope (both aromatic and aliphatic aldehydes and

secondary amines).

d. It proceeded faster and gave good to high yield, and its experimental process was simple

and easy.

Recently scientist working on C-H bond activation under room tempreture condition that will

decrease energy require for high temperature and high pressure.

Compound Characterization :

Compond Characterisation included in supporting material which has Detail information about

the method , apparatus, conditions, assumptions use in research gave better understanding of

research . The one example of compound N-(4-methylbiphenyl-3-yl) pivalamide shown in above

has general procedure of synthesis using Ph2IOTf (430 mg,1mmol) for 20h and 700C and then

after Purified by flash chromatography with 1/9 Hexanes/CH2CI2 on silica to give white color

solid. The Melting point is 156-1590C calculated by NMR spectroscopy. Use of highly

technically advanced testing equipment gave prominent resultuse for research. The procedure of

cleavage of pivanillide group is Describe in detail.The proof for selectivity place by representing

the given graph.


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source: orignal research paper 1


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Meta Selective C-H Bond Functional is at Ion