Chemistry

New Trends in
GREEN CHEMISTRY
New Trends in
GREEN CHEMISTRY
V. K. Ahluwalia
Visiting Professor
Dr. B. R. Ambedkar Centre for Biomedical Research
University ofDelhi. Delhi - J10007. India
M.Kidwai
Coordinator
International Chapter ofGreen Chemistry in India
Department ofChemistry. University ofDelhi.
Delhi - llO 007. India
..,
~
Kluwer Academic Publishers

BOSTON DORDRECHT LONDON
Anamaya Publishers
NEW DELHI
A C/.P. catalogue recordfor the book is available from the Library ofCongress
ISBN 978-94-015-7102-9 ISBN 978-1-4020-3175-5 (eBook)

DOI 10.1007/978-1-4020-3175-5
Copublished by Kluwer Academic Publishers,

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All rights reserved.

Copyright © 2004. Anamaya Publishers, New Delhi, India
Softcover reprint of the hardcover 1st edition 2004
No part of the material protected by this copyright notice may be reproduced or
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without the written permission from the copyright owner.
To
Professor Sukhdev, FNA
on his 80th birthday
Foreword
Organic chemistry has played a vital role in the development of diverse

molecules which are used in medicines, agrochemicals and polymers. Most
ofthe chemicals are produced on an industrial scale. The industrial houses
adopt a synthesis for a particular molecule which should be cost-effective.
No attention is paid to avoid the release of harmful chemicals in the
atmosphere, land and sea. During the past decade special emphasis has
been made towards green synthesis which circumvents the above problems.
Prof. V. K. Ahluwalia and Dr. M. Kidwai have made a sincere effort in this
direction.
This book discusses the basic principles of green chemistry incorporating
the use of green reagents, green catalysts, phase transfer catalysis, green
synthesis using microwaves, ultrasound and biocatalysis in detail. Special
emphasis is given to liquid phase reactions and organic synthesis in the solid
phase.
I must congratulate both the authors for their pioneering efforts to
write this book. Careful selection of various topics in the book will serve
the rightful purpose for the chemistry community and the industrial houses
at all levels.
PROF. JAVED IQBAL, PhD, FNA

Distinguished Research Scientist & Head
Discovery Research
Dr. Reddy's Laboratories Ltd.
Miyapur, Hyderabad - 500 050, India
Preface
Organic chemistry dealS' with the synthesis of molecules having diverse

uses in medicines, agio chemicals and biomolecules. The industries producing
such chemicals are basically concerned with the type of reaction involved,
the percentage yield etc. so that synthesis becomes cost effective. Special
attention is given to ensure that there is no environmental pollution. All
these form the basis of Green Chemistry-the pressing need of all nations.
This book discusses designing green synthesis, basic principles of green
chemistry with its role in day-to-day life, environmental pollution, green
reagents and catalysts, phase transfer catalysis in green synthesis, microwave
induced green synthesis, ultrasound assisted green synthesis, biocatalysts in
organic synthesis, aqueous phase reactions, organic synthesis in the solid
state, versatile ionic liquids as green solvents and finally some examples of
synthesis involving basic principles of green chemistry.
We are grateful to Dr. Dennis Hjersen, Director, Green Chemistry
Institute, USA; Professor Sukhdev, FNA, INSA Professor, New Delhi;
Professor Nityanand, FNA, Former Director, CDR! Lucknow; Prof. Harjeet
Singh, FNA, Professor Emeritus, Guru Nank Dev University, Amritsar;
Prof. Mihir K. Chaudhury, FNA, Head, Department of Chemistry, Indian
Institute of Technology, Guwahati; Prof. S. Chandrasekharan, FNA, Head,
Department of Chemistry, Indian Institute of Science (Bangalore);
Professor Javed Iqbal, FNA, Distinguished Research Scientist and Head,
Discovery Research, Dr. Reddy's Laboratories Ltd., Hyderabad, for their
valuable discussions.
V. K. AHLUWALIA
M. KJDWAI
Contents
Foreword vii
Preface ix
1. Introduction 1
2. Designing a Green Synthesis 2

2.1 Choice of Starting Materials 2
2.2 Choice of Reagents 2
2.3 Choice of Catalysts 2
2.4 Choice of Solvents 3
3. Basic Principles of Green Chemistry 5

3.1 Prevention of Waste/By-Products 5
3.2 Maximum Incorporation of the Reactants (Starting
Materials and Reagents) into the Final Product 6
3.2.1 Rearrangement Reactions 6
3.2.2 Addition Reactions 7
3.2.3 Substitution Reactions 7
3.2.4 Elimination Reactions 8
3.3 Prevention or Minimization of Hazardous Products 8
3.4 Designing Safer Chemicals 9
3.5 Energy Requirements for Synthesis 9
3.6 Selection of Appropriate Solvent 9
3.7 Selection of Starting Materials 10
3.8 Use of Protecting Groups 10
3.9 Use of Catalyst 11
3.10 Products Designed Should be Biodegradable 12
3.11 Designing of Manufacturing Plants l3
3.12 Strengthening of Analytical Techniques 14
4. Green Chemistry in Day-to-Day Life 15

4.1 Dry Cleaning of Clothes 15
4.2 Versatile Bleaching Agent 15
xii Contents
5. Environmental Pollution 17
6. Green Reagent 21
6.1 Dimethylcarbonate 21
6.2 Polymer Supported Reagents 22
6.2.1 Polymer SupportedPeracids 22
6.2.2 Polymer Supported Chromic Acid 22
6.2.3 Polymeric Thioanisolyl Resin 22
6.2.4 Poly-N-Bromosuccinimide (PNBS) 22
6.2.5 Polymeric Organotin Dihydride Reagent as a Reducing Agent 24
6.2.6 Polystyrene Carbodiimide 24
6.2.7 Polystyrene Anhydride 24
6.2.8 Sulfonazide Polymer 24
6.2.9 Polystyrene Wittig Reagent 25
6.2.10 Polymeric Phenylthiomethyl Lithium Reagent 25
6.2.11 Polymer Supported Peptide Coupling Agent 26
7. Green Catalysts 27
7.1 Acid Catalysts 27
7.2 Oxidation Catalysts 29
7.3 Basic Catalysts 30
7.4 Polymer Supported Catalysts 31
7.4.1 Polystyrene-aluminium Chloride 32
7.4.2 Polymeric Super Acid Catalysts 32
7.4.3 Polystyrene-metalloporphyrins 32
7.4.4 Polymer Supported Photosensitizers 33
7.4.5 Polymer Supported Phase Transfer Catalysts 33
7.4.6 Miscellaneous Illustrations 34
Ti0 2 Photocatalyst in Green Chemistry 34
Solid Support Reagents 34
Synthesis of Bromoorganics: Development of
Newer and Ecofriendly Sromination Protocols
and Brominating Agents 35
Synthesis ofPyridinium Fluorochromate (PFC) 35
Synthesis of Isooctane 36
8. Phase Transfer Catalysis in Green Synthesis 39

8.1 Introduction 39
'8.2 Applications ofPTC in Organic Synthesis 41
8.2.1Nitriles from Alkyl or Acyl Halides 41
8.2.2 Alkyl FluQrides from Alkyl Halides 42
8.2.3 Generation ofDihalocarbenes 42
8.2.4 Generation ofVinylidene Carbenes 44
8.2.5 Elimination Reactions 44
Contents xiii
8.2.6 C-Alkylations 45
C-Alkylation of Activated Nitriles 45
C-Alkylation of Activated Ketones 46
C-Alkylation of Aldehydes 46
8.2.7 N-Alkylations 46
N-Alkylation of Aziridines 46
N-Alkylation of P--Lactams 46
8.2.8 S-Alkylation 47
8.2.9 Darzen's Reaction 47
8.2.10 Williamson's Ether Synthesis 48
8.2.11 The Wittig Reaction 48
8.2.12 Sulphur Ylides 48
8.2.13 Heterocyclic Compounds 49
3-Alkyl Coumarins 49
Flavones 49
3-Aryl-2H-l,4-Benzoxazines 50
8.3 Oxidation Using Hydrogen Peroxide Under PTC Condition 50
8.4 Crown Ethers 51
8.4.1 Esterification 51
8.4.2 Saponification 51
8.4.3 Anhydride Fonnation 52
8.4.4 PotassiumPennanganate Oxidation 52
8.4.5 Aromatic Substitution Reaction 53
8.4.6 Elimination Reaction 54
8.4.7 Displacement Reaction 54
8.4.8 Generation of Carbene 54
8.4.9 SuperoxideAnionReaction 55
8.4.10 Alkylation 56
9. Microwave Induced Green Synthesis 59

9.1 Introduction S9
9.2 Applications 60
9.2.1 Microwave Assisted Reactions in Water 61
Hofinann Elimination 61
Hydrolysis 61
Oxidation of Toluene 62
Oxidation of Alcohols 62
Hydrolysis of Methylbenzoate to Benzoic Acid (Saponification) 63
9.2.2 Microwave Assisted Reactions in Organic Solvents 64
Esterification: Reaction of Carboxylic Acid and Alcohol 64
Esterification: Reaction of Carboxylic Acids and
Benzyl Ethers Using LnBr) (Ln = La, Nd, Sm, Dy, Er) 64
Fries Rearrangement 64
Orthoester Claisen Rearrangement 65
Diels Alder Reaction 65
Synthesis of Chalcones 65
Decarboxylation 66
xiv Contents
9.2.3 Microwave Solvent Free Reactions (Solid State Reactions) 66

Deacetylation 67
Deprotection 67
Saponification of Esters 68
Alkylation of Reactive Methylene Compounds 68
Condensation of Active Methylene Compounds with Aldehydes 68
Synthesis of Nitriles from Aldehydes 68
Synthesis of Anhydrides from Dicarboxylic Acid 69
Reductions 70
Synthesis of Heterocyclic Compounds 71
9.3 Conclusion 71
10. Ultrasound Assisted Green Synthesis 73

10.1 Introduction 73
10.2 Applications of Ultrasound 74
10.2.1 Esterification 74
10.2.2 Saponification 74
10.2.3 Hydrolysis 74
10.2.4 Substitution Reactions 75
10.2.5 Addition Reactions 76
10.2.6 Alkylations 77
10.2.7 Oxidation 78
10.2.8 Reduction 78
10.2.9 Hydroboration 80
10.2.10 Coupling Reactions 81
10.2.11 Fridel-Crafts Reaction 82
10.2.12 Diels-Alder Reaction 82
10.2.13 Sinunons-SmithReaction 82
10.2.14 BouveaultReaction 83
10.2.15 CannizaroReaction 84
10.2.16 Strecker Synthesis 84
10.2.17 Reformatsky Reaction 84
10.2.18 Conversion of Ketones into Tertiary Alcohols 85
10.2.19 SynthesisofChromenes 86
10.3 Conclusion 86
11. Biocatalysts in Organic Synthesis 88

11.2 Biochemical (Microbial) Oxidations 90
11.3 Biochemical (Microbial) Reductions 99
11.4 Enzymes Catalysed Hydrolytic Processes 102
11.4.1 Enantioselective Hydrolysis of Meso Diesters 102
11.4.2 Hydrolysis ofN-acylarnino Acids 103
11.4.3 Miscellaneous Applications of Enzymes 104
Contents xv
12. Aqueous Phase Reactions 108

12.2 Diels-Alder Reaction 109
12.3 Claisen Rearrangement 113
12.4 Wittig-Homer Reaction 116
12.5 Michael Reaction 117
12.6 Aldol Condensation 120
12.7 Knoevenagel Reaction 123
12.8 Pinacol Coupling 125
12.9 Benzoin Condensation 126
12.10 Claisen-Schmidt Condensation 127
12.11 Heck Reaction 129
12.12 Strecker Synthesis 131
12.13 Wurtz Reaction 132
12.14 Oxidations 132
12.14.1 Expoxidation 133
12.14.2 Dihydroxylation 136
Syn-Dihydroxylation 136
Anti Dihyrdoxylation 138
12.14.3 Miscellaneous Oxidations in Aqueous Medium 13 9
Alkenes 139
Alkynes 140
Oxidation of Aromatic Side Chains and Aromatic Ring System 140
Oxidation of Aldehydes and Ketones 140
Oxidation of Amines into Nitro Compounds 143
Oxidation of Nitro Compounds into Carbonyl Compounds 144
Oxidation ofNitriles 144
Oxidation of Sulphides 145
Oxidation with Hypochlorite 147
Oxidation with Ferricyanide 147
12.15 Reductions 148
12.15.1 Introduction 148
12.15.2 Reduction of Carbon-Carbon Double Bonds 148
12.15.3 Reduction of Carbon-Carbon Triple Bonds 150
12.15.4 Reduction of Carbonyl Compounds 152
12.15.5 Reduction of Aromatic Rings 155
12.15.6 Miscellaneous Reductions 156
12.16 Polymerisation Reactions 158
12.16.1 Polymers 158
Recycling of Polymers 158
Conversion of PET Materials into Monomers 158
To Make Polymers which are Biodegradable 159
Manufacture of Polycarbonates 159
Emulsion Polymerisation 160
12.17 Photochemical Reactions 162
xvi Contents
12.18 Electrochemical Synthesis 169

12.18.2 Synthesis of Adiponitrile 170
12.18.3 Synthesis ofSebacic Acid 171
12.18.4 Miscellaneous Electrochemical Reactions 171
12.19 Miscellaneous Reactions in Aqueous Phase 172
12.19.1 Isomerisation of Alkenes 172
12.19.2 Carbonylation 173
12.19.3 HydroformylationofOlefms 176
12.19.4 Homologation ofl,3-dihydroxyacetone 177
12.19.5 Weiss-Cook Reaction 178
12.19.6 Mannich Type Reactions 178
12.19.7 Conversion of o-nitrochalcones into
Quinolines and Indoles 179
12.19.8 Synthesis ofOctadienols 179
13. Organic Synthesis in Solid State 189

13.2 Solid Phase Organic Synthesis Without Using Any Solvent 189
13.2.1 Halogenation 189
13.2.2 Hydrohalogenation (addition ofHBr) 191
13 .2.3 Michael Addition 191
13.2.4 Dehydration of Alcohols to Alkenes 194
13.2.5 Aldol Condensation 195
13.2.6 Dieckmann Condensation 196
13.2.7 Grignard Reaction 196
13.2.8 Reformatsky Reaction 197
13.2.9 Wittig Reaction 197
13.2.10 Aromatic Substitution Reactions 198
Nuclear Bromination 198
Nitration 199
Synthesis of Amines 200
13.2.11 Pinacol-Pinacolone Rearrangement 200
13.2.12 Benzil-Benzilic Acid Rearrangement 201
13 .2.13 Beckmann Rearrangement 201
13.2.14 Meyer-Schuster Rearrangement 202
13.2.15 ChapmannRearrangement 202
13.2.16 Miscellaneous Reactions 203
Coupling Reactions 203
Solid Phase Synthesis ofOxazolidines 208
Synthesis of Azomethines 209
Synthesis ofHomoalIylic Alcohols 209
Synthesis of Cyclopropane Derivatives 209
Synthesis of Oxirazines 2 I 0
Synthesis of Aziridines 2 I 0
Synthesis of Disulphides 21 I
Contents xvii
Synthesis of Thiocarbonylimidazolide Derivatives 212

Synthesis of Secondary and Tertiary Halides 212
Formation of Ethers from Alcohols 212
Synthesis of High Molecular Weight Polypeptides 213
13.3 Solid Supported Organic Synthesis 213
13.3.2 Synthesis of Aziridines 214
13.3.3 Synthesisof~-lactams 215
13.3.4 Synthesis ofPyrrole 217
13.3.5 Synthesis ofFurans 217
13.3.6 Synthesis ofPyrazoles 217
13.3.7 Synthesis oflmidazoles 218
13.3.8 Synthesis ofAzoles 219
13.3.9 Synthesis ofPyridines 222
13.3.10 Synthesis of Chromenes and Flavones 222
13.3.11 Synthesis of Quinoline 223
13.3.12 Synthesis of Pyrimidines 224
13.3.13 Synthesis ofOxadiazines 225
13.3.14 Synthesis ofThiadiazepines 227
13.3.15 Miscellaneous Reactions 227
14. Versatile Ionic Liquids as Green Solvents 232

14.1 Green Solvents 232
14.2 Reactions in Acidic Ionic Liquids 233
14.3 Reactions in Neutral Ionic Liquids 235
14.3.1 Hydrogenations 235
14.3.2 Diel's-Alder Reaction 235
14.3.3 Heck Reaction 236
14.3.4 O-AlkylationandN-alkylation 236
14.3.5 Methylene Insertion Reactions 237
14.3.6 Miscellaneous Applications 238
Synthesis of Pharmaceutical Compounds 238
15. Synthesis Involving Basic Principles of

Green Chemistry: Some Examples 240
15.2 Synthesis of Styrene 240
15.3 Synthesis of Adipic Acid, Catechol and
3-dehydroshikimic Acid (a potential replacement for BHT) 241
15.4 Synthesis of Methyl Methacrylate 243
15.5 Synthesis of Urethane 245
15.6 An Environmentally Benign Synthesis of Aromatic Amines 245
15.7 Selective Alkylation of Active Methylene Group 247
15.8 Free Radical Bromination 247
15.9 Acetaldehyde 248
xviii Contents
15.10 Furfural from Biomass 249

15.11 Synthesis of (S)-metolachlor, an Optically Active Herbicide 249
15.12 Synthesis of Ibuprofen 250
15.13 Synthesis ofParacetamol 251
15.14 Green Synthesis of 3-phenyl Catechol 252
15.15 Synthesis of Epoxystyrene 253
15.16 Synthesis of Citral 253
15.17 Synthesis of Nicotinic Acid 254
15.18 Use of Molting Accelerators to Replace More
Toxic and Harmful Insecticides 254
15.19 An Environmentally Safe Marine Antifoulant 255
Suggested Readings 259

Index 261
New Trends in
GREEN CHEMISTRY
1. Introduction
Chemistry brought about medical revolution till about the middle of twentieth
century in which drugs and antibiotics were discovered. These advances
resulted in the average life expectancy rising from 47 years in 1900 to 75
years in 1990's. The world's food supply also increased enormously due to
the discovery of hybrid varieties, improved methods of farming, better seeds,
use of insecticides, herbicides and fertilizers. The quality oflife on earth became
much better due to the discovery of dyes, plastics, cosmetics and other
materials. Soon, the ill effects of chemistry also became pronounced, main
among them being the pollution ofland, water and atmosphere. This is caused
mainly due to the effects of by-products of chemical industries, which are
being discharged into the air, rivers/oceans and the land. The hazardous waste
released adds to the problem. The use of toxic reactants and reagents also
make the situation worse. The pollution reached such levels that different
governments made laws to minimise it. This marked the beginning of Green
Chemistry by the middle of 20 th century.
Green chemistry is defined as environmentally benign chemical synthesis.
The synthetic schemes are designed in such a way that there is least pollution
to the environment. As on today, maximum pollution to the environment is
caused by numerous chemical industries. The cost involved in disposal of the
waste products is also enormous. Therefore, attempts have been made to
design synthesis for manufacturing processes in such a way that the waste
products are minimum, they have no effect on the environment and their
disposal is convenient. For carrying out reactions it is necessary that the
starting materials, solvents and catalysts should be carefully chosen. For
example, use of benzene as a solvent must be avoided at any cost since it is
carcinogenic in nature. If possible, it is best to carry out reactions in the
aqueous phase. With this view in mind, synthetic methods should be designed
in such a way that the starting materials are consumed to the maximum extent
in the final product. The reaction should also not generate any toxic by-products.
2. Designing a Green Synthesis
In any synthesis of a target molecule, the starting materials that are made to
react with a reagent under appropriate conditions. Before coming to a final
decision, consider all the possible methods that can give the desired product.
The same product can also be obtained by modifying the conditions. The
method of choice should not use toxic starting materials and should eliminate
by-products and wastes. Following are some of the important considerations.
2.1 Choice of Starting Materials

It is very important to choose the appropriate starting materials. The synthetic
pathway will depend on this. Also consider the hazards that may be faced by
the workers (chemists carrying out the reaction and also the shippers who
transport these) handling the starting materials.
Till now, most syntheses make use of petrochemicals (made from
petroleum), which are non-renewable. Petroleum refining also requires
considerable amounts of energy. It is therefore important to reduce the use of
petrochemicals by using alternative starting materials, which may be of
agriculturallbiological origin. For example, some of the agricultural products
such as corn, potatoes, soya and molasses are transformed through a variety
of processes into products like textiles, nylon etc. Some of the materials that
have biological origin (obtained from biomass) are: butadiene, pentane, pentene,
benzene, toluene, xylene, phenolics, aldehydes, resorcinol, acetic acid, peracetic
acid, acrylic acid, methyl aryl ethers, sorbitol, mannitol, glucose, gluconic
acid, 5-hydroxymethyl furfural, furfural, levulinic acid, furan, tetrahydrofuran,
furfuryl alcohol etc.
2.2 Choice of Reagents

Selection of the right reagent for a reaction is made on the basis of efficiency,
availability and its effect on environment. The selection of a particular reagent
versus another reagent for the same transformation can effect the nature of
by-products, percentage yield etc. (see Chapter 6 for details).
2.3 Choice of Catalysts

Certain reactions proceed much faster and at a lower temperature with the use
of catalysts. Heavy metal catalysts should be avoided as they cause
environmental problems and are toxic in nature. Use of visible light to carry
Designing a Green Synthesis 3
out the required chemical transformation should be explored. Certain

biocatalysts (enzymes) can also be used for various steps. This aspect will be
discussed separately in Chapters 7, 11 and 12.
2.4 Choice of Solvents

Most of the common solvents generally used cause severe hazards. One of
the commonly used solvents, benzene is now known to cause or promote
cancer in humans and other animals. Some ofthe other aromatic hydrocarbons,
for example toluene could cause brain damage, have adverse effect on speech,
vision and balance, or cause liver and kidney problems. All these solvents are
widely used because of their excellent solvency properties. These benefits
nevertheless, are coupled with health risks.
Commonly used halogenated solvents, like methylene chloride, chloroform,
perchloroethylene and carbon tetrachloride have long been identified as
suspected human carcinogens.
The chlorofluorocarbons (CFCs) were used up to 20 th century as cleaning
solvents, blowing agents for molded plastics and for refrigeration. Despite
the fact that CFCs have very low direct toxicity to humans and wild life (being
non-inflammable and non-explosive, they have low accident potential), the
single effect of CFCs in causing depletion of the ozone layer is a sufficient
reason for not using them.
A versatile solvent, carbon dioxide l is used as liquid CO 2 or supercritical
CO 2 fluid (the states of CO 2 most commonly used for solvent use). A gas is
normally converted to a liquid state by increasing the pressure exerted upon it.
However, if the substance is placed at a temperature above its critical temperature
Tc (31°C for CO 2) and critical pressure Pc (72.8 atm for CO 2), a supercritical
fluid is obtained. The Tc of a substance is the temperature above which a
distinct liquid phase of the substance cannot exist, regardless of the pressure
applied. Pc is the pressure at which a substance can no longer exist in gaseous
state. In a supercriticalliquid, the individual molecules are pressed so close
together (due to high pressure) that they are almost in liquid state. Supercritical
liquids have density close to that of the liquid state and viscosity close to that
of gaseous state.
It is ideal to carry out the reaction in aqueous phase if possible. The use
of water as a solvent has distinct advantages. This aspect has been discussed
separately in Chapter 12.
Another way to carry out the reaction is without the use of solvent (solvent
less reactions). One such reaction comprises those reactions in which the
starting materials and the reagents serve as solvents. Alternatively, the reactions
can be performed in the molten state to ensure proper mixing. There is still
another reaction that can be carried out on solid surfaces such as specialized
clays. All such methods obviate the need of the solvent and will be discussed
subsequently in Chapter 13.
4 GREEN CHEMISTRY
A versatile solvent, ionic-liquid for carrying out reactions is discussed in

Chapter 14.
Reference
I. lA. Hyatt, Liquid and Supercooled Carbon Dioxide as Organic Solvents, J. Am. Chern.
Soc., 1986,49,5097-5101.
3. Basic Principles of Green Chemistry
Green chemistry is defined as environmentally benign chemical synthesis.

Any synthesis, whether performed in teaching laboratories or industries should
create none or minimum by-products which pollute the atmosphere. According
to the work carried out by Paul T. Anastas, the following basic principles of
green chemistry have been formulated I:
• Prevention of waste/by-products.
• Maximum incorporation of the reactants (starting materials and reagents)
into the final product.
• Prevention or minimization of hazardous products.
• Designing of safer chemicals.
• Energy requirement for any synthesis should be minimum.
• Selecting the most appropriate solvent.
• Selecting the appropriate starting materials.
• Use of the protecting group should be avoided whenever possible.
• Use of catalysts should be preferred wherever possible.
• Products obtained should be biodegradable.
• The manufacturing plants should be so designed as to eliminate the possibility
of accidents during operations.
• Strengthening of analytical techniques to control hazardous compounds.
3.1 Prevention ofWaste/By-Products

It is most advantageous to carry out a synthesis in such a way so that formation
of waste (by-products) is minimum or absent. It is especially important because
in most of the cases the cost involved in the treatment and disposal of waste
adds to the overall production cost. Even the unreacted starting materials
(which mayor may not be hazardous) form part of the waste. Hence, the next
basic principle is important and should carefully be considered as "prevention
is better than cure" applies in this case also. In other words, the formation of
the waste (or by-products) should be avoided as far as possible. The waste
(or by-products) if discharged (or disposed off) in the atmosphere, sea or
land not only causes pollution but also requires expenditure for cleaning-up.
6 GREEN CHEMISTRY
3.2 Maximum Incorporation ofthe Reactants (Starting Materials

and Reagents) into the Final Product
Chemists globally consider that if the yield of a reaction is about 90%, the
reaction is good. The percentage yield is calculated by
Actual yield of ~he product x 100
% yield = - - - - - - - - - - - -
Theoretical yield of the product
In other words, if one mole of a starting material produces one mole of
the product, the yield is 100%. Such synthesis is deemed perfectly efficient
by this calculation. A perfectly efficient synthesis according to the percentage
yield calculations may, however, generate significant amount of waste (or by-
products) which is not visible in the above calculation. Such synthesis is not
green synthesis. Typical examples like Wittig reaction and the Grignard reactions
illustrate the above contention. Both these reactions may proceed with 100%
yield but do not take into account the large amounts of by-products obtained.
The reaction or the synthesis is considered to be green if there is maximum
incorporation of the starting materials and reagents in the final product. We
should take into account the percentage atom utilisation, which is determined
by the equation
MW of desired product x 100
% atom utilization =
MW of (desired product + waste products)
The concept of atom economy developed by B.M. Trost2 is a consideration of
'how much of the reactants end up in the final product'. The same concept
determined by R.A. Sheldon3 is given as
FW of atoms utilized
% atom economy = - - - - - - - - - - - - - - - - x 100
FW of the reactants used in the reaction
Let us consider some of the common reactions viz., rearrangement,
addition, substitution and elimination to find out which is more atom economical.
3.2.1 Rearrangement Reactions

These reactions involve rearrangement ofthe atoms that make up a molecule.
For example, allyl phenyl ether on heating at 200°C gives o-allyl phenol.
CH 0
HC"-::::: ' C / ""CH
I I I 2
200°C
HC~ /CH ~CH

CH H2 C
Allyl phenyl ether a-Allyl phenol
Basic Principles of Green Chemistry 7
This is a 100% atom economical reaction, since all the reactants are incorporated
into the product.
3.2.2 Addition Reactions

Consider the addition of hydrogen to an olefin.
Ni
- - . . H3C-CH2-CH3
Propene Propane
Here also, all elements of the reactants (propene and hydrogen) are
incorporated in the final product (propane). The reaction is a 100% atom
economical reaction.
Similarly, cycloaddition reactions and bromination of olefins are 100%
atom economical reactions.
Butadiene Cyc10hexene
1,2-Dibromopropane
3.2.3 Substitution Reactions

In substitution reactions, one atom (or group of atoms) is replaced by another
atom (or group of atoms). The atom or group that is replaced is not utilised in
the final product. So the substitution reaction is less atom-economical than
rearrangement or addition reactions. Consider the substitution reaction of ethyl
propionate with methyl amine
Ethyl propionate Methyl amine Propionamide Ethyl alcohol
In this reaction, the leaving group (OC 2Hs) is not utilised in the formed
amide. Also, one hydrogen atom of the amine is not utilised. The remaining
atoms of the reactants are incorporated into the final product.
The total of atomic weights of the atoms in reactants that are utilised is
8 GREEN CHEMISTRY
87.106 g/mole, while the total molecular weight including the reagent used is
133.189 g/mole (see table). Thus, a molecular weight of 46.069 g/mole remains
unutilised in the reaction.
Reactants Utilised Unutilised

Formula FW Formula FW Formula FW
C SH 1O O2 102.132 C 3 H sO 57.057 C 2H sO 45.061
CHsN 31.057 CH 4 N 30.049 H 1.008
Total C 6 H 1S N0 2 133.189 C 4 H 9 NO 87.106 C 2HpH 46.069
~
Therelore, th e 01
10 atom economy = 87.l06 x 100 -- 65.40 0/
II0 •
133.l89
3.2.4 Elimination Reactions
In an elimination reaction, two atoms or group of atoms are lost from the
reactant to form a 7t-bond. Consider the following Hofmann elimination
The elimination reaction is not very atom-economical. The percentage

atom economy is 35.30%. In fact this is least atom-economical of all the
above reactions.
Consider another elimination reaction involving the dehydrohalogenation
of 2-bromo-2-methylpropane with sodium ethoxide to give 2-methylpropene.
CH 3
H C-t:-CH NaOC2H5~
3 I I 2
Br H
2-Bromo-2-methylpropane 2-Methylpropane
This dehydrohalogenation (an elimination reaction) is also not very atom-

economical. The percentage atom economy or utilisation is 27% which is
even less atom-economical than the Hofinann elimination reaction.
3.3 Prevention or Minimization of Hazardous Products

The most important principle of green chemistry is to prevent or at least
minimize the formation of hazardous products, which may be toxic or
environmentally harmful. The effect of hazardous substances if formed may
be minimised for the workers by the use of protective clothing, engineering
controls, respirator etc. This, however, adds to the cost of production. It is

found that sometimes the controls can fail and so there is much more risk
involved. Green chemistry, in fact, offers a scientific option to deal with such
situations.
3.4 Designing Safer Chemicals

It is of paramount importance that the chemicals synthesised or developed
(e.g. dyes, paints, adhesives, cosmetics, pharmaceuticals etc.) should be safe
to use. A typical example of an unsafe drug is thalidomide (introduced in
1961) for lessening the effects of nausea and vomiting during pregnancy
(morning sickness). The children born to women taking the drug suffered
birth defects (including missing or deformed limbs). Subsequent~y, the use of
thalidomide was banned, the drug withdrawn and strict regulations passed for
testing of new drugs, particularly for malformation-inducing hazards.
With the advancement of technology, the designing and production of
safer chemicals has become possible. Chemists can now manipulate the
molecular structure to achieve this goal.
3.5 Energy Requirements for Synthesis

In any chemical synthesis, the energy requirements should be kept to a
minimum. For example, if the starting material and the reagents are soluble in
a particular solvent, the reaction mixture has to be heated to reflux for the
required time or until the reaction is complete. In such a case, time required
for completion should be minimum, so that bare minimum amount of energy
is required. Use of a catalyst has the great advantage of lowering the energy
requirement of a reaction.
In case the reaction is exothermic, sometimes extensive cooling is required.
This adds to the overall cost. If the final product is impure, it has to be purified
by distillation, recrystallisation or ultrafiltration. All these steps involve the use
of energy. By designing the process such that there is no need for separation
or purification, the final energy requirements can be kept at the bare minimum.
Energy to a reaction can be supplied by photochemical means, microwave
or sonication and will be discussed in subsequent chapters.
3.6 Selection of Appropriate Solvent

The solvent selected for a particular reaction should not cause any environmental
pollution and health hazard. The use ofliquid or supercriticalliquid CO 2 should
be explored. Ifpossible, the reaction should be carried out in aqueous phase or
without the use a of solvent (solventless reactions). A better method is to
carry out reactions in the solid phase (for details see Chapter 13).
One major problem with many solvents is their volatility that may damage
human health and the environment. To avoid this, a lot of work has been
10 GREEN CHEMISTRY
carried out on the use of immobilised solvents. The immobilised solvent

maintains the solvency of the material, but it is non-volatile and does not
expose humans or the environment to the hazards of that substance. This can
be done by tethering the solid molecule to a solid support or by binding the
solvent molecule directly on to the backbone of a polymer. Some new polymer
substances having solvent properties that are non-hazardous are also being
discovered.
3.7 Selection of Starting Materials

Starting materials are those obtained from renewable or non-renewable material.
Petrochemicals are mostly obtained from petroleum, which is a non-renewable
source in the sense that its formation take millions of years from vegetable
and animal remains. The starting materials which can be obtained from
agricultural or biological products are referred to as renewable starting materials
(sec. 2.1). The main concern about biological or agricultural products however,
is that these cannot be obtained in continuous supply due to factors like crop
failure etc.
Substances like carbon dioxide (generated from natural sources or synthetic
routes) and methane gas (obtained from natural sources such as marsh gas)
are available in abundance. These are considered as renewable starting materials.
3.8 Use of Protecting Groups

In case an organic molecule contains two reactive groups and you want to use
only one of these groups, the other group has to be protected, the desired
reaction completed and the protecting group removed. For example
HOyyCHO
Reactions of this type are common in the synthesis of fine chemicals,

pharmaceuticals, pesticides etc. In the above protection, benzyl chloride (a
known hazard) and the waste generated after deprotection should be handled
carefully.
Another reaction involving protection of a keto function by using 1,2-
ethanediol is as follows:
/"... JOH
HO' ........",. 0
°I I°11°C-OCH 3
----;~~
° OH
2RMgBr
• cY~+HifVOH
Thus, we see that the protecting groups that are needed to solve a
chemoselectivity problem should be added to the reaction in stoichiometric
amounts only and removed after the reaction is complete. Since these protecting
groups are not incorporated into the final product, their use makes a reaction
less atom-economical. In other words the use of protective group should be
avoided whenever possible. Though atom-economy is a valuable criteria in
evaluating a particular synthesis as 'green', other aspects of efficiency must
also be considered.
3.9 Use of Catalyst

It is well known that use of a catalyst facilitates transformation without the
catalyst being consumed in the reaction and without being incorporated in the
final product. Therefore, use of catalyst should be preferred whenever possible.
Some of the advantages are:
(i) Better yields. Hydrogenation or reduction of ole fins in presence of nickel

catalyst Ni
H3C--CH=CH2 + H2 ~ H3C--CH2--CH3
Propene Propane
Phase transfer
C6H5CH2CI + aqueous KCN -----......,~~ C6H5CH2CN
Catalyst
Benzyl chloride 90% yield
Benzyl cyanide
o
~COOH
(0]
aq. KMnO.
Crown ether
Toluene Benzoic acid
85% yield
12 GREEN CHEMISTRY
(ii) The reaction becomes feasible in those cases where no reaction is normally
possible
HgSO•
H 2 SO.
..
Pd
oII
.. CH3-n-C-OCH3
CH2
Methyl methacrylate
(shell corporation)
(iii) Selectivity enhancement
H3C-C=CH + H2 Pd-BaSO. .. H3 C- CH=CH2

mono addition
Propyne Propene
Selectivity in C-methylation versus O-methylation
In addition to the above mentioned beneficial use of catalysts, there is significant

advantage in the energy requirement. With advances in the selectivity of
catalysts, certain reactions in green synthesis have become very convenient.
A special advantage of the use of catalysts is better utilisation of starting
materials and minimum waste product formation.
3.10 Products Designed Should be Biodegradable

The problem of products not being biodegradable is encountered particularly
in insecticides and polymers.
Insecticides
It is well known that farmers use different types of insecticides to protect
crops from insects. The more widely used insecticides are organophosphates,
carbamates and organochlorides. Of these, organophosphates and carbamates
are less persistent in the environment compared to the organochlorides (for
example aldrin, dieldrin and DDT). Though the latter are definitely effective
but they tend to bioaccumulate in many plant and animal species and incorporate
into the food chain. Some of the insecticides are also responsible for the
population decline 4 of beneficial insects and animals, such as honeybees,
lacewings, mites, bald eagles etc.
Cl-{ }-9-{ }-Cl

H x
\I
RX-P-OR
¥~
H3C- N-C-O-R
CI-C-Cl
I Carbamate
OR
I
CI Organophosphate
X=OorS
DDT R' = CH 3 or CH2CH3
Considering the above, it is of utmost importance that any product (e.g.

insecticides) synthesised must be biodegradable. It is also equally important
that during degradation the products themselves should not possess any
toxic effects or be harmful to human health. It is possible to have a molecule
(e. g. insecticide) which may possess functional groups that facilitate its
biodegradation. The functional groups should be susceptible to hydrolysis,
photolysis or other cleavage.
Some of the diacylhydrazines (developed by Rohm and Hass Company)
which have been found to be useful as insecticides are:
° t
NHllN
0
I~
#
Tebufenozide Halofenozide
""""'0ij',........Nt~~
o
I NH #
# 0
Methoxyfenozide
3.11 Designing of Manufacturing Plants

The importance of prevention of accidents in manufacturing units cannot be
over emphasised. A number of accidents have been found to occur in industrial
units. The gas tragedy in Bhopal (December 1984) and several other places
has resulted not only in loss of thousands of human lives but also rendered
many persons disabled for the rest of their lives. The hazards posed by toxicity,
explosions, fire etc. must be looked into and the manufacturing plants should
be so designed to eliminate the possibility of accidents during operation.
14 GREEN CHEMISTRY
3.12 Strengthening of Analytical Techniques

Analytical techniques should be so designed that they require minimum usage
of chemicals, like recycling of some unreacted reagent (chemical) for the
completion of a particular reaction. Further, placement of accurate sensors to
monitor the generation of hazardous by-products during chemical reaction is
also advantageous.
References
1. Paul T. Anastas and John C. Warner, Green Chemistry, Theory and Practice, Oxford
University Press, New York, 1998.
2. Barry M. Trost, Science, 1991,254, 1471-1477.
3. Roser A. Sheldon, Chern. Ind. (London), 1992,903-906."
4. Colin Baird, Environmental Chemistry, W.H. Freeman, New York, 1999.
4. Green Chemistry in Day-to-Day Life
With the advancement of science, green chemistry has changed our life style.
Some of its important applications are described.
4.1 Dry Cleaning of Clothes

Perchloroethylene (PERC), CI 2C=CCI2 is commonly being used as a solvent
for dry cleaning. It is now known that PERC contaminates ground water and
is a suspected human carcinogen.
A technology, known as Micell Technology developed by Joseph De
Simons, Timothy Romack, and James McClain made use of liquid carbon
dioxide and a surfactant for dry cleaning clothes, thereby replacing PERC.
Dry cleaning machines have now been developed using this technique.
Micell technology has also evolved a metal-cleaning system that uses carbon
dioxide and a surfactant, thereby eliminating the need of halogenated solvents·.
4.2 Versatile Bleaching Agent

It is common knowledge that paper is manufactured from wood (which
contains about 70% polysaccharides and about 30% lignin). For good quality
paper, the lignin must be completely removed. Initially, lignin is removed by
placing small chipped pieces of wood into a bath of sodium hydroxide and
sodium sulfide (that is how pulp is formed). By this process about 80-90% of
lignin is decomposed. The remaining lignin was so far removed through reaction
with chlorine gas. The use of chlorine removes all the lignin (to give good
quality white paper) but causes environmental problems. Chlorine also reacts
with aromatic rings of the lignin (by aromatic substitution) to produce dioxins,
such as 2,3,7 ,8-tetrachloro-p-dioxin and chlorinated furans. These compounds
are potential carcinogens and cause other health problems.
Cl
Cl~0YyCl ---i+-Cl
Cl~O~Cl
2,3,7,8-Tetrachloro- Chlorinated
dibenzo-p-dioxin furans
16 GREEN CHEMISTRY
These halogenated products find their way into the food chain and finally
into products like dairy products, pork, beef and fish. In view of this, use of
chlorine has been discouraged. Subsequently, chlorine dioxide was used. Other
bleaching agents like hydrogen peroxide, ozone or oxygen also did not give the
desired results.
A versatile bleaching agent has been developed by Terrence Collins of
Carnegie Mellon University. It involves the use of hydrQgen peroxide as a
bleaching agent in the presence of some activators known as TAML activatorsz
that act as catalysts which promote the conversion of HzOz into hydroxyl
radicals that are involved in oxidationlbleaching. The catalytic activity ofTAML
activators allows HPz to break down more lignin in a shorter time and at
much lower temperature.
These bleaching agents also find use in laundry and result in lesser use of
water.
References
1. Miceli Technologies, Website: wwwmicell.com, accessed Dec. 1999.

2. J.A. Hall, L.D. Vuocolo, l.D. Suckling, C.P. HOIwitz, R.w. Allison, L.J. Wright and
T. Collins, A new catalysed hydrogen peroxide bleaching process, Proceedings of the
53,d APPITA Annual Conference April 19-22, 1999, Rotorua, New Zealand.
5. Environmental Pollution
The term pollution is used to describe the introduction of harmful substances

into the environment as a result of domestic, agricultural or industrial activities.
Substances which pollute the air include gases like oxides of carbon, sulphur
and nitrogen and the hydrocarbons emitted by thermal plants, motor vehicles
and chemical industries. The increase in the level of carbon dioxide produces
greenhouse effect, while nitrogen and sulphur oxides come down as acid rain
causing destruction of vegetation and aquatic life. Water is normally polluted
by effluents from industries, pesticides and fertilizers washed down from
agricultural fields and city sewage. The greatest release of hazardous waste to
the environment is from industries. Toxic chemicals flowing into rivers often
kill fish. People who eat the contaminated fish have been known to develop
health related problems, at times even fatal. Oil spills are also a major cause of
water pollution which, if happens near the shore may seriously affect coastal
flora and fauna. The increasing level of noise is also another cause of pollution
which effects the environment. Pollution in any form is harmful to human life,
and unless checked in time may threaten our very survival.
As already stated, environmental pollution results in a variety of ways.
Presently, only the environmental pollution caused by the use of solvents,
reagents and products will be dealt with.
The solvents that are mostly employed include volatile organic solvents
(VOCs) like methylene chloride, chloroform, perchloroethylene (PERC) and
carbon tetrachloride. Some VOCs like, isopropyl alcohols, xylenes, toluenes
and ethylenes have been used as cleaning fluids because of their ability to
dissolve oils, waxes and greases. Also, they readily evaporate from the items
that they are being used to clean (VOCs readily evaporate or vaporise at room
temperature). When VOCs come in contact with sun light and nitrogen oxides
(by-products from the combustion of fossil fuels), these are transformed into
ozone, nitric acid and partially oxidised organic compounds.
VOCs + NO + Sunlight - - - 0 3 + HN03 + Organic compounds

(partially oxidised)
This product mixture (consisting of ozone, nitric acid and partially oxidised
organic compound) is formed at the ground level and is commonly called
smog. Continued exposure to smog may result in aggravating asthma and may
induce respiratory problems) and can also cause lung cancer.2
18 GREEN CHEMISTRY
This phenomenon leads to elevated levels of tropospheric ozone (one of

the components of smog) and may cause damage to crops, discolour fabrics
and harden rubber.
The use of chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons
(HCFCs) as solvents creates environmental problems. When CFCs are released
into the atmosphere, these being inert, rise through the troposphere into the
stratosphere (the CFCs are also released to the atmosphere from refrigeration
industries), where they are photochemically decomposed by high-energy
ultraviolet radiation from the sun. In fact the ozone layer present in the
stratosphere prevents the harmful ultraviolet radiations from reaching the earth.
On photochemical decomposition, the CFCs result in the formation of atomic
chlorine (chlorine radical), which destroys the ozone by abstracting an oxygen
atom from an ozone molecule and converting it into oxygen. The CIa radical
formed, can react with an oxygen atom to form an oxygen molecule and
regenerate a chlorine radical.
CF 2CI 2 + UV-----l~~ CF 2CI + CI·

0 3 + C( ~ O2 + CIO·
CIO· + 0 ~ CI· + O 2
The overall reaction is the conversion of ozone into oxygen.
This results in depletion of the ozone layer and so the harmful ultraviolet
radiations reach the surface of the earth. These ultraviolet radiations are
responsible for causing skin cancer and cataract among humans.
Due to above reasons, the governments around the world have forbidden
the use ofCFCs. The Montreal Protocol, signed in Canada in 1987 and 1989,
and subsequently in London in 1990 decided to speed up the phasing out of
CFCs. It has already been stated (sec 2.4) that liquid and supercritical carbon
dioxide has replaced CFCs which were also used as blowing agents for
polystyrene. 3 Subsequently in place of CFCs, aliphatic hydrocarbons (e.g.,
pentane) were used as blowing agents for polystyrene. Though aliphatic
hydrocarbons are not ozone depleting, they can lead to the formation of ground
level smog (a mixture of ozone, nitric acid and partially oxidised organic
compounds) if their emissions are not captured. A harmless blowing agent
viz. carbon dioxide has been developed. The advantage of CO 2 is that it does
not deplete the ozone layer, does not form smog, is economical, handling is
easier and is nonflammable.
Environmental Pollution 19
However, carbon dioxide is a greenhouse gas. It is commonly known that

in the atmosphere, CO 2 allows UV and visible radiations to reach the earth's
surface but reflects the IR radiations (heat) coming from the earth's surface
and directing it back to the earth. Thus, excess levels of CO 2 in the atmosphere
can significantly raise the temperature of the earth's atmosphere, which is
responsible for global warming.
Nitrous oxide (NP), commonly known as laughing gas is also known to
cause environment pollution. Nitrous oxide is obtained as a by-product during
the manufacture of adipic acid as follows:
oBenzene
Ni or Pt.
Cyclohexane
02~ 6°
Cat
Cyclohexanone
+ 6 0H
Cyclohexanol
HOOC-(CH2)4-COOH + N 20
Adipic acid
The production of Np as a by-product can cause 10% annual increase of

Np levels. 4 The Np is obtained as a by-product in a number of reactions
involving oxidation with RN0 3 • The Np formed rises into the stratosphere
and plays a role in the destruction of the ozone layer. The first step in this
process is the reaction of Np with atmospheric oxygen to produce NO·,
which acts as a catalyst to deplete ozone l (steps 2 and 3). Nitric oxide abstracts
an oxygen atom from an ozone molecule, giving 02 and NO; (step 2). The
resulting NO~ then reacts with an additional oxygen atom regenerating NO·
and forming another molecule of 02' The regenerated NO· (step 3) can react
again (steps 2 and 3) resulting in significant loss of ozone for every molecule
ofN 20.
NP+O· --.....,~. 2NO· (1)

NO· + 0 3 ----'>. NO; + 02 (2)
NO·2 +0· ----'>. NO· + 02 (3)
The overall reaction is
---I~~ 20 2
20 GREEN CHEMISTRY
Np also acts as a greenhouse gas and causes global warming (as in the case
of CO). Also, air pollution is a result of exhaust emissions particularly CO 2
(already discussed) and nitrogen oxides. The nitrogen oxide part of the exhaust
mixes with moisture in the atmosphere and then comes down in the form of
acid rain. During lightening and thunderstorm, the nitrogen in the atmosphere
combines with oxygen to give nitric oxide, which combines with oxygen to
give N0 2 • The N0 2 dissolves in water to give HN0 2 and HN0 3 , which finally
come to earth in the form of acid rain.
Electric discharge
N+O - - - - - - - - ,... NO
NO + ° -----~~.. N0 2
2N0 2 + H 2 0 -----~~.. HN0 2 + HN0 3
Acid rain is detrimental to plants and aquatic life. In some extreme cases,
when the pH falls below 4.5, acid rain is responsible for making lakes devoid
of aquatic life. 5
References
1. C. Baird, Environmental Chemistry, W.H. Freeman, New York, 1999.

2. Smog linked to lung cancer in men. www.web.netlmeniair.htm. accessed Dec. 1999.
3. Ozone depleting substances, www.epa.govlspdpublidods.html, accessed Dec. 1999.
4. K.M. Draths and J. W. Frost, Environmentally Compatible Synthetic of Adipic Acid
from D-glucose, J. Am. Chem. Soc., 1994, 116,399-400.
5. P. Buell and J. Girard, Chemistry: An Environmental Perspective, Prentice Hall,
Englewood Cliffs, NJ, 1994.
6. Green Reagent
In order to carry out the transfonnation of selected feedstock into the target
molecule the criteria of efficiency, availability and effect of the reagent used
must be kept in mind. Some of the green reagents are as follows.
6.1 Dimethylcarbonate
Conventional methylation reactions employ methyl halides or methyl sulfate.
The toxicity ofthese compounds and their environmental consequences render
these syntheses somewhat undesirable. Tundo 1•2 developed a method to
methylate active methylene compounds selectively using dimethy1carbonate
(DMC) (Scheme I) in which no inorganic salts are produced.
R R
Scheme 1
Dimethy1carbonate (DMC) can also act as an organic oxidant.

Cyclopentanone and cyclohexanone react with DMC and a base ~C03 to
yield adipic and pimelic methyl (or ethyl) esters, respectivelyl (Scheme 2).
n= 1,2
Scheme 2
Many oxidative processes have negative environmental consequences. By

creating long-lived catalytic and recyclable oxidants, metal ion contamination
22 GREEN CHEMISTRY
in the environment can be minimized by using molecular oxygen as the primary

oxidant. Several ligand systems that are stable towards oxidative decomposition
in oxidizing environments are being developed by Collins. 4
6.2 Polymer Supported Reagents

Besides DMC, there are a group of reagents which though are ordinary reagents,
are bound to polymer support. The main advantage of using these reagents is
that any excess of the reagent can be recovered by filtration and used again.
Also, the isolation of the product is very easy. Some of such reagents are
given as follows:
6.2.1 Polymer Supported Peracids

These are used for epoxidations of alkenes in good yields S (Scheme 3).
Scheme 3
6.2.2 Polymer Supported Chromic Acid

The polymer supported chromic acid (Amberlyst A-26, HCrO~ form is
commercially available) and has been used to oxidise primary and secondary
alcohol to carbonyl compounds6 and also oxidizes allylic and benzylic halides
to aldehydes and ketones. 7
6.2.3 Polymeric Thioanisolyl Resin

Polystyrene methyl sulphide on reaction with chlorine in the presence of
triethylamine forms s-chloro sulfonium chloride resin, which acts as a selective
oxidant for the alcohols 8 (Scheme 4).
6.2.4 Poly-N-Bromosuccinimide (PNBS)

It is an efficient polymer based brominating agent and is used as benzylic and
allylic brominating agent. Thus, cumene on bromination9 yield a,~,~'
tribromocumene (Scheme 5). However, bromination with NBS gives
a,~-dibromocumene and a-bromocumene.
Green Reagent 23
®-{ }-S-CH l _C_1

Et3N
2_.. ®-{ }-1-cHlcr Cl
\':17
s-Chloro sulfonium chloride
l OH (CH 2).OH
HO (CH 2)._1 CHO (50.2%)

+
OHC (CH 2)._2 CHO (2.2%)
Scheme 4
PNBS
CCl4
Q
::::::.... ......Br
......C. . . .
Q
BrH2C CH2Br
a,p,p' -Tribromocumene
CH
H3C...... ........CH3
Cumene NBS
Q
::::::.... ......Br
C
+
Q
::::::.... ......Br
......C. . . .
H3C.............CH3 H3C CH2Br
a-Bromocumene a,p-Dibromocumene
PNBS=
0
I
Br n
Scheme 5
24 GREEN CHEMISTRY
6.2.5 Polymeric Organotin Dihydride Reagent as a Reducing Agent

The versatility and selectivity of organotin hydride. is well documented. The
use of polymeric organotin dihydride reagent involves ease of operation and
reaction workup and avoids toxic vapours, characteristic of tin hydride.
The polymer supported organotin dihydride reagent has been used lO for
the conversion of aldehydes and ketones to alcohols in 80-90% yields and the
reduction of halides to hydrocarbons. The use of organotin hydride for the
reduction of alkyl and aryl halides in presence of other functional groups is
generally superior to lithium aluminium hydride. This can also be used for the
selective reduction of only one functional group of a symmetrical difunctional
aldehyde (terephthaldehyde).
6.2.6 Polystyrene Carbodiimide

Polystyrene carbodiimide is useful for the synthesis of anhydrides II. It can
also be used for the Moffatt oxidation of alcohols to aldehydes and ketones.
Even the labile prostaglandin intermediate (A) is readily converted to the desired
aldehyde (B) (Scheme 6).
o 0
q~ ~CH'_N=C=N_C{H' O~
O--CH,OH - CH, ~ Q-CHO
O-C-R O-C-R
II II
o 0
(A) (B)
Scheme 6
6.2.7 Polystyrene Anhydride

Acetylation of aniline with polystyrene anhydride gives 12 benzanilide in 90%
yield. Similarly, ethyl benzoate is obtained in 90% yield by acylation of
ethanol.
6.2.8 Sulfonazide Polymer

It provides a route by which diazo group can be transferred13 to 1,3-dicarbonyl
compounds very conveniently (Scheme 7).
Green Reagent 25
o 0 0 0
II II I 25°C II II I IT\\
(E)-S02N3 + Et3N + R-C-CH2-C-R --.~ R-C-C-C-R + \,!J-S02NH2
II
N2
Scheme 7
6.2.9 Polystyrene Wittig Reagent

The polymeric Wittig reagent14 (prepared as given in Scheme 8) reacts witil
carbonyl compounds (e.g. C6HsCOCH3 , p-CIC6H4CHO, C6HsCHO etc.)
to give the usual products (Scheme 8).
~ >- U CIPPh, ~ ~PPh, RR1CHBr
Polystyrene
Wittig reagent
Scheme 8
6.2.10 Polymeric Phenylthiomethyl Lithium Reagent

The polymeric phenylthiomethyllithium reagent 1S is useful for lengthening
of side chain of alkyl iodide in good yield (Scheme 9).
~ )-SCH2 U+ + ICH,(CH,)"R ~
~ )-SCH,(CH,)n+,R DMF
Scheme 9
26 GREEN CHEMISTRY
6.2.11 Polymer Supported Peptide Coupling Agent

Ethyl-l,2-dihydro-2-ethoxy-l-quinolinecarboxylate (EEDQ) is used for
forming peptide bond with no racemization. This reagent is now used as
polymer supported EEDQ16. The preparation of the polymer supported
reagents is described in literature 17 •
References
1. P. Tundo, F. Trotta and G. Moraglio, J. Org. Chern., 1987,52, 1300.

2. P. Tundo, F. Trotta and G. Moraglio, J. Chern. Soc., Perkin Trans. 1, 1989, 1070.
3. M. Selva, c.A. Marques and P. Tundo, Gazz. Chirn. Ital., 1993, 123,515.
4. T.l Collins, Ace. Chern. Res., 1994, 27, 279.
5. (a) lMJ. Frehet and K.E. Haque, Macrornolecules, 1975,8, 130.
(b) C.R. Harrison and P. Hodge, J. Chern. Soc., Chern. Cornrnun., 1974, 1009.
6. G. Cainelli, G. Cardillo, M. Orena and S. Sandri, J. Arn. Chern. Soc., 1976,98,6737.
7. G. Cardillo, M. Orena and S. Sandri, Tetrahedron Lett., 1976,3985.
8. G.A. Crossby, N.M. Weinshenkar and H.S. Lin, J Arn. Chern. Soc., 1975,97,2232.
9. (a) C. Yaroslavsky, A. Patchorink and E. Katehalski, Tetrahedron Lett., 1970,3629.
(b) C. Yaroslavsky, E. Patchonik and E. Katchalski, Israel J Chern., 1970,37.
10. N.M. Weinshenkar, G.P. Crosby and lY. Wong, J Org. Chern., 1975,40,1966.
11. N.M. Weinshenker and C.M. Shen, Tetrahedron Lett., 1972,3281.
12. M.B. Shambhu and G.A. Digens, Tetrahedron Lett., 1973, 1627.
13. WR. Roush, D. Feitler and l Rebek, Tetrahedron Lett., 1974, 1391.
14. (a) M.l Farrall and J.M.J. Frechet, J Org. Chern., 1976,41,3877.
(b) W Heitz and R. Michels, Angew. Chern. Int. Ed., 1972, 11,298.
15. G.A. Crossby and M. Katu, J Arn. Chern. Soc., 1977,99,278.
16. l Brown and R.E. Williams, Can. J Chern., 1971,49,3764.
17. Y.K. Ahluwalia and Renu Aggarwal, Organic Synthesis: Special Techniques, Narosa
Publishing House, New Delhi, 2001, pp. 150-190 and the references cited therein.
7. Green Catalysts
Some of the major advances in chemistry especially industrial chemistry, over

the past decade have been in the area of catalysts. Through the use of catalyst,
chemists have found ways of removing the need for large quantities of reagents
that would otherwise have been needed to carry out the transformations and
ultimately would have contributed to the waste stream.
Catalysts playa major role in establishing the economic strength of the
chemical industry and the clean technology revolution in the industry will
provide new opportunities for catalysis and catalytic processes. Following are
some different types of catalysts used.
7.1 Acid Catalysts

The traditional catalyst hydrogen fluoride, an extremely corrosive, hazardous
and toxic chemical used in the production oflinear alkylbenzenes (LAB's), has
been successfully replaced by a solid acid catalyst, viz. fluorided silica-alumina
catalyst, which does not require special material of construction (of the
container), involves lower operating costs and obviates the need for an acid
scrubbing system and waste disposal of calcium fluoride.·
Microencapsulated Lewis acids have replaced traditional corrosive
monomeric Lewis acids in the reactions like MichaeF, Friedel Crafts3 , Mannich4 ,
IminoaldoP reactions (Schemes 1 to 4).
° ° Ph °
Ph~Ph + Ph~OMe
Scheme 1
MCSc(OTf), ~ M e C 0 - U - OMe
CH,NO z' LiCI04 ~
50·C,6h
Scheme 2
28 GREEN CHEMISTRY
OSiMe3 Ph"'-..
0
Jl
MCSc(OTt)3 NH
+Ph~ ~ ~
PhCHO + PhNH2
I'
-C-H-3C-N-,-R-T,-3;.,.h.....
Ph' 'Ph
Scheme 3
OSiMe3 MCSc(OTt)3
+Ph~
[MCSc(OTt)31= Microencapsulated scandium trifluoro methane sulfonate
Scheme 4
Several large-scale industrial processes utilizing heteropolyacids (HPA)
catalysts exist. The two examples are hydration of the isobutylene and the
polymerization of the tetrahydrofuran. 6' 8
Zeolites are widely used in the petrochemical industry in acid catalyzed
processes and there are several reviews concerning recent developments in
their use in the synthesis of fine and speciality chemicals9•lo (Schemes 5
and 6).
Pentasilzeolites
300 ·C, 300 bar
Scheme 5
o
/\ o
~
~CH-CH2 Pentasilzeolite liq. or
CH~H
gas phase •
R yield> 90%
R
Scheme 6
Clayzic has been used to catalyze various Friedel-Crafts reactions including

those of aromatic substrates with alkyl halides, aldehydes and alcohols. Other
applications include the preparation of benzothiophenes by cyclisations of
Green Catalysts 29
phenylthioacetals (nonnal catalysts can cause extensive polymerisation of the

thiophene). The pores in clayzic are believed to favour the desired intramolecular
cyclisation at the expense of polymerisation (Scheme 7)11 and the olefination
of benzaldehyde involving a previously unknown reaction mechanism
Roo
(Scheme 8).12
Clayzic
PhCl, 132·C ~ S
Scheme 7
EPZ 10
MeN0 2
room temp.
Scheme 8
7.2 Oxidation Catalysts

A large number of supported reagents have been used in the liquid phase
partial oxidation of organic substrates. 13 •14 There has been considerable success
in the use of molecular sieves (titanium and vanadium) in commercial unitsY
The most important application oftitanium silicates (TS-I) is the hydroxylation
of phenol, giving mixtures of hydroquinone and catechol (Scheme 9). The
process is clean, giving excellent conversion to product with very little waste.
© ¢ +©lOH+ ©r
OH OH OH OH
TS-1 OH
OH
81% 7% 12%
Scheme 9
30 GREEN CHEMISTRY
Vanadium silicate molecular sieves are capable of selectively oxidising

4-chlorotoluene to 4-chlorobenzaldehyde using hydrogen peroxide as the source
of oxygen in acetonitrile solvent (Scheme 10).16
CRO CR 20R
VS-2IHP2
~ + +
373 KlMeCN
OR
CI CI CI CI
66% 21% 8%
Scheme 10
Recent reports of oxidation catalysts based on chemically modified support

materials include cobalt, copper and iron. Effective catalysts include cobalt
immobilised on silica which has been derivatised with carboxylic acid functions
(Scheme 11),11
E OR
OR
OR
(EtO)3Si(CH2)2CN
~
I 0,
O-"Si~O-~
0/
.?i CO (OAol,
Scheme 11
7.3 Basic Catalysts

In contrast to the areas of heterogeneous oxidation catalysis and solid acid
catalysis, the use of solid base catalysis in liquid phase reactions has not met
the same level of breakthrough.
The industrial applications of basic catalysts are in the alkylation of
phenol, side chain alkylation and isomerisation reactions (Schemes 12 to
14).18.19
Green Catalysts 31
Scheme 12
KOH/KI
Scheme 13
Scheme 14
Besides what has been stated above, the following catalysts/catalytic processes
find wide applications in industry.
1. Biocatalysis: The most important conversions in the context of green

chemistry is with the help of enzymes or biocatalysts20 (for details see
Chapter 11).
2. Phase transfer catalysis and crown ethers: These find numerous

applications in organic synthesis in industry and in the laboratories21 (for
details see Chapter 8).
3. Photocatalysis: A large number of conversions/syntheses have been

carried out photolytically (for details see Chapter 12).
7.4 Polymer Supported Catalysts

The conventional catalyst which is normally used in the homogenous phase, is
linked to a polymer backbone and is used in this form to catalyse different
32 GREEN CHEMISTRY
reactions. Following are some of the polymer supported catalysts and their
applications.
7.4.1 Polystyrene-aluminium Chloride

It is used to prepare ethers from alcohols. Thus, dicyclopropyl carbinol on
treatment with polystyrene-Alel3produces diedicyclo-propylcarbinyl) ether in
high yield (Scheme 15).22
Dicyc1opropyl carbinol Di(dicyc1opropylcarbinyl)ether
Scheme 15
Polystyrene-Alel3is a useful catalyst for synthetic reactions, which require

both a dehydrating agent and a Lewis acid. Thus, acetals are obtained in good
yield by the reaction of aldehyde, alcohol and polymeric AICl 3 in an organic
inert solvent.
Polystyrene-Alel3 is also an effective catalyst for hydrolysis of acetals,
e.g., heating the diethyl acetal of o-chlorobenzaldehyde with polymeric-AlCl3
in benzene-methanol-water (2:6:1) for 17.5 hr gave o-chlorobenzaldehyde in
60% yield. Without the use of catalyst, the yield of aldehyde is only 4%.
7.4.2 Polymeric Super Acid Catalysts

A polymeric super acid catalyst is obtained23 by binding aluminium chloride to
sulfonated polystyrene. This polymeric super acid catalyst is used for the
cracking and isomerisation of alkanes (e.g. n-hexane) at 357°C at atmospheric
pressure. Normally the above cracking and isomerisation is carried out in the
presence of Lewis acid at high temperature and high pressure.
7.4.3 Polystyrene-metaUoporphyrins
These catalysts24 are useful for the oxidation of thiols to disulphide (a very
facile reaction) in presence of base and is rapid even at room temperature
(Scheme 16).
Green Catalysts 33
RSH + base ..--;:::=====

, ~ RS - + H+ + base
...
2RS- + O2 ~ 2RS + 02-

2RS' ~ R2S2
02 - + H20 .. 20H + Y£)2
Scheme 16
7.4.4 Polymer Supported Photosensitizers

The photosensitizers supply molecular oxygen in a photochemical reaction.
Examples of usual photo sensitizers are Rose-Bengal, eosin-y, fluorescein.
The photo sensitizers are bound to Merifield type resin via ester bond
(Scheme 17).25
A polymer-bound rose-bengal photosensitizer is commercially available.
The efficiency of SENSITOX is about 65% of that of Rose-Bengal, but the
high yields of the products and the ease of isolation more than compensate
the slightly longer reaction periods (Scheme 17).
Cl
DMF
+ cv--O-CH2Cl 60°C,
20 hr
Cl
Rose-Bengal
Polystyrene Rose-Bengal (SENSI TOX)
Scheme 17
7.4.5 Polymer Supported Phase Transfer Catalysts

The use of phase transfer catalysts and crown ether will be discussed in
Chapter 8. When the organophi1ic orium salts and crown ethers are immobilised
34 GREEN CHEMISTRY
on a polymer matrix, they retain most of their catalytic activity. However, the
reaction rates are slower because of the difficulty in bringing the reacting
species in contact with the catalytic site. This drawback is overcome by using
a long chain to bind the catalyst to the polymer matrix. The advantage of using
these polymer supported catalysts is that the product formed is separated
from the reaction mixture by simple filtration and that the recycling of the
catalyst is possible.
Using the above catalyst, l-cyanooctane can be prepared by stirring a
mixture of I-bromooctane and potassium cyanide in the presence of resin
P-(CH2)6-P+ (C4H9-n)3 Br- for 1.6 hr (Scheme 18).26 Similarly, l-iodooctane
and n-octyl phenylsulphide are obtained as shown in (Scheme 18).
n-C 8HI7Br
I-Bromooctane
KCN
®-PTC
.. n-C 8 H I7 CN
l-cyanooctane (80%)
n-C 8 HI7Br
I-Bromooctane
KI
®-PTC
.. n-C 8H 171
l-iodooctane
n-C 8 HI7Br
I-Bromooctane
PhSK
... n-C 8H I7 SPh
n-octylphenylsulphide
®-PTC
Scheme 18
The preparation of various polymer supported phase transfer catalysts is

described in literature. 27
7.4.6 Miscellaneous Illustrations

Following are some typical illustrations using catalysts in green chemistry.
7.4.6.1 TiD2 Photocatalyst in Green Chemistry

Titanium oxide-based photocatalytic systems have been developed28 and are
important for the purification of polluted water, the decomposition of offensive
atmospheric odours as well as toxins, the fixation of CO2 and the decomposition
of chlorofluorocarbons on a huge global scale.
7.4.6.2 Solid Support Reagents

Using solid support reagents29 the following synthesis have been carried out
(Scheme 19).
Green Catalysts 35
(a) Cyanoethylation of alcohols and thioalcohols
RXH + A CN
Hydrotalcite
X=OorS
(b) Selective synthesis of ~-nitroalkanols
Mg-AI-hydrotalice • R +OH
H N0 2
(c) Acylation of alcohols with carboxylic acids
Clay catalyst
R-OH + AcOH -........:....--=---l.~ R-OAc + ROR + H2 0
(d) Fonnation ofC-C bond
LDH-F
LDH-F is a layered double hydroxide fluoride-solid base catalyst

Scheme 19
7.4.6.3 Synthesis of Bromoorganics: Development of Newer and Ecofriendly

Bromination Protocols and Brominating Agents
The bromoorganics are important precursors for the preparation of
phannaceutical, agrochemicals and other speciality chemicals. 30 The preparation
of these compounds involve the use of toxic chemicals, especially Br2, which
has been a cause of great concern globally. It has been possible to develop
newer and ecofriendly bromination protocols and brominating agents.31 Some
examples ofbromination are given in (Scheme 20).
7.4.6.4 Synthesis ofPyridinium Fluorochromate (PFC)

PFC is one of the most useful oxidants for partial and selective oxidations of a
variety of organic substrates.32 PFC is obtained as shown in Scheme 21. 33
36 GREEN CHEMISTRY
~
- - - - - i.. Ar-Br + Bu4NBr + RBr
~ Br
Br>=<R
R =::.R + Bu4NBr3 - - - - i..
~ --- +
R Br
Scheme 20
crt), + 0 + FF
Scheme 21
7.4.6.5 Synthesis ofIso octane
Isooctane constitutes an integral part of gasoline. Its conventional method of
synthesis requires large amount of highly toxic and corrosive acids. A convenient
method34 involves the use of suitable solid acids such as alumina, zeolites or
nafion polymer (perfluoropolymer with -S03 side group) (Scheme 22).
+ /'V
Isooctane
Scheme 22
Green Catalysts 37
References
1. P. T. Anastas and 1.c. Warner, 'Green Chemistry, Theory and Practice', Oxford University
Press (1998).
2. S. Kobayashi, I. Hachiya, H. Ishitani and M. Araki, Synlett., 1993,472.
3. A. Kawada, S. Mitamura and S. Kobayashi, Synlett., 1994,545.
4. S. Kobayashi, M. Araki and M. Yasuda, Tetrahedron Lett., 1995,36,5773.
5.. S. Kobayashi, M. Araki, H. Ishitani, S. Nagayama and S. Hachiya, Synlett., 1995,233.
6. M. Misono, Catal. Rev. Sci-Eng., 1987,29,269; 1987,30,339.
7. (a) T. Okuhara, N. Mizuno and M. Misono, Adv. Cala!., 1996,41, 113.
(b) N. Mizuno and M. Misono, Chern. Rev., 1998,98, 199.
8. M. Misono and N. Nojiri, Appl. Catal., 1990,64, 1.
9. A. Corma, Chern. Rev., 1995,95,559.
10. A. Corma and H. Garcia, Catal. Today, 1997,38,257.
II. P.O. Clark, A. Kirk and 1.G.K. Yee, J Org. Chern., 1995,60, 1936.
12. H.P. Van Shaik, RJ. Vjin and F. Bickelhaupt, Angew Chern. Int. Ed. Eng!., 1994,33,
1611.
13. Solid Supports and Catalysts in Organic Synthesis, ed. K. Smith, Ellis Horwood,
Chichester, 1992.
14. l.H. Clark, 'Catalysis of Organic Reactions using Supported Inorganic Reagents', VCH,
New York, 1994.
15. A.W. Ramaswamy, S. Sivbasanker and P. Ratnasamy, Microporous Mater, 1994,2,451.
16. T. Selvamand A.P. Singh,J Chern. Soc. Chern. Cornrnun., 1995, 883.
17. AJ. Butterworth, 1.H. Clark, S.J. Barlow and T.W. Bastock, u.K. Patent Appl., 1996.
18. 1.H. Clark, A.P. Kybett and OJ. Macquarrie, 'Supported Reagents: Preparation, Analysis
and Applications', VCH, New York, 1992.
19. T. Ando, S.1. Brown, l.H. Clark, D.G. Cork, T. Hanatusa, 1. Lehira, l.M. Miller and
M.J. Robertson, J Chern. Soc., Perkin Trans., 1986, 2, 1133.
20. M. Held, A. Schmid, 1.B. Van Beilen and B. Withold, Pure Appl. Chern., 2000, 72(7),
1337.
21. M. Makosza, Pure Appl. Chern., 2000, 72(7), 1399.
22. D.C. Neckers, D.A. Kooistra and G.w. Green, J Arn. Chern. Soc., 1972,9284.
23. VL. Magnotta, B.C. Gates and G.C.A. Schuit, J Chern. Soc. Chern. Cornrnun., 1976,
342; VL. Magnotta and B.C. Gates, J Pol. Sci. Polyrn. Chern. Ed., 1977,15, 1341;
VL. Magnotta and B.C. Gates,J Catal., 1977,46,266.
24. L.D. Rollmann,J Arn. Chern. Soc., 1975,97,2132.
25. E.C. Blossey, D.C. Neckers, A.L. Thayes and A.B. Schapp, J Arn. Chern. Soc., 1973,
95,5820; A.P. Schapp, A.L. Thayer, E.C. Blossey and D.C. Neckers,J. Arn. Chern. Soc.,
1975,97,3741.
26. M. Cinouini, S. Colonna, H. Molinari and F. Montanari,J. Chern. Soc. Chern. Cornrnun.,
1976,396.
27. VK. Ahluwalia and Renu Aggarwal, Organic Synthesis, Special Techniques, Narosa
Publishing House, New Delhi, 2000, p. 150-190 and the references cited therein.
28. M. Anpo, Pure Appl. Chern., 2000, 72, 1265.
29. l.S. Yadav and H.M. Meshram, Pure Appl. Chern., 2001, 73, 199; B.M. Choudary,
M. Lakshmi Kantam and B. Kavita, Green Chern., 1999, 1, 289; B.M. Choudary,
V. Bhaskar, M. Lakshmi Kantam, K.K. Rao and K.V. Raghavan, Green Chern., 2000,
2, 67; B.M. Choudary, M. Lakshmi Kantam, V Neeraja, K.K. Rao, F. Figneras and
I. Delmotte, Green Chern., 2001, 3, I.
38 GREEN CHEMISTRY
30. G.w. Gribbe, Chern. Soc. Rev., 1999,28,335; A. Butler and lY. Walker, Chern. Rev.,
1993,93,1937.
31. M.K. Chaudhuri, A.T. Khan, B.K. Patel, D. Dey, W. Kharmawphlang,
T.R. Lakshmiprabha and G.c. Mandel, Tetrahedron Lett., 1998,39,8163; U. Bora, G.
Bose, M.K. Chaudhuri, S. Dhar, R. Gopinath, A.T. Khan and B.K. Patel, Org. Lett.,
2000,2,247; B. Bora, M.K. Chaudhuri, D. Dey and S.S. Dhar, Pure Appl. Chern., 2001,
73,93; G. Bose, P.M. Bujar Barna, M.K. Chaudhuri, D. Kalita and A.T. Khan, Chern.
Lett., 2001,290.
32. J.H. Clark (ed.), Chemistry of Waste Minimization, Chapman and Hall, London, 1995.
33. U. Bora, M.K. Chaudhuri and S.K. Dehury, Current Science, 2002, 82, 1427.
34. lA. Cusumano, Cherntech, 1992,485.
8. Phase-Transfer Catalysis in
Green Synthesis
8.1 Introduction
Most ofthe pharmaceuticals or agricultural chemicals (insecticides, herbicides,
plant growth regulators) are the result of organic synthesis. Most of the
syntheses require a number of steps in which additional reagents, solvents and
catalysts are used. In addition to the syntheses of the desired products, some
waste material (by-products) is generated, the disposal of which causes
problems and also environmental pollution. In view of this, attempts have
been made to use procedures that minimise these problems. One of the most
general and efficient methodologies that takes care of the above problems is to
use a phase-transfer catalyst (PTC).1.3
Difficulties are often encountered in organic synthesis if the organic
compound is soluble in organic solvent and the reagent in water. In such
cases, the two reactants will react very slowly and the reaction proceeds only
at the interface where these two solutions are in contact. The rate of the
reaction can, of course, be slightly increased by stirring the reaction mixture
and by using aprotic polar solvents, which solvate the cations so that the
anions are free. Such solvents (like dimethylsulfoxide, dimethylformamide)
are expensive and their removal is difficult. Also the use of strong bases (which
are necessary for the reactions like Wittig etc.) create other problems and
many side reactions take place. These problems can be overcome by using a
catalyst, which is soluble in water as well as in the organic solvent. Such
catalysts are known as phase-transfer catalysts (PTC).
The PTC reaction, in fact, is a methodology for accelerating the reaction
between water insoluble organic compounds and water soluble reactants
(reagent). The basic function ofPTC is to transfer the anion (from the reagent)
from the aqueous phase to the organic phase. As a typical example, the reaction
of I-chioro octane with N aCN in water does not give I-cyanooctane even if
the reaction mixture is stirred for several days. However, if a small quantity of
an appropriate PTC is added the product is formed in about 2 hr giving 95%
yield (Scheme 1).
40 GREEN CHEMISTRY
Scheme 1
The mechanism of the PTC reaction is well known and is described in

relevant literature. 1·3
Phase transfer catalysts used are the quaternary 'onium' salts, such as
ammonium, phosphonium, antimonium and tertiary sulphonium salts. In
practice, however, only a limited number of ~onium and phosphonium
salts are widely used. Some of the PTCs normally used are:
(i) Aliquat 336: methyl trioctyl ammonium chloride, N+CH3 (CsH17)3CI-
(ii) Benzyl trimethyl ammonium chloride or bromide (TMBA),
N+(CH3)3CH2C6HsX- (X = CI or Br)
(iii) Benzyl triethyl ammonium chloride or bromide (TEBA), N+ (C 2H s)3
CH2C6HsX- (X = CI or Br)
(iv) Tetra-n-butyl ammonium chloride, bromide, chlorate or hydroxide,
N+(n-Bu)4X- (X = CI, Br, CI0 4, OH)
(v) Cetyl trimethyl ammonium chloride or bromide (CTMAB for bromide),
N+ (CH3)3 (CH2)ISCH3X- (X = CI or Br)
(vi) Benzyl tributyl ammonium chloride, C6HsCH2 (n-C 4H9)3 N+ CI-
(vii) Benzyl triphenyl phosphonium iodide, C6HsCH2(C6Hs)3P+I-
Besides the above, another catalyst, crown ether is also widely used as PTC.
It is now well known that PTC reactions have considerable advantage
over the conventional procedures. PTC reactions:
(i) Are fast and do not require vigorous conditions.
(ii) Do not require expensive aprotic solvents.
(iii) The reaction usually occurs at low temperature.
(iv) The reaction is conducted in water and hence does not require anhydrous
conditions.
(v) With the help ofPTC the anion is made available in the organic solvent
and so the nUc1eophilicity increases.
(vi) The work-up procedure is simple.
(vii) Use of strong bases (like alkoxide, sodamide, sodium hydride) in the
reactions is avoided. The reaction proceeds even with OH- as it becomes
strong nuc1eophile in presence of PTC.
(viii)Except the reactions which are sensitive to water, all other reactions
can be carried out by PTC.
(ix) The reactions which do not proceed in the normal way can be made to
proceed in good yields.
Phase-Transfer Catalysis in Green Synthesis 41
A number of phase transfer catalysts are commercially available. However,

these can be conveniently synthesised. 4 Some of the advantages of phase-
transfer catalysts which are relevant to green synthesis are as follows:
(i) As the reaction is in two phases, a benign solvent may be used since
PTC devoids the solubility for all the reactants like dipolar aprotic solvent
and dimethylcarbonate. Moreover, in some cases organic solvents may
not be required at all, the substrate forming the second phase.
(ii) The procedures of separation are simple resulting in less waste as the
organic layer is mainly free from water soluble compounds and can
easily be decanted off. It is important to vigil the concentration of anion
in organic phase as it should not exceed the concentration of catalyst
(unless it is soluble in absence of a catalyst).
(iii) PTC catalysed reactions are very rapid as the anions in the organic
phase have very few water molecules associated with them making
them highly reactive because of less activation energy which causes
higher productivity.
(iv) These reactions can be run at a lower temperature owing to reduced
activation energy that causes greater selectivity and lesser by-product
formation.
8.2 Applications ofPTC in Organic Synthesis

As already mentioned, PTC can be used in numerous types of organic reactions
due to its advantages over conventional procedures. Some of the applications
are as follows.
8.2.1 Nitriles from Alkyl or Acyl Halides

Reaction Ref.
NaCN/Hp
CH3(CH)6~CI ~
~(~)6~CN
PTC 94% 5
CI6H3l+(n-C4H9)3Br- (purity 97%)
2 hr, 105°C
C6Hs~~CI
PTC
NaCNlHzO
.. C)Is~~CN
91%
6
W(CH 3))CH ZC6H sC)-

3 hr, 90-95 °C
C6HsCOCI
NaCN/Hp
PTC Bu4WX-
.. C)IsCOCN
60-70%
7
42 GREEN CHEMISTRY
8.2.2 Alkyl Fluorides from Alkyl Halides

The reaction of alkyl halides (chlorides or bromides) with KF in presence of a
PTC give alkyl fluorides. Scheme 2 gives the preparation of I-fluorooctane. 8
CH3(CH2)6CH2CI + KF _ _ _P_T_C_ _ _•• CH3(CH2)6CH2F

l-Chlorooctane
1- Fluorooctane
77%
Scheme 2
The above procedure is far superior to the conventional methods 9 and can also
be used for the preparation oflabelled alkyl halides having 36C1 by reacting the
alkyl halide with labelled Na36Cl. Scheme 3 illustrates lO the synthesis of
l-chlorooctane 36Cl.
CH3(CHz)6CH2Cl + Na36 CI
l-Chlorooctane
Scheme 3
8.2.3 Generation of Dihalocarbenes

Dihalocarbenes, synthetically useful intermediates, are normally generated by
the action of a base on chloroform.
-CI-
------i.~ :CeI2
Dichlorocarbene
(a) The in situ generated carbene can add on to across the double bonds to
give adducts. The use ofPTC gives the adduct in 60-70% yield 11 (Scheme 4).
No catalyst
()x CI
o
CI
+ CHCh + NaOH 0.5%
()x
aq.
PTC CI
CI
60-70%
Scheme 4
(b) This method is used for making diazomethane (Scheme 5). The generated
dichlorocarbene in situ is made to react with hydrazine to give diazomethane. 12
CH 2N 2 in ether or CH 2Cl 2
Diazomethane (35%)
Scheme 5
However, use of crown ether gives better yield (48%).

(c) The dichlorocarbene generated by the PTC method reacts with primary
amines to yield isonitriles (Scheme-6). \3
+ -
C6H sCH2N Et3CI ~ R-N=C
RNH2 + CHCl3 + NaOH
aq. Isonitrile
40-60%
Scheme 6
This is a convenient method compared to the two step process. 14

(d) The dichlorocarbene generated by PTC techniques reacts with amides,
thioamides ls , aldoximes and amidines to give the corresponding nitriles
(Scheme 7).
RCONH 2
+
RCSNH2 C6HsCH2NEt3 CC
RCH=NOH + CH3Cl + NaOH ~ R--CN
aq.
RC-NH2
II
NH
Scheme 7
(e) Alcohols on reaction with dichlorocarbene generated in a PTC catalysed

system 16 gave good yield of chlorides (Scheme 8). In case of steroidal alcohols,
the OH is replaced with CI with retention of configuration. 17
+
C6HsCH2NEt3CI-
ROH + CHCl3 + NaOH ~ RCI+ NaCl+ H20
aq.
Scheme 8
(f) Reaction with aromatic aldehydes. Dichlorocarbene generated by PTC

method reacts with aromatic aldehydes to give mandelic acids (Scheme 9).18
44 GREEN CHEMISTRY
R
O ~
I
CHO
+ CHCll + NaOH
aq.
~ OI
R ~
yH-C0 2H
OH
Mandelic acids
75-83%
Scheme 9
8.2.4 Generation ofVinylidene Carbenes

These can be generated l9 from 3-chloro-3-methyl-I-butyne with base under
vigorously anhydrous conditions. These add on to olefins in situ to give
dimethyl vinylidinecyclopropanes (Scheme 10). Use of PTC technique with
aqueous NaOH gives better yields and is more convenient. 20
R-CH-CH-R
\/
(CH 3hC-C=CH Base C
RCH=CH.. II
I .. .. (CH 3)2 C=C=C:
Cl anhyd. conditIOn V' l·d b C
my I ene car ene II
3-Chloro-3-methyl- C
I-butyne H3 C ................ CH 3
Dimethylvinylidene
cyclopropanes
Scheme 10
8.2.5 Elimination Reactions

(a) Dehydrohalogenation can be achieved by the reaction of alkyl halides with
aq. NaOH in presence ofPTC.
PTC
T
R H-CH 2R' ---;~.. RCH=CHR'
Br
(b) The vic-dibromoalkanes can be neatly debrominated21 by the PTC process
using sodium thiosulphate with a catalytic amount of sodium iodide
(Scheme 11).
Scheme 11
Using this procedure the following compounds (Scheme 12) are obtained. 22
Ph-C=C-Ph ~ PhC=C-Ph
I I (75%)
BrBr
Ph-C=C-H ~ PhC=CH
I I (87%)
BrBr
H3C~~-H ~ H3C~==C-H
BrBr (77%)
Scheme 12
8.2.6 C-A1kylations
8.2.6.1 C-Alkylations of Activated Nitrites

Normally C-alkylation involves the use of expensive condensing agents like
sodamide, metal hydrides, potassium tertiary butoxide etc. and involves the
use of anhydrous organic solvents. Due to the high selectivity of PTC, it is
used for synthesis of mono alkyl derivatives ofnitriles (Scheme 13).23
The C-alkyl derivatives of activated nitriles are useful intermediates for the
manufacture of various pharmaceuticals and are commonly used in industry.
Similarly, N -benzoyl-l ,2-dihydroisoquinaldenitrile can be alkylated
(Scheme 14)24 in presence ofNaOH (aq.) and TEBA.
NaOH (50010)
IEBA
..
Scheme 14
46 GREEN CHEMISTRY
Alkaline hydrolysis of the alkylated product gives isoquinoline derivatives which

are starting materials for the synthesis of alkaloids.
8.2.6.2 C-Alkylation of Activated Ketones

Activated ketones (having an aromatic substituent at the a-CH2 group) can be
activated using PTC system (Scheme 15).25
C6HsCH2COCH3 + RX + N aOH
aq
Scheme 15
8.2.6.3 C-Alkylation of Aldehydes

Aldehydes containing only an a-hydrogen atom, e.g. isobutyraldehyde, can
be alkylated with alkyl halides in presence of 50% aq. NaOH and catalytic
amount of tetrabutyl ammonium ions (Scheme 16).26
R
Bu4NY- I
(CH3hCHCHO + RX + NaOH -~---:~~ (CH3h-C-CHO
aq.
Scheme 16
8.2.7 N-Alkylations
8.2.7.1 N-Alkylation ofAziridines

Aziridines cannot be easily N-alkylated using conventional conditions due to
rapid ring opening. However alkylation of aziridine can be achieved using PTC
conditions (Scheme 17).27
\7 \7
N
N +RX
H TEBA
I
R
Scheme 17
In a similar way, N-alkylation ofpyrrole under PTC conditions gives the

N-alkylated product as the major compound. 28 However, under normal
conditions C-alkylations also occur at positions 2 and 3.
8.2.7.2 N-Alkylation of J3 -Lactams

N-Alkylation of p-lactams has been carried out using PTC (Scheme 18).29
This is an important step in the synthesis of norcardicin.
H
TEBA.. (H)ChCO~HN~N 0"0CH)
O~j'CH~
I
C02C(CH3h
Scheme 18
8.2.8 S-Alkylation
The reaction of benzothiazole-2-thione with chlorobromomethane and PTC
conditions gave the corresponding 2-chloromethylthio-products (Scheme 19).30
PTC
Scheme 19
S-Alkylation of 2-pyridinethiones, 2-quinolinethiones and pyrimidine

derivatives has also been carried out.
8.2.9 Darzen's Reaction

The usual Darzen's reaction consists of the reaction of aldehydes or ketones
with a-haloester or a-halonitriles in presence of a base like potassium
tertiarybutoxide to give glycidic esters or nitriles, respectively (Scheme 20).
R __ K tert. butoxide R,
/C=O + CICH 2R R1/C\ /CH-R
Rl R=COORorCN
o
R=COORor CN
Scheme 20
This reaction has been found to occur in alkali solution in presence of
PTC (benzyl triethylammonium chloride).31
48 GREEN CHEMISTRY
8.2.10 Williamson's Ether Synthesis

The PTC technique provides a simple method for conducting Williamson ether
synthesis. Use of excess alcohol or alkyl halide, lower temperature and larger
alcohol (e.g. CSH1PH) give higher yields of ethers (Scheme 21).32
(Bu)4N+S04-
C gH 17 0H + CJ19C1 --N...;..aO-H---..:.----i.~ C gH 17 0CJ19 + C gH 17 0C gHI7
Byproduct
Scheme 21
Attempts to prepare ethers from alcohols by reacting with dimethyl sulphate

in aq. NaOH or even by the use of alkali metal alkoxide have been unsuccessful.
However, use of PTC (e.g. tetrabutyl ammonium salts) gives high yield of
ethers.33
8.2.11 The Wittig Reaction

The usual Wittig reaction consists in the treatment of a phosphonium salt with
a base (e.g. NaH) to give an ylide, which can react with aldehydes or ketones
to give ~lkenes (Scheme 22).
Phosphonium salt Ylide
R2C=O
---.....,.~ R 1CH=CR2 + Ph3 P=O
Alkene
Scheme 22
It has been found that the formation of ylide from phosphonium salt
(Scheme 22)34 can be very conveniently effected by using a PTC in aq. NaOH.
In PTC method the yield of the olefin increases. However, this PTC method is
applicable only to aldehydes; no olefin is obtained from ketones. Even with
this limitation, this method is very convenient for the preparation of a number
of ole fins of the type RCH=CHRI.
8.2.12 Sulphur Ylides

The sulphur ylides are generally prepared by the treatment of a sulphonium
salt with a base like alkyl lithium (Scheme 23).
Phase- Transfer Catalysis in Green Synthesis 49
RLi
(CH 3hS + CH3I ..
----;~ (CH 3)3 S+-
I -----i~
..
Dimethyl Methyl Sulphonium

sulphide iodide salt
+
(CH 3hS-CH 2 ~~-~
.. (CH 3hS=CH 2
Sulphur ylide
Scheme 23
It has now been found that in place of strong base (like alkyl lithium), a
PTC like (C6Hs)4N+I- in presence of aq. NaOH can be used. 3s
8.2.13 Heterocyclic Compounds
8.2.13.1 3-Alkyl Coumarins

3-Alkyl Coumarins are increasingly being used as optical brightners36 and were
obtained in low yields using anhydrous conditions37 . These have now been
obtained (Scheme 24) in excellent yield and purity by the use ofPTC in presence
of aq. K 2C0 3 by the reaction of o-hydroxycarbonyl compounds with phenyl
acetyl chlorides. 38
H'CW:~, CH3
4,6-Dimethyl-3-phenyl
coumarin (96%)
Scheme 24
8.2.13.2 Flavones
Flavones are an in'oortant class of natural products. These were synthesised
in low yields by a nJmber of methods. 39 These have now been obtained in
excellent yields by the reaction of an appropriate o-hydroxyacetophenone with
50 GREEN CHEMISTRY
an appropriately substituted benzoyl chloride in benzene solution with a PTC

in presence of NaOH or Na 2C0 3 followed by cyclisation of the formed
o-hydroxydibenzoyl methane with p-toluene sulphonic acid (Scheme 25).40
- -07
0 C6Hs
PTSA
R
::::::,....
I I
°
Flavones
Scheme 25
8.2.13.3 3-Aryl-2H-I,4-Benzoxazines
The title compounds known for their anti-inflammatory activity were prepared
earlier in low yields. 41 Polymer supported phase transfer catalysts have also
been used (for details see sec 7.4.5) for various reactions. These have now
been prepared42 by the condensation of2-aminophenols with phenacyl bromide
in presence of a PTC in aq. K 2C0 3 (Scheme 26).
R -EXI
:::::"..
0H
NH2
+
Scheme 26
In addition to the above, a number of other heterocyclic compounds,

for example, 2-aroylbenzofurans, 1,3-benzoxathioles, dihydropyrans,
l,4-benzoxazines, hydantoin derivatives, piperazine-2,5-diones, thioethenes,
l-arylbenzimidazoles, benzofuran-l-oxides, piperazinones, thiazoles,
5-thiacyclohexanecarboxaldehyde, pyrroles, triazines, fused napthoquinone
derivatives and ~-lactams have been synthesised using PTC technique. 43
8.3 Oxidation Using Hydrogen Peroxide Under PTC Condition

Hydrogen peroxide is an excellent environmentally benign oxidant that produces
water as the only by-product. It is used in relatively dilute form (30 volume).
Hydrogen peroxide could be used in place of higher waste generating peroxides
such as peracetic acid or tertiary butyl hydrogen peroxide. There are two
possible mechanisms for transferring peroxide to the organic phase. First
transporting the H0 2- ion. This anion is strongly hydrophilic and has a high
hydration energy that does not exchange readily with other anions. It shows
that the classical mechanism is followed. The second mechanistic approach
seems to involve extraction via complexes of the type R+X--HP2' Hydrophobic
quaternary salts such as (C 6H 13)4 NBr are most widely used. In some cases
hydrogen peroxide is not involved in direct oxidation, the main oxidant in these
cases are metal complexes of W or Mo. In this case the role of hydrogen
peroxide is to reoxidize the metal complexes in situ that make the process a
catalytic one with respect to metal. The major environmental benefit for the
usage of hydrogen peroxide is exemplified in alkene cleavage. Thus,
cyclohexene on treating with 30% hydrogen peroxide in presence of catalytic
amount of sodium tungstate and methyltricetylammonium hydrogen sulphate
at 90°C gives adipic acid in excellent yield. 44 The commercial viability of this
route holds obviously high potential (Scheme 27).
Scheme 27. Noyori synthesis of adipic acid
8.4 Crown Ethers

This is a group of cyclic polyethers which are used as phase transfer catalysts.
These have been used for esterifications, saponifications, anhydride formation,
oxidations, aromatic substitution reactions, elimination reactions, displacement
reactions, generation of carbenes, alkylations etc. Some of the examples are
as follows:
8.4.1 Esterification
Crown ethers are useful for esterification. Reaction of p-bromophenacyl
bromide with potassium salt of a carboxylic acid using 18-crown-6 as the
solubilizing agent have been used to prepare 4S p-bromophenacyl esters
(Scheme 28).
8.4.2 Saponification
The main problem of using potassium hydroxide for saponification is its
insolubility in organic solvents like toluene, but this can be solved by using
hydrophobic and hydrocarbon soluble macrocyclic derivatives like dicyclohexyl
18-crown-6, it has been shown that potassium hydroxide is soluble in toluene.
This special observation46 has been used for the hydrolysis of sterically hindered
esters using potassium hydroxide complex in toluene (Scheme 29).
52 GREEN CHEMISTRY
R = H, CH3, CH3CH2, CH3CH2CH2, C6HS, 2-CH3C6~,

2,4,6-trimethylbenzoyl, 4-t-butyl C6H4
Scheme 28
~I
CH3 ~-OR ~CH3 ~ 00
,... K+ dicyclohexyl
+ -OH -------l.~
~ I - + ROH
~ [18] Crown-6 ~
H3 CH3 H3 CH3
R = CH3, t-Bu, neopentyl
Scheme 29
8.4.3 Anhydride Formation

A convenient synthesis of anhydrides has been described47 by the reaction of
potassium or sodium salts of carboxylic acids with activating halides (ethyl
chloroformate, cyanuric chloride and benzyl chloroformate) in acetonitrile
in the presence of 18-crown-6. Using this procedure, cinnamic acid,
p-nitrobenzoic acid, benzoic acid, acetic acid and propionic acid are also
converted into their anhydrides (Scheme 30).
-EY
0 0 0
R
,...
"-
~
I
II
C- OK 0" 18-Crown-6
+ CI-C-OC 2Hs -----~ R
CH)CN
~
II
-(YC-O
II
- C~
I~
'6
R
~
Room temprature
1.5 hr
Scheme 30
8.4.4 Potassium Permanganate Oxidation

Potassium permanganate is the most widely used reagent for the oxidation of
organic compounds. It is usually used in aqueous solution and this restricts its
usefulness since many compounds are not sufficiently soluble in water and
only a few organic solvents like acetic acid, t-butanol, dry acetone and pyridine
are resistant to the oxidising action of the reagent. Alternatively, oxidation in
presence of crown ether, dicyclohexano-18-crown-6 forms a permanganate
complex. Under these conditions permanganate becomes soluble in benzene

and the resulting solutions are excellent reagents for oxidation of a variety of
organic substrate in organic solvents (Scheme 31).
MnO~
Scheme 31
Applying this technique, substituted catechols are converted into
corresponding o-quinones in excellent yields47 wherein only one equivalent of
KMn04 is used (Scheme 32).
OH
KMn04
~
[18]-Crown-6
OH CH 2C1 2
Scheme 32
Oxidation of a.-pinene in the presence of crown ethers yield pinonic acid

in 90% yield (Scheme 33).48
~O_
dicyc1ohexano
[18]-Crown-6 l2t:5 00H
Pinonic acid
a-Pinene
Scheme 33
8.4.5 Aromatic Substitution Reaction

The substitution of 2-chloropyridine by 1,6-dihydroxyhexane in good yield
was carried out using 18-crown-6 as a catalyst. Furthermore, the electron
rich ring undergoes methoxide substitution in excellent yield using the same
catalyst (Scheme 34).49
54 GREEN CHEMISTRY
2 0
l:. __ A
HO(CH2)60HKOH~
18-crown-6 Cl~o0
N Cl N ~_.) 0
W
N
H3 CO
KOCHl' benzene ~ I
[18]-Crown-6 ~ N
CH 3
Scheme 34
8.4.6 Elimination Reaction

Crown ethers ability to enhance or alter the reaction is significantly important. 49
This is depicted in (Scheme 35).
H Ph
~Ph (yPh
TsOllH U
KO'Bu
+
syn-elimination anti-elimination
30% 70%
Dicyc1ohexano[18]-Crown-6
Scheme 35
In the absence of crown ether syn-elimination takes place in 91 % yield

along with 9% of anti-elimination.
8.4.7 Displacement Reaction

Crown ether has been used for nucleophilic displacement of chloride by cyanide
at hindered position. At room temperature the reaction of 2-chloro-2-methyl
cyclohexanone with potassium cyanide in acetonitrile in presence of 18-crown-
6 affords the cyanide in excellent yield, but when the reaction is conducted at
reflux temperature Favorskii rearrangement occurs to yield five membered
compound in high yield (Scheme 36).
8.4.8 Generation of Carbene

Dicyclohexyl-18-crown-6 has been used50 to convert cyclohexene and trans
stilbene to the respective gem dihalocyclopropanes in 30-70% yields by the
reaction of sodium hydroxide and chloroform at 40°C. Dibenzo lS-crown-6
has also been used 51 as liquid-liquid phase transfer catalyst for carbene generation
(Scheme 37).
KCN [18]-Crown-6
~
CH)CN or C6H6
Room temperature
o~
~ Q< II
C-CN KCN
[ 18]-Crown-6 CH 3 [18]-Crown-6
A A
Scheme 36
CH2=CH-X + CHCl3
50% aqueous NaOH
----------------~.
~ CI~CIx
dibenzo [18]-Crown-6
X=Ph, CN
X =Ph 87%
X=CN 40%
Scheme 37
8.4.9 Superoxide Anion Reaction
The most important application of crown ether is in superoxide chemistry. In
fact the use of superoxide (~o and NaOz) has been limited due to the solubility
problem. Use of crown ether along with a superoxide for the oxidative
dimerisation is a typical application. A cheap potassium superoxide (K0 2) is
available from commercial source and is a source for the generation of
superoxide radical anion readily available for the reaction (Scheme-38).s2
[ 18]-Crown-6ITHF
Scheme 38
56 GREEN CHEMISTRY
When tropone is treated with K0 2 and 18-crown-6 in DMSO solution

salicylaldehyde is obtained. This is an addition induced rearrangement
(Scheme 39).
6 DMSO, KOz
[ 18]-Crown-6
Scheme 39
(XI~
CHO
OH
8.4.10 Alkylation
Many aldehydes and ketones condense with acetonitrile in the presence of
solid potassium hydroxide using 18-crown-6 as a catalyst (Scheme 40).S2
[18]-Crown-6 R ............
~ l/C=CHCN
KOH R
Scheme 40
Similarly, phenyl acetone can be aikyiated S3 with n-butyl bromide in aqueous

sodium hydroxide using dicyclohexyl-18-crown-6 as a catalyst (Scheme 41).
Dicyc10hexyl
[18]-Crown-6, 80°C
C6HsCH 2COCH 3 + n-BuBr -"-....;...-.------l~~ C6Hs-CH-COCH 3
50% aqueous I
NaOH Bu(n)
Scheme 41
N-alkylation of pyrrole is carried outS4 using crown ether. The indolyl

anion behaves as an ambidient nucleophile and alkylation occursss at nitrogen
and at C-3 (Scheme 42).
~+RX
~N)
H
Base
Crown
ether
• en 0-r:Rr?)-(R
~N) ~N)-t~N)
R
+
H I
R
Scheme 42
Phase- Transfer Catalysis in Green Synthesis 57
References
1. E.Y. Dehmlov and S.S. Dehmlov, Phase transfer catalyst, 3rd ed., Verlag Chemie,
Weinheim, 1993.
2. C.M. Starks, c.L. Liotta and M. Halpen, Phase transfer catalysts: Fundamentals,
Applications and Industrial Perspectives, Chapman & Hall, New York, 1994.
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10. D. Forster,J Chern. Soc. Chern. Cornrnun., 1975,918.
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17. R.1kan, A. Makus and Z. Goldschmidt,J Chern. Soc., 1973, 11,591.
18. A. Merz., Synthesis, 1974, 724.
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20. G.F. Hennison, J.J. Sheehan and D.E. Maloneg, J Am. Chern. Soc., 1950,72,3542; G.F.
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23. M. Makosza, Tetrahedron Lett., 1968,24,175.
24. M. Makosza, Tetrahedron Lett., 1969,677.
25.1. Jamouse and C.R. Hebd, Seances Acad. Sci. Ser. C, 1951, 232, 1424; 1. Jonczyk,
B. Serafin and M. Makosza, Roz. Chern., 1971,45, 1027; 1. Jinczyk, B. Serafin and
E. Skulemowska, Rocz. Chern., 1975,45,2097.
26. H. Dietl and K.C. Brannock, Tetrahedron Lett., 1973, 1273.
27. M. Maurette, A. Lopez, R. Martino and A. Lattes, CR. A cad. Sei. Ser. C, 1976,282,
599.
28. A. Jonezyk and M. Makosza, Rocz. Chern., 1975,49, 1203.
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30. c.T. Gokalshi and G.A. Burk, J Org. Chern., 1977,42,3094.
31. A. Jonczyk, M. Fedorynski and M. Makosza, Tetrahedron Lett., 1972,2395.
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and R.A. Dubois, Tetrahedron Lett., 1975,3251.
33. A. Merz, Angew. Chern. Int. Ed. Engl., 1973,12,846.
58 GREEN CHEMISTRY
34. G. Markl and A. Merz, Synthesis, 1975,245; S. Hung and J. Stemmier, Tetrahedron
Lett., 1974,315; W. Tagaki, I. Inouse, Y. Yano and T. Okanogi, Tetrahedron Lett., 1974,
2587.
35. A. Merz and C. Markl, Angew. Chern. Int. Ed. Engl., 1973, 12, 846.
36. I. Dorlars, C. W. ScheIlhammer and J. Schroeder, Angew. Chern. International Ed., 1975,
14,665.
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ltial., 1879,9,478; T.R. Seshadri and S. Varadarajan, J. Sci. Ind. Res., 1952, 11B, 48;
Proc. Indian Acad. Sci., 1952, 35A, 75.
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Khanduri, IndianJ.Chern., 1989, 28B, 599.
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1391; H.S. Mahal and K. Venkatararnan, Curr. Sci., 1933,4,214; Y.N. Gupta and T.R.
Seshadri,J. Sci. Ind. Res. (India), 1957, 16B, 116.
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Synthesis, 1982,221.
41. D.R. Sridhar, C.V. Reddy Sastry, O.P. Bansal and R. PuIla Rao, Indian J. Chern., 1983,
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Publishing House, New Delhi, 2001, and the references cited therein.
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Molecular Engineering. Practical Chemo- and Stereoselective Hydrogenation of Ketones' ,
Angew. Chern. Int. Ed. Engl., 2001, 40, 40.
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9. Microwave Induced Green Synthesis
9.1 Introduction
Nonnally microwaves have wavelengths between 1 cm and 1 m (frequencies
of 30 GHz to 300 Hz). These are similar to frequencies of radar and
telecommunications. In order to avoid any interference with these systems,
the frequency of radiation that can be emitted by household and industrial
microwave oven is regulated, most of the appliances operate at a fixed frequency
of 2.45 GHz.
The microwaves, as we know, are used for heating purposes. The
mechanism of how energy is given to a substance which is subjected to
microwave irradiation is complex. One view is that microwave reactions involve
selective absorption of electromagnetic waves by polar molecules, non-polar
molecules being inert to microwaves. When molecules with a pennanent dipole
are submitted to an electric field, they become aligned and as the field oscillates
their orientation changes, this rapid reorientation produces intense internal
heating. The main difference between classical heating and microwave heating,
lies in core and homogenous heating associated with microwaves, whereas
classical heating is all about heat transfer by preheated molecules.
The preferred reaction-vessel for microwave induced organic reaction, is
a tall beaker (particularly for small scale reactions in the laboratory), loosely
covered and the capacity ofthe beaker should be much greater than the volume
of the reaction mixture. Alternatively, teflon and polystyrene containers can be
used. 1,2 These materials are transparent to microwaves. Metallic containers
should not be used as reaction vessels.
In microwave induced organic reactions, the reactions can be carried out
in a solvent medium or on a solid support in which no solvent is used. For
reactions in a solvent medium, the choice of the solvent is very important. 1,2
The solvent to be used must have a dipole moment so as to absorb microwaves
and a boiling point at least 20-30 °e higher than the desired reaction temperature.
An excellent solvent in a domestic microwave oven is N ,N -dimethylfonnarnide
(DMF) (b.p. 160 °e, E = 36.7). The solvent can retain water fonned in a
reaction, thus, obviating the need for water separation. Some other solvents
of choice are given as follows:
60 GREEN CHEMISTRY
Solvent b.p. eC) Dielectric constant (E)

Fonnamide 216 11.1
Methanol 65 32.7
Ethanol 78 24.6
Chlorobenzene 214 5.6
1,2-Dichlorobenzene 180 1.53
1,2,4-Trichlorobenzene 214 1.57
1,2-Dichloroethane 83 10.19
Ethylene glycol 196 37.7
Dioxane 101 2.20
Diglyrne 162 7.0
Triglyrne 216 1.42
Hydrocarbon solvents, for example, hexane (I> = 1.9), benzene (E = 2.3),

toluene (I> = 2.4) and xylene are unsuitable because ofless dipole moment and
also because these solvents absorb microwave radiations poorly. However,
addition of small amounts of alcohol or water to these solvents can lead to
dramatic coupling effects. Liquids which do not have a dipole moment cannot
be heated by microwaves. By adding a small amount of a dipolar liquid to a
miscible non-dipolar liquid, the mixture will rapidly achieve a uniform temperature
under irradiation.
Microwaves may be considered as a more efficient source of heating than
conventional steam (or oil heated vessels), since the energy is directly imparted
to the reaction medium rather than through the walls of a reaction vessel. In
fact, the rapid heating capability of the microwave leads to considerable saving
in dissolution or the reactiop time. The smaller volume of solvent required
contributes to saving in cost and diminishes the waste disposal problemY
Microwave procedures are limitedS by the presence of solvents which
reach their boiling points within a very short time (- 1 min) of exposure to
microwave. Consequently, high pressures are developed, leading to damage to
the vessels material or the microwave oven itself and may occasionally lead to
explosion.
Well-designed industrial microwave ovens are available now. Consideration
of safety aspects coupled with the limitations of the solvents imposed by
microwave heating, has led to many reactions being carried out in water or
more commonly under solvent free conditions. This is a major green advantage
of microwave reactions. It is believed that due to high polarity and non-volatility,
ionic liquids (see also Chapter 14) might be ideal for carrying out high
temperature reactions efficiently, since temperatures of over 200°C can be
readily attainable.
9.2 Applications
It is possible to carry out a number of microwave organic synthesis. These
syntheses are grouped in the following three categories:
Microwave Induced Green Synthesis 61
(i) Microwave-assisted reactions in water.

(ii) Microwave-assisted reactions in organic solvents.
(iii) Microwave solvent-free reactions (solid state reactions).
Some important microwave assisted organic synthesis are:
9.2.1 Microwave Assisted Reactions in Water
9.2.1.1 Hofmann Elimination

In this method, normally quaternary ammonium salts are heated at high
temperature and the yield of the product is low. Use of microwave irradiation
has led to high-yielding synthesis of a thermally unstable Hofmann elimination
product (Scheme 1). In this water-chloroform system is used.
Water/CHC1 3
~
mwlmin
OEt OEt
Scheme 1
9.2.1.2 Hydrolysis
Microwave reactions have been extensively used for hydrolysis.
9.2.1.2.1 Hydrolysis of Benzyl Chloride

Hydrolysis of benzyl chloride with water in microwave oven gives 97% yield6
of benzyl alcohol in 3 min (Scheme 2). The usual hydrolysis in normal way
takes about 35 min.
mw
C 6 H sCH 2 CI + H 2 0 C 6 H sCH 2 0H
3 min
Benzyl chloride Benzyl alcohol
(97%)
Scheme 2
9.2. J.2.2 Hydrolysis of Benzamide

The usual hydrolysis of benzamide takes 1 hr. However, under microwave
conditions, the hydrolysis is completed in 7 min giving5 99% yield of benzoic
62 GREEN CHEMISTRY
acid (Scheme 3).
20% H 2S0 4
C 6 H sCONH2 C 6 H sCOOH
Benzamide mw7min Benzoic acid
(99%)
Scheme 3
9.2.1.2.3 Hydrolysis ofN-phenyl Benzamide

The acid hydrolysis ofN-phenylbenzamide usually takes 18-20 hr. However,
under microwave conditions the reaction is completed in 12 min giving6 74%
of benzoic acid (Scheme 4).
20% H2S04
C 6 H sCOOH
mw 12 min
N-phenylbenzamide Benzoic acid
(74%)
Scheme 4
9.2.1.3 Oxidation o/Toluene

Oxidation of toluene with KMn04 under normal conditions ofrefluxing takes
10-12 hr compared to reaction in microwave conditions5 , which takes only
5 min and the yield is 40% (Scheme 5).
[0]
---------l~ .. C 6H sCOOH
aq.KMn0 4 + aq. KOH
mw 5 min Benzoic acid
(40%)
Scheme 5
9.2.1.4 Oxidation 0/ Alcohols

A number of primary alcohols can be oxidised to the corresponding carboxylic
acid (Scheme 6) using sodium tungstate as catalyst in 30% aqueous hydrogen
peroxide.
30% H,02
R~OH
Primary alcohol Carboxylic acid
Scheme 6
Similarly, secondary alcohols have been oxidised5a under microwave

irradiation by using doped supports like clayfen (montmorillonite KIO + iron

(III) nitrate), silica manganese dioxide, claycop (montmorillonite KIO +
copper(II) nitrate)-H 20 2 , Cr0 3-wet alumina, iodobenzenediacetate-alumina,
CuS0 4-alumina, oxone-wet alumina (Scheme 6a).
Doped supports
mw
R, RI = various aromatic, aliphatic and heterocyclic groups
Scheme 6a
Also oxidation oflinear and cyclic secondary alcohols and benzylic alcohols
to the corresponding carbonyl compounds under microwave irradiation
conditions can be achieved.
Arenes on oxidation with KMn04 impregnated on alumina under microwave
irradiation in dry media (instead of several days under classical conditions)
gave 5b ketones (CH2 group is oxidised to keto) (Scheme 6b).
KMn04-alumina
mw
Scheme 6b
Thiols have been oxidised5b to disulphides on mineral supports like silica,

celite, florisel, alumina (Scheme 6c).
Air, mineral support

2R-SH --------------~.~ R-S-S-R
mw
R-SH = p-nitrophenylmercaptan, 2-mercaptopyridine, thiosalicyclic acid
Scheme 6c
9.2.1.5 Hydrolysis of Methylbenzoate to Benzoic Acid (Saponification)

Saponification of methylbenzoate in aqueous sodium hydroxide under
microwave conditions (2.5 min) gives 5 84% yield of the benzoic acid
(Scheme 7).
64 GREEN CHEMISTRY
aq. NaOH
C 6H 5COOCH 3 -----''-----"""'~~ C 6H 5COOH
mw2.5min
Methylbenzoate Benzoic acid
(84%)
Scheme 7
9.2.2 Microwave-Assisted Reactions in Organic Solvents

This section includes those microwave induced reactions in which one or
both the reactants (ifliquid) act as a solvent and also those reactions in which
organic solvent is used to assist the reaction.
9.2.2.1 Esterification: Reaction of Carboxylic Acid and Alcohol

A mixture of benzoic acid and n-propanol on heating in a microwave oven for
6 min in presence of catalytic amount of cone. sulphuric acid gives 5,6,7
propylbenzoate (Scheme 8).
C 6H 5COOH + nC 3 H 70H C6H5COOC3H7

mw6min
Benzoic acid Propylbenzoate
70%
Scheme 8
9.2.2.2 Esterification: Reaction of Carboxylic Acids and Benzyl Ethers Using

LnBr3 (Ln = La, Nd, Sm, Dy, Er)
A mixture of carboxylic acid and benzyl ether on heating in a microwave oven
in the presence of LnBr3 afforded8 the esters in 2 min (Scheme 9).
Ln Br3 • AICH2 OCOR1 + ROH

Ln = Ld, Nd Sm, Dy, Er
mw2min
Scheme 9
9.2.2.3 Fries Rearrangement

Fries rearrangement is a useful method for the preparation of phenolic ketones
and is usually carried out by heating a mixture of substrate and aluminium
chloride.
There is considerable rate enhancement of Fries rearrangement by
conunercial microwave ovens over conventional methods. Thus, a mixture of
p-cresyl acetate and anhydrous aluminium chloride are heated in dry
chlorobenzene in a sealed tube in a microwave oven for 2 min to give 9 85%
yield of the product (Scheme 10).
9.2.2.4 Orthoester Claisen Rearrangement

In the usual conventional procedure, a mixture of allyl alcohol, triethyl
orthoacetate and propanoic acid is heated in a sealed tube for 48 hr. However,
under microwave conditions lO a mixture of allyl alcohol, triethyl orthoacetate
and propanoic acid in dry dimethylformamide is heated in microwave oven for
10 min. The product (Scheme 11) is obtained in 83% yield.
Chlorobenzene
c¢rCOCHl
mw 2 min
CH 3
p-Cresyl acetate 2-Hydroxy-4-methyl

acetophenone
85%
Scheme 10
Triethyl or thoacetate
~OH CH,CH,CH,COOH, DMF•
mw 10 min
_ (00'" 83%
Scheme 11
9.2.2.5 Diels Alder Reaction

The reaction involves 1,4-addition of an alkene (e.g., maleic anhydride) to a
conjugated diene (e.g. anthracene) to form an adduct of six membered ring.
Under usual conditions '1 the reaction requires a reflux period of 90 min.
However, under microwave conditions3,12 diglyme is used as a solvent and
80% yield of the adduct is obtained in 90 sec (Scheme 12).
9.2.2.6 Synthesis o/Chalcones

Microwaves have been used for the synthesis 13 of chalcones and related enones.
Considerable rate enhancement is observed, bringing down the reaction time
from hours to minutes in improved yield (Scheme 13).
66 GREEN CHEMISTRY
9.2.2.7 Decarboxylation
Conventional decarboxylation of carboxylic acids involve refluxing in quinoline
in presence of copper chromite and the yields are low. However, in the presence
of microwaves 14, decarboxylation takes place in much shorter time as illustrated
in Scheme 14.
ceo Go
0
Diglyme
+ to 0
~ ~ ~ mw 90 sec
0
Anthracene
Maleic
Adduct
anhydride
80%
Scheme 12
R~ + OHC Ar
EtOH to R 0
~c
fAr
~COCH3 Aldehyde
Catalytic NaOH
30 sec - 2 min II
Ketone o
Chalcone
90-100%
Scheme 13
CHO~N/
~COOH _mw_I_2lTIl_·n---..-~ quinoline
0)1'
~
CH 30 N
3 H H
6-Methoxy indole-2- 6-Methoxyindole
carboxylic acid 99%
Scheme 14
9.2.3 Microwave Solvent Free Reactions (Solid State Reactions)

Application of microwave irradiation in organic reactions has added a new
dimension to solid phase synthesis. By the use of this technique, it is now
possible to carry out reactions without the use of toxic or other solvents,
which is one of the main problems associated with green synthesis. In these,
the reactants are dissolved in a suitable solvent like water, alcohol, methylene
chloride etc. and the solution stirred with a suitable adsorbent or solid support
like silica gel, alumina or phyllosilicate (Mn+-montomorillonite). After stirring,
the solvent is removed in vacuo and the dried solid support on which the
reactants have been adsorbed are used for carrying out the reaction under
microwave irradiation. Following are some of the important applications of
solid support synthesis.
9.2.3.1 Deacetylation
Aldehydes 1S , phenols 16 and alcohols 16 are protected by acetylation. After the
reaction, the deacetylation of the product is carried out usually under acidic or
basic conditions; the process takes long time and the yields are low. Use of
microwave irradiation reduces the time of deacetylation and the yields are
good. Some examples are (Scheme 15) as follows:
Neutral alumina
C 6 H SCH(OAc)2 -------l~.. C6HsCHO
mw40 sec
Benzaldehyde Benzaldehyde
diacetate
Alumina Alumina
mw 30 sec mw2.5min
OH OAc OH
Scheme 15
9.2.3.2 Deprotection
The carboxylic function is generally protected by the benzyl protecting group.
After the reaction sequence, the deprotection of benzyl ester is carried out by
using potassium carbonate 17 , aluminium chloride 18 , Na-NH 3 19 etc. Most of the
deprotection procedures give moderate yields and a longer reaction time is
required. The microwave irradiation procedure 20 is completed in 3-10 min
and yields are high (89-92%) (Scheme 16).
Acidic alumina
---~.
mw7min R
-0-' _ C0 2H
R= H or CH 3
Scheme 16
68 GREEN CHEMISTRY
In a similar way, t-butyl dimethylsilyl group can be removedY
9.2.3.3 Saponification of Esters

Hindered esters which take 5 hr under classicaF2,23 heating with alkali can
be easily saponified under microwave irradiation 24 using KOH-Aliquat
(Scheme 17).
o (i) KOH-Aliquat 0
II 1 _ _m_w_4_-_l0_m_i_n ---i.~ R-~-OH + R 1OH
R-C-OR
(ii)HCl
Scheme 17
9.2.3.4 Alkylation of Reactive Methylene Compounds

Efficient and rapid alkylation of compounds containing reactive methylene
group (e.g., ethylacetoacetate) can be achieved in a microwave oven24,25, using
tetrabutyl ammonium chloride (TBAC) as PTC without solvent (Scheme 18).
R
RX, KOH-K 2COl , TBAC I
CH 3 COCH 2 C0 2Et ----m-w....:3'-m-i..:....n----i.~ CH 3 COCHC0 2Et
Scheme 18
In a similar way, alkylation of ethyl mercaptoacetate can be achieved 26

(Scheme' 19).
__RX_,'--K_O_H_-_K.....2C_O~l"-'_T_B_A_C_-J.~ C6H s SCH-C0 2 Et

mw I
R
Scheme 19
9.2.3.5 Condensation ofActive Methylene Compounds with Aldehydes

Condensation of compounds containing active methylene group can be made
to react with the aromatic aldehydes to give corresponding arylidene
derivatives27 ,28,29 (Scheme 20).
9.2.3.6 Synthesis of Nitriles from Aldehydes

This conversion is generally achieved by converting the aldehyde into oxime
followed by its dehydration by a variety of reagents. 30 One pot synthesis has
also been developed31.32, but these methods suffer from a number of drawbacks.
In the microwave assisted reaction, the aldehyde is converted into oxime by
reaction with hydroxylamine hydrochloride and potassium fluoride on alumina
r--f.0 r--f.0
ArCHO + H3C-C-N N-C-CH3 CH-C-N N-C-CH3
II \ /
°
II mw 15 min 311~1
O,r--
°
1,4-Diacetylpiperazine-2,5-dione
°° °AI
KF-AI 2 0 3
C6HsS02-CH2-Z + ArCHO ----=---"-.~ C6 HS- S02-O=CHAr
mw5min I
Arylsulphones Z
+
o
O Montmorillonite-KSF
•
0tfR+
o 0
mw
° 0
Tetronic acid (Z) (E)
Scheme 20
without a solvent. The absorbed oxime is converted into nitrile in the second
step by treatment with carbon disulphide (Scheme 21). This method is quick,
simple and convenient33 and gives nitriles in good yield.
(i) NHPH.HCI on AI 20 3 -KF

mw,S min
R-CHO ------------------~.~ RC-N
(ii) CS 2, 20°C, 20-48 hr
Scheme 21
9.2.3.7 Synthesis ofAnhydrides from Dicarboxylic Acid

Dicarboxylic acids can be converted into anhydrides (Scheme 22) in the
presence of isopropenyl acid (which acts as a water scavenger) under
microwave irradiation34 using montmorillonite-KSF. The driving force is the
formation of acetone.
,J~
Montmorillonit,-KSF
- m w- - - . . yO
Scheme 22
°
70 GREEN CHEMISTRY
This method is rapid and convenient and avoids using corrosive reagents
like CH3COCI, SOCI2 , (CH 3CO)p.
9.2.3.8 Reductions
Sodium borohydride has been extensively used as a reducing agent. The solid
state reduction with NaBH4 requires longer time and use of solvents slow
down the reaction. A microwave irradiation reaction has been developedsa for
the reduction of aldehydes and ketones using alumina supported NaBH4
(Scheme 23).
ro,
R = -Cl, Me, N03 , H, Ph,
Rl = H, Me, Ph, PhCH(OH)
Scheme 23
Sodium borohydride in combination with wet montmorillonite KIO clay has

been used sa for reductive amination of carbonyl compounds (Scheme 24).
R = i-Pr, Ph, o-OHC 6H.-, p-MeOC 6H.-, p-N02 C6H.-, p-C1C 6H.-, Et, n-CSH 11
R 1= H, -(CH)s-' -(CH 2)6-' n-Pr
R2= Ph, n-Pr, morpholine, piperidine, n-C 1oH21
Scheme 24
Leukart reductive amination of carbonyl compounds was considerably

enhancedsa (in comparison to conventional heating) by a specific microwave
effect under solvent-free conditions using monomode microwave reactor
(Scheme 25).
0 NHCHO
Rl
A R2
HC02NH 4 , HCONH r HCOOH
mw
~
Rl
A R2
(A)
©J'©,
0
(A) =
MeO OMe
0 0
MeO MeO OMe
MeO MeO OMe
Scheme 2S
9.2.3.9 Synthesis ofHeterocyclic Compounds

Heterocyclic compounds are immensely important due to their wide spectrum
of biological activity. A number of diverse heterocyclic systems have been
synthesised. For details see Sec. 13.3.
9.3 Conclusion
The use of microwaves has led to substantial savings in time for many syntheses
in the laboratory as well as in industry. Microwave induced reactions can be
carried out in water or organic solvents. The organic solvents if used, are
required in very small quantities. The most important feature of microwaves
induced reactions is that these can also be carried out in the solid state, i.e.,
without the use of any solvent.
References
1. D. Michael, P. Mingos and D.R. Baghrust, Chern. Soc. Rev., 1991,20,1.

2. A.K. Bose, M.S. Manhas, B.K. Banik and E.W. Robb, Res. Chern. lnterrned., 1994,
20(1), 1.
3. S.S. Bari, A.K. Bose, A.G. Chaudhary, M.S. Manhas, V.S. Raju and E.W. Robb,J. Chern.
Ed., 1992,69(11),938.
4. Shui-Teinchem, Shyh-Horngchiou and Kung-Tsungwang, J. Chern. Soc. Chern. Cornrnun.,
1990,807.
72 GREEN CHEMISTRY
5. M.N. Gedye, F.E. Smith and K.C. Westaway, Can. J. Chern., 1988,66, 17.
5a. R.S. Verma and R.K. Saini, Tetrahedron Lett., 1997,38,2623; R.S. Verma and D. Kumar,
Synth. Cornrnun., 1999,29,1333.
5b. A. Loupy, D. Monteux, A. Petit, 1. Aizpurua, E. Domingulz and C. Plomu, Tetrahedron
Lett., 1996,37,8177.
6. R.N. Gedye, W Rank and K.C. Westaway, Can. J. Chern., 1991,69,700.
7. R.N. Gedye, F. Smith, K. Westaway, H. Ali, L. Baldisera, L. Laberge and J. Rousell,
Tetrahedron Lett., 1986,27,279.
8. J. Gulin and G. Guncheng, Synthetic Cornrnun., 1994,24(7),1045.
9. V. Sridar and V.S. Sundara Rao,lndian J. Chern., 1994, 33B, 184.
10. A. Srikrishna and S. Nagaraju,J. Chern. Soc. Perkin Trans. 1,1992,311.
11. O.C. Dermer and 1. King, J. Arner. Chern. Soc., 1941, 63, 3232.
12. R.I. Giguene, T.L. Bray and S.M. Duncan, Tetrahedron Lett., 1986,27(41),4945.
13. G. Opitz and E. Tempel, Liebigs Ann. Chern., 1966,699,68.
14. G.B. Jones and B.I. Chapman, J. Org. Chern., 1993, 58, 5558.
15. R.S. Varma, A.K. Chatterjee and M. Verma, Tet. Lett., 1993, 34(20), 3207.
16. R.S. Varma, M. Varma and A.K. Chatterjee, J. Chern. Soc. Perkin Trans. I, 1993,999.
17. WF. Huffimann, R.F. Hall, 1.A. Grant and H.G. Holden,J. Med. Chern., 1978,21,413.
18. T. Tsuji, T. Kataoka, M. Yoskioka, Y. Sendo, S. Nishitant, S. Hirai, T. Maeda and
W Nagata, TetrahedronLett., 1979,2793.
19. C.W Roberts,J. Arn. Chern. Soc., 1954,76,6203.
20. R.S. Varma, A.K. Chaterjee and M. Varma, Tetrahedron Lett., 1993,34,4603.
21. R.S. Varma, 1.B. Lamture and M. Verma, Tet. Lett., 1993,34(19),3029.
22. A. Loupy, M. Pedoussaut and 1. Sanoulet, J. Org. Chern., 1986,51, 740.
23. A. Dietrich and 1.M. Lehn, Tetrahedron Lett., 1973, 1225.
24. Loupsy, P. Pigeon, M. Ramdani and P. Jaequault, Synthetic Cornrnun., 1994, 24(2), 159.
25. D. Ruhua, W. Guliang and J. Yao Zhing, Synthetic Cornrnun., 1994,24(1), Ill.
26. D. Ruhua, W Yuliangand Y. Yaozhong, Synthetic Cornrnun., 1994,24(13),1917.
27. D. Villernin and A.B. Alloum, Synthetic Cornrnun., 1990,20(21),3325.
28. D. Villemin and A.B. Alloum, Synthetic Cornrnun., 1991,21(1),63.
29. S. Ge\in and P. Pollut, Synthetic Cornrnun., 1980,10,805; D.G. Schmidt, P.D. Seemuth
and H. Zimmer,J. Org. Chern., 1983,48,1914.
30. H.G. Foreyand D.R. Dalton, J. Chern. Soc. Chern. Cornrnun., 1973,628; 1.C. Krause
and S. Shaikh, Synthesis, 1974,563; H. Shinogaki, M. Imaizumi and M. Tajima, Chern.
Lett., 1983,929.
31. S.N. Karmarkar, S.L. Kelkar and Wadia, Synthesis, 1985, 510; D. Dauzonne, P.
Demerseman and R. Royer, Ibid., 1981,739; M. Miller and G. Loudon,J. Org. Chern.,
1975,40,126.
32. C. Fizet and J. Streith, Tetrahedron Lett., 1974,3187.
33. D. Villemin, M. Lalaoui and A.B. Alloum, Chern. Ind., 1991, 176.
34. D. Villemin, B. Labiad and A. Loupy, Synthetic Cornrnun., 1993,23(4),419.
10. Ultrasound Assisted Green Synthesis
10.1 Introduction
The word 'ultrasound' has become common knowledge due to the widespread
use of ultrasound scanning equipments in medical applications. Ultrasound
refers to sound waves having frequencies higher than those to which the
human ear can respond (fl, > 16 KHz) (Hz = Hertz = cycles per second). High
frequency ultrasound waves are used in medical equipments. The ultrasound
frequencies ofintetest for chemical reactions (about 20-100 KHz) are much
lower than those used for medical applications, but the power used is higher.
The ultrasound is generated with the help of an instrument having an
ultrasonic transducer, a device by which electrical or mechanical energy can
be converted into sound energy. The most commonly used are the
electromechanical transducers which convert energy into sound - they are
mostly made of quartz and are commonly based on the piezoelectric effect.
When equal and opposite electrical charges are applied to opposite faces of a
crystal of quartz, expansion or contraction occurs. Application of rapidly
reversing charges sets up a vibration that emits ultrasonic waves called the
piezoelectric effect. In modern ultrasonic equipments, the piezoelectric
transducers are made from ceramic impregnated barium titanate. Such devices
convert over 95% of the electrical energy into ultrasound. In practice, the
devices only have an optimum operating frequency.
When a sound wave, propagated by a series of compression and refraction
cycles, pass through a liquid medium, it causes the molecules to oscillate
around their mean position. During the compression cycle, the average distance
between the molecules is reduced and during refraction, the average distance
between the molecules is increased. In the refraction cycle, under appropriate
conditions, the attractive forces of the molecules of the liquid may be overcome,
causing formation of bubbles. In case the internal forces are great enough to
ensure collapse of these bubbles, very high local temperature (around 5000°C)
and pressure (over 1000 bar) may be created. It is this very high temperature'
and pressure that initiate chemical reactions.
The term 'sonochemistry' is used to describe the effect of ultrasound
waves on chemical reactivity. A number of reviews on the chemical applications
of ultrasound have been published. l -s
74 GREEN CHEMISTRY
10.2 Applications of Ultrasound

Following are some of the important applications of ultrasound in chemical
synthesis. Most of the reactions/syntheses reported are carried out at room
temperature unless otherwise specified. The symbol ))5) is used for reactions
carried out on exposure to ultrasound.
10.2.1 Esterification
This is generally carried out in presence of a catalyst like sulphuric acid,
p-toluenesulphonic acid, tosylchloride, polyphosphoric acid, dicyclo-
hexylcarbodiimide etc. The reaction takes longer time and yields are low.
A simple procedure for the esterification of a variety of carboxylic acids with
different alcohols at ambient temperature using ultrasound has been reported6
(Scheme 1).
RCOOR 1
Scheme 1
10.2.2 Saponification
Saponification can be carried out under milder conditions using sonification. 7,8
Thus, methyl 2,4-dimethylbenzoate on saponification (20 KHz) gives the
cQrresponding acid in 94% yield (Scheme 2), compared to 15% yield by the
usual process of heating with aqueous alkali (90 min).
COOCH 3 COOH
CH 3
Scheme 2
10.2.3 Hydrolysis
Nitriles can be hydrolysed9 to carboxylic acids (Scheme 3) under basic condition
on sonication.
Ultrasound Assisted Green Synthesis 75
ArCN ArCOOH
Scheme 3
10.2.4 Substitution Reactions

Halides can be converted into cyanides. Thus, the reaction of benzyl bromide
in toluene with potassium cyanide, catalysed by alumina, on sonication gives!O
the substitution product, viz. benzyl cyanide in 76% yield. In the absence of
ultrasound alkylation is the preferred pathway (Scheme 4). The difference is
because ultrasound forces cyanide into the surface of alumina, enhancing
cyanide nucleophilicity and reducing the lewis acid character.
Scheme 4
Sonication of acyl chloride and potassium cyanide in acetonitrile gave!!

the corresponding acyl cyanides (Scheme 5).
o 0
II
R-C-Cl
KCN, MeCN
-----:---..~
II
R-C-CN
50°C ))5)
70-85%
Scheme 5
Similarly, alkyl bromides on sonication with KSCN in presence of a PTC

catalyst gave l2 the corresponding sulphocyanide in 62% yield (Scheme 6).
76 GREEN CHEMISTRY
/,,--/Br
Scheme 6
10.2.5 Addition Reactions

1,4-addition to (l,~-unsaturated carbonyl compounds is generally 12 carried
out by organocopper reagents. However, improvement in yields, rates and
ease of experimental techniques is observed 13 when organocopper compounds
are generated in situ by sonication of copper (I) compounds, organic halides
and lithium in diethyl-ether-THF at O°C (Scheme 7).
OO+RBr Li, Cu (I),

1HF, )5), 0 C
Et2~ ~O 1
[
\---1" ~.
R Cu
+
H+O ~
3.)-10
R
R = n-Bu89010
Scheme 7
In a similar way, aryl zinc compounds are generated ultrasonically14

(Scheme 8).
Li, ZnBr2, THF

ArBr ------~----~~. A~Zn
)'55)
Ni(acac)2
Ar~O
Scheme 8
1,3-Dipolar cycloaddition ofnitrones to olefins gave excellent yield 1s of

the product in much shorter time (Scheme-9) compared to the usual reaction
conditions. 16
R #
R-
~
~
~_
"'l-Ph
_
+ Ar~ --)~-~---l~~
Toluene
o Ar
Scheme 9
10.2.6 Alkylations
N-Alkylation of secondary amine takes place under sonication in the presence
of a PTC reagent, polyethylene glycol monomethyl ether. Similarly N -alkylation
of diphenyl amine is accomplished I? under sonication (Scheme 10).
This reaction does not take place in the absence of ultrasound.
C-Alkylation ofisoquinoline derivatives can be effected l8 using sonication
under PTC conditions (Scheme 11).
The O-Alkylation of primary alcohols with benzyl bromide in the presence
of silver oxide gives 72% yield of the O-benzylated product l9 (Scheme 12).
Under normal conditions without sonication, the yield is very low.
OJ ~ N
H
Mel/Solid KOH/toiuene
PEG methyl ether
20 °C, 30 min, )'5j)

~
OJ 65%
Me
I
PhCH~Br/Solid KOH/toluene
Ph2NH ~ Ph2NCH 2Ph
PEG methyl ether
98%
20 °C, 1 hr,)"5»)
Scheme 10
~ ~
~~-COPh NaOH, )'5j),
20-25 min
RT ~-COPh
H CN R CN
R = PHCH z (60%)
Scheme 11
9H
Ph'v/0~C02Me
THF, 0 °C, ®
72%
Scheme 12
78 GREEN CHEMISTRY
S-alkylation is accelerated20 under sonication (Scheme 13).
___K~2~C_O~/_D_M_F__~~~ RSR1
))5)
Scheme 13
In the above S-alkylation, ~C03 is broken into small particles in the DMF
solvent which liberates a high energy by cavitation.
10.2.7 Oxidation
The oxidation of alcohols by solid potassium permanganate in hexane or
benzene is enhanced considerably by sonication21 (Scheme 14).
Rl
;CHOH _ _KM_n_°....:r.4_1_he_x_an-:-e_o_r_b_en_z_en_e_--..~
R2/ RT, ))5)
Scheme 14
Using the above method, octan-2-01 gives corresponding ketone in 92.8%

yield in 5 hr compared to 2% yield by mechanical stirring. Similarly, cyc1ohexanol
gave 53% yield of cyc1ohexanone by oxidation under sonication (5 hr) compared
to the 4% yield under usual conditions.
Oxidation of cinnamyl alcohol with manganese dioxide in a suitable solvent
(like hexane or octane) gives 22 the corresponding aldehyde on sonication. It is
believed that under sonication the low reactive manganese dioxide is activated.
Benzylic halides can be oxidised with aqueous sodium hypochlorite23 at
room temperature on sonication. The oxidations are believed to proceed via
benzylic hypohalides (Scheme 15).
ArRCHX + NaOCl [ArRCHOClJ
~
ArRCO
Scheme 15
10.2.8 Reduction
Sonication increases considerably24 the reactivity of platinum, palladium and
rhodium black in formic acid medium making easier the hydrogenation2S of a
wide range of alkenes at room temperature by sonication. Also, hydrazine-
palladium on copper couple is useful for the hydrogenation of alkenes in ethanol

at room temperature using an ultrasonic bath26 • A commercially used example
of a sonochemically enhanced catalytic reaction is the ultrasonic hydrogenation
of soyabean oiI.27
Sonic~tion also increases the activation of nickel powdef28 which is used
for the reduction of alkenes.
Sonochemical reduction of nickel salts such as chloride with zinc powder
gives catalytically active nickel. 29 Under these conditions the excess of metallic
zinc also gets activated and reduces the water present in the medium producing
hy.drogen gas. In this way, not only the catalyst but also the reagent is produced
in situ with maximum efficiency and safety. This process has been used for
the reduction of carbon-carbon double bonds in a,p-unsaturated carbonyl
compounds; the C-C double bond is reduced much faster than the carbonyl
group. The variation in the conditions, especially pH permits30 the selective
reduction of C = C in preference to C = 0 (Scheme 16).
~_z_n_-N_iC
~
.......12,-,(_9:....;.I)_/_Et_O_H-_H.....
RT,2.5 hr,))j)
P_('-1:--,1)_.. A
~
97%
(the reaction takes 48 hr

in the absence of ultrasound)
Zn-NiCI (9:1) / EtOH-H ° (1:1)

RT, 3 hr, )5.»
o 96%
Zn-NiCI 2 (9: 1) / EtOH-H 20 (1: 1)

pH 8, RT, 1.5 hr,)55)
Scheme 16
80 GREEN CHEMISTRY
Carbonyl groups can be reduced by sonication using metal and THF.

Thus camphor on sonication3 ! in THF gives a mixture of endo and exo borneol
in the same ratio as by using metal in ammonia solution (Scheme 17).
~ o
Metal/THF
--------~.~
RT, I hr,)"5j)
~
OH
+
H
~
H
OH
endo exo
Scheme 17
The endo product is obtained in 73, 68 or 42% yield by the use ofLi, Na
or K, respectively, as the metal in the above reduction.
Carbonyl groups as in quinones or a-diketones can be reduced on sonication
with zinc in presence of trimethylchlorosilane. 32 The Clemmensen reduction
can also be carried out by sonication in better yields. 33
10.2.9 Hydroboration
Hydroboration could be enhanced34 by ultrasound, especially in heterocyclic
systems. Some of the important hydroboration reactions are given in
(Scheme 18).
0 a~
BH 3'SMe 2
THF, I hr, )))) •
(50 KHz, ISO W)
0 BHBr2·SMe/CH 2CI 2
RT, I hr, ))5) •
O.",..;ssr,. SMe,
RT, I hr
Scheme 18
10.2.10 Coupling Reactions

Homocoupling of organometallic generated in situ by the reaction of alkyl,
aryl of vinyl halides with lithium in THF takes place on sonication3s •36
(Scheme 19). No reaction takes place in absence of ultrasound.
Li, THF • C H -C H
)~ 6 5 6 5
Scheme 19
In a similar way, coupling of benzyl halides in presence of copper or

nickel powder generated by the lithium reduction of the corresponding halides
in the presence of ultrasound give high yields 37 of dibenzyl (Scheme 20).
)~
C6HsCH 2Cl + Cu· • C6HsCH2CH2C6Hs
)~t Li/THF
CuBr2
Scheme 20
The classical Ullmann's coupling takes place at high temperature giving

low yields. However, in sonication, the size ofthe metal powder is considerably
reduced. 38 Breaking of the particles brings them in contact with the reactive
solutions a fresh surface, the reactivity of which is not hindered by the usual
oxide layer. The coupling of o-iodonitrobenzene with copper powder is given
in (Scheme 21).
70%
Cu+DMF
Scheme 21
82 GREEN CHEMISTRY
10.2.11 Friedel-Crafts Reaction

The Friedel-Crafts acylation of aromatic compounds is facilitated 39 by ultrasound
(Scheme 22).
R=~
Scheme 22
10.2.12 Diels-Alder Reaction

Sonication facilitates Diels-Alder reaction. Therefore, the addition of
dimethyl acetylene dicarboxylate to furan in water at 22-45 °C gives quantitative
yield of the adduct (Scheme 23).
x
22-45 °c
y
y
Scheme 23
The Diels-Alder cyc1oaddition of various dienes (mostly belonging to

I-vinyl cyc1ohexenes) with o-quinone proceeds very we1140 under ultrasound
conditions to give the expected adducts in 59% yield (Scheme-24) compared
to 30% under normal reaction conditions. Better results are obtained by
soniciation of the neat mixture.
10.2.13 Simmons-Smith Reaction

In this reaction, sonochemically activated zinc and methylene iodide are
used. The generated carbene adds on to an olefinic bond to give 91 % yield
of the cyclopropane derivative compared (Scheme 25) to 51 % yield by the

normal route.
(1) Diels-Alder,'5)))
~
(2) DDQ
59%
1 2 3
R = H, OR; R = H, CH3; R = H, CH3 +
2 3
R ,R = -O(CH2)O-
o
Scheme 24
Me(CH2hV(CH2hC02Me
Me(CH2h" /(CH2hC02Me Zn, CH212 ~
))j), 50 KHz 91 %
Scheme 25
The' above method can be scaled Up41 and has several advantages. The
reagent used, ZnlCH 2I2 is known as Simmons-Smith reagent.
Ketones on reaction with Simmons-Smith reagent results in methylenation42
of carbonyl group (Scheme 26). Normally such methylenation of carbonyl
group requires complex reagents. It can now be accomplished by sonication.
10.2.14 Bouveault Reaction

Sonication of aryl halides with lithium with low intensity ultrasonic gives
organolithium reagents. These are used in Bouveault reaction giving higher
yields of aldehydes (Scheme 27) than the traditional methods. 42
The non-ultrasonic Bouveault reaction suffers from numerous side
reactions.
84 GREEN CHEMISTRY
CH)/Zn/THF
RT, ))5) -
R= RI = alkyl
R= alkyl, RI = H
Scheme 26
Scheme 27
10.2.15 Cannizaro Reaction

The Cannizarro reaction under heterogenous conditions catalysed by barium
hydroxide is considerably accelerated (Scheme 28) by sonication. The yields
are 100% after 10 min, whereas no reaction is observed during this period
with the use of ultrasound. 43
Scheme 28
10.2.16 Strecker Synthesis

The Strecker synthesis of aminonitriles is possible using sonication44
(Scheme 29).
RINH2 , KCN, AcOH
Scheme 29
10.2.17 Reformatsky Reaction
The Reformatsky reaction using sonication gave excellent yields compared to
the traditional methods using activated zinc or trimethyl borate as a cosolvent. 4S
In the sonication procedure the metal zinc is activated by iodine and the reaction
is done in dioxane (Scheme 30).

Reformatsky reaction with nitriles leads to the formation of imine, which
readily hydrolyse to the ketones. Using appropriate nitrile, keto-y-butyrolactone
is obtained in good yield 46 (Scheme 31).
Rl
'C=O ___B_r_C_H....2C_O-,2i...E_tl_Z_n_/I=-.2---l.~
R2/ dioxaneR.T.5-30min, ))))
RI = H; R2 = Ph or (CH 3)2CH
RI_R2 = - (CH 2)4-
Scheme 30
Zn/THF, RT, 2 hr °'1---f(:2

)J5) ~ RIAoAO
Scheme 31
10.2.18 Conversion of Ketones into Tertiary Alcohols

Ketones are generally converted into tertiary alcohols by treatment with
separately prepared Grinard reagent. However, under sonication conditions,
ketones on treatment with alkyl halide and lithium in THF give good yields of
the tertiary alcohols 47 (Scheme 32).
RT, \ 0-\5 min, ))5.)

(70-100%)
Scheme 32
In the above reaction, known as Barbier reaction, even non-reactive aldehydes

can be used. Even reactive allyl or benzylhalides which normally undergo
Wurtz coupling can also be used (Scheme 33).
86 GREEN CHEMISTRY
BuBr, Li/THF
RT, 15 min, ))))
Scheme 33
10.2.19 Synthesis ofChromenes

The condensation of o-hydroxybenzaldehyde with p-nitrostyrene using basic
alumina catalyst gives good yield of 3-nitro-2H-chromene on sonication48
(Scheme 34).
(XI 0R
+
~ eRO
Scheme 34
10.3 Conclusion
Ultrasound assisted organic synthesis gives excellent yields compared to other
reactions. It can dramatically effect the rates of chemical reactions and is
helpful for a large number of organic transformations. In fact, a combination
of sonication with other techniques, e.g., phase transfer techniques, reactions
in aqueous media etc. give best results. Sonication has also been shown to
stimulate microbiological reactions.
References
I. J.P. Lorimer and T.J. Mason, Chern. Soc. Rev., 1987, 16,239-274.
2. J.L. Lindly and T.J. Mason, Chern. Soc. Rev., 1987,16,275-311.
3. C. Einhorn, J. Einhorn and J.L. Luche, Synthesis, 1987,787-813.
4. J.M. Khurana, Chemistry Education, 1990,24-29.
Publishing House, New Delhi, 200 I, 116-149.
6. J.M. Khurana, P.K. Sahoo and G.c. Markop, Synth. Cornrnun., 1990,2267.
7. S. Moon, L. Duclin and J.Y. Craney, Tetrahedron Lett., 1979,3917.
8. D.S. Krislol, H. Klotz and R.C. Parker, Tetrahedron Lett., 1981, 22, 407.
9. J. Elguero, P. Goya, J. Lissavestzky and AM. Valdeomillos, CR. Acad. Sci. Paris, 1984,
298,877.
10. T. Ando, S. Smith, T. Kaweta, 1. Jehihara and T. Haatusa, J. Chern. Soc. Chern. Cornrnun.,
1984,439.
11. T. Ando, 1. Kawate and T. Hanatusa, Synthesis, 1983,637.
12. G.H. Posner, Org. React. (NY), 1972, 19, 1.
13. 1.L. Lunche, e. Petrier, AL. Gemal and N. Zirk,J. Org. Chern., 1982,47,3805.
14. J.e.S. Barboza, e. Petrier and J.L. Luche, Tetrahedron Lett., 1985,26,829.
15. P.A. Griew and P. Garner, Tetrahedron Lett., 1983,24,1897.
16. D.R. Borthakur and 1.S. Sandhu, J. Chern. Soc. Chern. Cornrnun., 1988, 1444.
17. R.S. Davidson, AM. Patil, A. Safdar and D. Thomthwalite, Tetrahedron Lett., 1983,
24,5907.
18.1. Ezquema and 1. Alvarez-Bullis, J. Chern. Soc. Chern. Cornrnun., 1984,54.
19. R.D. Walkup and R.T. Cunningham, Tetrahedron Leit., 1987,28,4019.
20. 1.M. Khurana and P.K. Sahoo, Syn. Cornrnun., 1992, 1691.
21. J. Yamakawi, S. Sumi, T. Ando and 1. Hanatusa, Chernistry Lett., 1983,379.
22. T. Kimura, M. Fuji1a and T. Ando, Chernistry Lett., 1988, 137.
23. J.M. Khurana, P.K. Sahoo, S.S. Titus and O.L. Mailap, Synth. Cornrnun., 1900, 1357.
24. A.W. Mattsev, Russ. J. Phys. Chern., 1976,50,993.
25. J. Jurezak and R. Ostaszewki, Tetrahedron Lett., 1988,29,959.
26. D.H. Shin and B.H. Han, Bull. Korean Chern. Soc., 1985,6,247.
27. KJ. Moulton, S. Koritala and E.N. Frankel, J. Arn. Oil Chern. Soc., 1983,60,1257.
28. K.S. Suslick and DJ. Casadonte,J. Arn. Chern. Soc., 1987,109,3459.
29. C. Petrier and J.L. Luchi, Tetrahedron Lett., 1989,28,2347.
30. e. Petrier and J.L. Luchi, Tetraderon Lett., 1987,28,2351.
31. K.S. Suslick and DJ. Casadonli,J. Arn. Chern. Soc., 1987,109,3459.
32. P. Boudjouk and J. Su, Synthetic Cornrnun., 1986,16,775.
33. w.P. Reeves, J.A Murry, D.W. Willoughby and W.J. Friedrid, Synthetic Cornrnun., 1988,
18, 1961.
34. H.C. Brown and u.S. Racherla, Tetrahedron Lett., 1985,26,2187.
35. B.H. Han and P. Boudjouk, Tetrahedron Lett., 1981,22,2757.
36. T. Kitazumi and N. Ishikawa,J. Arn. Chern. Soc., 1985,107,5186.
37. P. Boudjouk, D.P. Thompson, W.H. Ohrborm and B.H. Hans, Organornetallics, 1986,5,
1257.
38. J. Lindly, T.J. Mason and J.P. Lorimer, Ultrasonics, 1987, 25, 45; L. Lindley,
J.P. Lorimer and TJ. Mason, Ultrasonic, 1986, 24, 292.
39. D.M. Trose and B.P. Coppola, J. Arn. Chern. Soc., 1982,104,6879.
40.1. Lee and 1.K. Sayder, J. Arn. Chern. Soc., 1989,111, 1522.
41. H. Tso, T. Chou and H. Hung, J. Chern. Soc. Chern. Cornrnun., 1887, 1552.
42. C. Petrier, AL. Gemal and 1.L. Luck, Tetrahedron Lett., 1982,23,3361.
43. A. Fuentes and V.S. Sinisterra, Tetrahedron Lett., 1986,27,2967.
44. J. Menedez, G.G. Trigo and M.M. Solhuber, Tetrahedron Lett., 1986,27,3285.
45. B. Han and P.J. Boudjouk,J. Org. Chern., 1982,47,5030.
46. T. Kitazume, Synthesis, 1986, 853.
47. 1.L. I uche and J.e. Damianu, J. Arn. Chern. Soc., 102,7926.
11. Biocatalysts in Organic Synthesis
11.1 Introduction
The most important conversions in the context of green chemistry is with the
help of enzymes. Enzymes are also referred to as biocatalysts and the
transformations are referred to as biocatalytic conversions. Enzymes are now
easily available and are an important tool in organic synthesis. The earliest
biocatalytic conversion known to mankind is the manufacture of ethyl alcohol
from molasses, the mother liquor left after the crystallisation of cane sugar
from concentrated cane juice. This transformation is brought about by the
enzyme 'invertase' which converts sucrose into glucose and fructose and
finally by the enzyme zymase which converts glucose and fructose into ethyl
alcohol. It is well known that most of the antibiotics have been prepared using
enzymes (enzymatic fermentation).
The biocatalytic conversions have many advantages in relevance to green
chemistry. Some of these are given below:
• Most of the reactions are performed in aqueous medium at ambient
temperature and pressure.
• The biocatalytic conversions normally involve only one step.
• Protection and deprotection of functional groups is not necessary.
• The reactions are fast reactions.
• The conversions are stereospecific.
One of the most common examples is the biocatalytic conversion of
Penicillin into 6-APA by the enzyme 'Penacylase' (one step process). However,
the chemical conversion requires a number of steps (Scheme 1).
A special advantage of the biochemical reactions is that they are
chemoselective, regioselective and stereoselective. Also, some of the
biochemical conversions are generally not possible by conventional chemical
means. Two such examples in heterocyclic compounds are given in
(Scheme 2). I
A number of diverse reactions are possible by biocatalytic processes,
which are catalysed by enzymes. The major six classes of enzymes and the
type of reactions they catalyse are discussed as follows:
1. Oxidoreductases: These enzymes catalyse oxidation-reduction reactions.
This class includes oxidases (direct oxidation with molecular oxygen)
and dehydrogenases (which catalyse the removal of hydrogen from one
substrate and pass it on to a second substrate).
Biocatalysts in Organic Synthesis 89
I) Me 3SiCI
2) PCl/CHzCl z
PhN Mez
Scheme 1
©" C0 H
2
O~
Achromobacter
xylosoclans
·Q
0 HO
C0 H
2
yield> 90%
N O~
P. obeovorans ~ ff C02H
Scheme 2
2. Transferases: These enzymes catalyse the transfer of various functional

groups, e.g. transaminase.
3. Hydrolases: This group of enzymes catalyse hydrolytic reactions, e.g.

penteases (proteins), esterases (esters) etc.
4. Lyases: These are of two types, one which catalyses addition to double
bond and the other which catalyses removal of groups and leaves double
bond. Both addition and eliminations of small molecules are on Sp3_
hybridized carbon.
90 GREEN CHEMISTRY
5. Isomerases: These catalyse various types of isomerisation, e.g.

racemases, epimerases etc.
6. Ligases: These catalyse the formation or cleavage of sp3-hybridized

carbon.
As already stated the enzymes are specific in their action. This specificity of
enzymes may be manifested in one of the three ways:
(i) An enzyme may catalyse a particular type of reaction, e.g. esterases
hydrolyses only esters. Such enzymes are called reaction specific.
Alternatively, an enzyme may be specific for a particular class of
compounds. These enzymes are referred to as substrate specific, e.g.,
urease hydrolyses only urea and phosphatases hydrolyse only phosphate
esters.
(ii) An enzyme may exhibit kinetic specificity. For example, esterases
hydrolyse all esters but at different rates.
(iii) An enzyme may be stereospecific. For example, maltase hydrolyses a-
glycosides but not J3-glycosides. On the other hand emulsin hydrolyses
the J3-glycosides but not the a-glycosides.
It should be noted, that a given enzyme could exhibit more than one specificities.
11.2 Biochemical (Microbial) Oxidations

The oxidations accomplished by enzymes or microorganisms excel in
regiospecificity, stereospecificity and enantioselectivity. The optical purity
(enantiomeric excess) is usually very high nearing 100%. An unbelievably
large number of enzymatic (or microbial) oxidations have been accomplished.
Two important enzymatic oxidations have been very well known since
early times. One is the conversion of alcohol into acetic acid by bacterium
acetic in presence of air (the process is now known as quick-vinegar process)
(Scheme-3) and the second one is the conversion of sucrose into ethyl alcohol
by yeast (Scheme-4) (this process is used for the manufacture of ethyl alcohol).
Bacterium acetic
CH 3 CH 2 0H + O 2 - - - - - - - . . CH 3 COOH + H 2 0
Ethyl alcohol Acetic acid
Scheme 3
In a similar way, lactose can be converted into lactic acid (Scheme 5).
The above enzymatic oxidations are referred to as fermentation.
Microbial oxidations occur under very mild conditions, usually around
70°C and in dilute solution. They are slow and often take days.
Invertase
C12H22011 + H 20 ------i~~ 2C 6H 1206
yeast
Sucrose Glucose & fructose
Invertase
------i~~ 2C2H s OH + 2C0 2
yeast
Ethyl alcohol
Scheme 4
Bacillus acidic
4CH 3CH(OH)C0 2H
Lactic
Lactose Lactic acid
Scheme 5
Considerable amount of work has been reported in the hydroxylation of
aromatic rings. Thus, benzene on oxidation with Pseudomonas putida in
presence of oxygen gives the cis-diol (Scheme 6). 2 The cis-diol obtained could
be converted by four steps into 1,2,3 ,4-tetrahydroxy compound, conduritol-
p3 and by five steps into the hexahydroxy compound, pinitol, an antidiabetic
agent (Scheme 6).4
However, Micrococcus spheroids like organism converts benzene into
trans, trans-muconic acid (Scheme 7). s
In a similar way, toluene, halogensubstituted benzenes, halogensubstituted
toluene gave the corresponding cis diols (Scheme 8). 6
The cis-diol obtained from chlorobenzene is converted into 2,3-
isopropyliden-L-ribose-y-Iactone in four steps (Scheme 9).7
Enzymatic conversion of ketones to esters is commonly encountered in
microbial degradation. 8 A typical transformation in the enzymatic Baeyer-Villiger
oxidation, which converts cyclohexanone into the lactone (Scheme 10) using
a purified cyclohexanone oxygenase enzyme. 9. 10 Some more examples of
Baeyer-Villiger oxidation are given (see pages 95 and 96).
This enzyme also converts phenylacetaldehyde into phenylacetic acid in
65% yield.
Similarly, 4-methylcyclohexanone can be converted into the corresponding
lactone (Scheme 11) in 80% yield ll with> 98% ee with cyclohexanone
oxygenase, obtained from Acineto bacter.
92 GREEN CHEMISTRY
o
Benzene
Pseudomonas putida
~
~OH
~OH
cis-3,5-cyclohexdiene-l,2-diol
5"'1'/
(cis diol)
~steps
QH QH
H 0 ' - N0H H 0 ' - N0H
HOII""~OH ~OH
OH Conduritol-F
Pinitol
Scheme 6
oBenzene
Micrococus spheroids
like organism
~
C0 2H
trans, trans-Muconic acid
Scheme 7
x
NOH
X
Pseudomonas putida
-----'----~.. YOH
R R
R = H; X - Cl, Br, I, F
R = CH 3 ; X = Cl, Br, I, F
R=CH 3 ; X =H
Scheme 8
2) ~putidu .. (x ~
CI OH
OH
4 steps
- - - - - - - '.......
25% overall yield Db:><
('"
Chloro benzene OH
2,3-Isopropylidene-
L-ribose-y-lactone
Scheme 9
Cyclohexanone oxygenase. FAD

NADPH,02
.. 0 0
+ NADP' + H20
Cyclohexanone Lactone
Scheme 10
D°°
6
Cyclohexanone oxygenase
NADPH,02
-------G-l-u-co-s-e--6---p-h-os~p-h-at-e------~~
Me
Me. Lactone
4-Methylcyclohexanone Scheme 11
94 GREEN CHEMISTRY
In case of steroids, many different positions can be hydroxylated by different

microorganisms, and usually, only one diastereomer is formed. From achiral
molecules, optically active compounds are generated.
A number of microbial reagents have been used for successful oxidation
of steroids, isoprenoids, alkaloids, hydrocarbons and other type of molecules.
A number of reviews and monographs are available. 12 Here we have given few
cases which offer synthetic utility because they can afford excellent yield or
they give single product that is inaccessible by other methods. Following are
some typical microbial oxidations:
1. Progesterone can be converted by several microorganisms 13 particularly
Rhizopus nigrioans and Aspergillus ochraceus into
11 a-hydroxyprogesterone. This is a commercial method of
manufacturing of 11 a-hydroxyprogesterone as raw material for
medicinally important steroids (Scheme 12).
Aspergillus ochraceus
~
o
Progesterone II a-Hydroxyprogesterone
Scheme 12
2. Hydroxylation of 9~-10a-pregna-4,6-diene-3,20-dione to give the

corresponding 16a-hydroxy derivative by Sepedonium ampullosporium. 14
This reaction has been carried out in 81 % yield on a kilogram scale
(Scheme 13).
3. Oxidation of oesterone by Gibberella fujikuroi gives lS 75% yield of
15a-hydroxyoesterone (Scheme 14).
4. Hydroxylation of the cholesterol by Mycobacterium sp. gives l6
cholest-4-en-3-one (Scheme 15).
5. Allylic oxidation of 17-methyltestosterone by Gibberella saubinetti gives 17
the corresponding 6~-hydroxy product (Scheme 16).
6. Baeyer-Villiger oxidations of steroids are accomplished biochemically.
Thus, 19-Nortestosterone on treatment with Aspergillus tamarii gives
70% yield of 19-nortestololactone. 18 Progresterone and testosterene are
converted into L1' -dehydrotestololactone by fermentation with
cylindrocarpon radicicola. 19 Testololactone is obtained from progesterone
by oxidation with Penicillium chrysogenum and from 4-androstene-3,
17-dione by treatment with Penicillium lilacinum (Scheme 17).20
Biocatalysts in Organir: Synthesis 95
CH3 CH3
I
co I
co
Sepedonium OH
..'"
ampullosorium
..
9P, lOa-Pregna-4, 6-diene-3, 20-dione 16a-Hydroxy product

81%
Scheme 13
Gibberella
fujikuroi
HO
Oestrone 15 a-Hydroxy oestrone
Scheme 14
Mycobacterium sp.
~
HO o
Cholesterol Cholest-4-en-3-one
Scheme 15
96 GREEN CHEMISTRY
o
17-Methyltestosterone OR
6p-Hydroxy-17-methyl
testosterone
Scheme 16
o COCH, OR
o
4-Androstene-3,17-dione Progesterone Testosterone
Penicilliu~ henicilliu~ / Cylindrocarpon

/ chrysogenum ~ / radicicola
illacinu':' ~ (70%) (50%)
(79%) o 0 o 0
o o
Testololactone ~' -dehydrotestololactone
Scheme 17
Sometimes, a single enzyme is capable of many oxidations. Some examples

are:
(i) Cyc1ohexanone oxygenase from Acinotobactor strain NCIB 9871 in
presence ofNADH (reduced nicotinamide adenine dinucleotide) converts
aldehydes into esters (Baeyer-Villiger reaction) ; phenylboronic acids into
phenols; sulphides into optically active sulfoxides; and selenides into
selenoxides (Scheme 18),21
(ii) Horse liver dehydrogenase oxidises primary alcohols to acids (esters)22
and secondary alcohols to ketones 23 (Scheme 19).
(iii) Horseradish peroxidase catalyses dehydrogenative coupling24 and oxidation

of phenol to quinones 2s (Scheme 20).
(iv) Mushroom polyphenol oxidase hydroxylates phenols and oxidizes them
to quinones26 (Scheme 21).
Besides the above, there are a number of other examples involving the use of
enzymes in oxidations. 27
(v) Some important transformations (oxidations) of diols with horse liver
a1cohol- dehydrogenase (LHADH) using NAD are given (Table 1):
C 6H sCH2 CHO
Phenyl acetaldehyde Phenylacetic acid Benzylfonnate Benzyl alcohol
(65%) (12%) (23%)
C~SCH2COCH3 -..";-..",.......".,..",...,...,..,..~,."...",,,....--I•• C 6H sCH20COCH 3
0" Enz-FAD, NADPH, H'
Phenylacetone Benzyl acetate
S Cyclohexanone
~ oxygenase
(CH3hC......t----./ •
cis Sulfoxides trans
4-tertbutyl
Thiacyclohexane
o
Cyclohexanone oxygenase II
C6HsSeCH3 -~--.,.-~:;"""-- ..
~ C6H5SeCH3
(Acinetobacter sp.)
Methyl phenyl Selenoxide
selenide
Selenone
-fr-om-=-ac-in-e-to-ba-c-ter-s-tra;;.:i;;..n--.... C6 H50 H
Phenyl boronic acid NCIB 9781 phenol
Scheme 18
_ _ . [(X -
Horse liver alcohol _
dehydrogenase pH9,
20°C
CH 0H
2
COOH
(X0
o
Part. oxidation 72-77%
product
Horse liver
(± )-trans-3-methycyclohexanol - - - - - - - - '.. ~ (- )-(S)-3-methy Icyc lohexanone
alcohol dehydrogenate 50% yield ee 100%
Horse liver
(±)-cis-3-methycyclopentanol --..--,;.~---.,;--~ .. (+ )-(S )-2-methylcyc Iopentanone
alcohol dehydrogenate 55% yield ee 96%
Scheme 19
98 GREEN CHEMISTRY
HO
(1) Horse radish peroxidase

0.02% HP, 1 hr Et3N HO
~
(2) W
HO
OH
Laudanosline Apomorphine
methiodide methochloride
CH3
~ OH
Horse radish
.
peroxidase
~
H3C CH3
Q OCH3
OH
OCH3
Horse radish
peroxidase
pH4.7, R.T. 60 hr
~
CH3~OOCH3
0-0
- -
CH30 OCH3
76%
Scheme 20
~OH Mushroom polyphenol

oxidase
~
o-chlorophenol 62%
Scheme 21
Table 1
Substrate Product ee(%) Ref.
0):) 100 28
S~OH
~OH (=Go o
100 28
)'(
HO OH xY 100 28
~ ~~
}(A OH OH
29
~_) 96 30
HO OH o 0
11.3 Biochemical (Microbial) Reductions

Like enzymatic oxidations, the enzymatic reductions are straight forward and
highly stereoselective. Prelog was the first to study the reduction of carbonyl
compounds with a number of enzymatic systems. For example, reduction of
ketones with curvularia fulcata gave predictable stereochemical induction based
on the groups present (large and small) in the keto group. This is known as
Prelog's rule. 31 According to this rule, if the steric difference between large
(L) and small (S) groups attached to the carbonyl group is large enough, the
enzyme delivers hydrogen from the less hindered face to give the corresponding
alcohol.
~
HO""'IH
enzyme.
L S
Two most common enzymatic systems are yeast alcohol dehydrogenase

(YAD) and horse liver alcohol dehydrogenase (HLADH). The selectivity
100 GREEN CHEMISTRY
observed with these enzymes is· determined by non-bonded interaction of

substrate and enzyme in the hydrogen transfer transition state. 3l .
Baker's yeast (Saccharomyces cerevisiae) is a very common 'reagent'
and it selectively reduces p-ketoesters and p-diketones. Thus, reduction of
ethylacetoacetate with Baker's yeast gave the (S)-alcohol. On the other hand,
reduction of ethyl p-ketovalerate gave the (R)-alcohol (Scheme 22).
0 QR
Baker's yeast
~C02Et • ~C02Et
Ethyl acetoacetate (S)-Alcohol

(67%)
0 OR
Baker's yeast
~C02Et • ~C02Et
Ethyl p-ketovalerate (R)-Alcohol
(71%)
Scheme 22
It was shown that the selectivity of reduction changed from (S) selectivity
with small chain esters to (R) selectivity with long chain esters.32
The (S)-alcohol obtained above (Scheme 22) is used in the Mori's synthesis
of (S)-( +)-sulcatol. 33
The selectivity of reduction is also illustrated by the observation that
2-butanone is reduced by Thermoanaerobium brockii which gave the (R)-
alcohol (2-butnaol) in 12% yield and 48% ee, R, but the large ketones are
reduced to the (S)-alcohol (85% yield and 96% ee, S)34 (Scheme 23).
The above examples illustrate the enantioselectivity of the reduction and
that selectivity depends on the size and nature of the groups around the carbonyl.
The (S)-alcohol obtained above (Scheme 23) is used in the Mori's synthesis
(S )-(+)-sulcatol. 33
There are a number of synthetic applications of the use of Baker's yeast.
Thus, reduction of the p-ketoester (Scheme 24) gave 71 % yield of the alcohol,
which was used in the Hoffmann's synthesis of the cigarette beetle. 34a
The selectivity of all these reductions is in consistent with the (S)-selectivity
as predicted by Prelog's rule. It is found that 1,3-diketones are normally reduced
to p-ketoalcohol. Thus, 2,4-hexanedione gave quantitatively (S)-5-hydroxy-
3-hexanone (90% ee).35
Reduction of ethyl acetoacetate with Aspergillus niger gives 98% of a
75:21 mixture favouring (R)-alcohol. This is in contrast to the formation of
(S)-alcohol with Baker's yeast or geotrichum candidum. 36
0 OH
)V
2-Butanone
T. brockii
~
N
(R)-2-Butanol
(I 2%, 48% ee)
0 OH
Jvv T. brockii
~
~
2-Hexanone (S)-2-Hexanol
(85%,96% ee)
Scheme 23
(r
o
C02Et _Baker's
_ _,---.
yeast
~ 0: 9H
",
".C02Et
S S
(S)-AIcohol
Scheme 24
Baker's yeast reduces simple ketones 37 as shown by the selective reduction

of the ketonic moiety on the side chain of the cyclopentadione to the (R)-
alcohol (Scheme 25). The formed (R)-alcohol is used in the synthesis is
norgestral. 38
Me~
M~~,,::w ------i..
Baker's yeast Me,~~?tJ"".
HO
0
I'II'ITT'
'H 0
o 0
(R)-Alcohol
Scheme 25
Geranial on reduction with Baker's yeast gave (R)-citronellol. However,

reduction of the Z isomer (neral) gave a 6:4 R:S mixture probably due to
isomerisation of the double bond in neral prior to the delivery ofhydrogen. 39
102 GREEN CHEMISTRY
Miscellaneous Reductions
Asymmetric reduction of carbonyl compounds and production of isotopically
labelled species has been achieved. A system based on deuterated formate and
formate dehydrogenase provides the best system for the introduction of
deuterium through nicotinamide-cofactor catalysed process 40 (Table 2).
Table 2
Substrate Enzyme Product Ref.

(ee%)
:©C
(cofactor)
o
o T••. •... H
NT
II RO
R0"rAYc... HlADH OH 41
(NADH)
MeO (100%)
MeO
HlADH 42
(NADH)
H0'x.•• D
43
HlADH F3c' 'H
(NADH) (>97%)
o 9H
CI :: 44
Cl~ e L-LDH
~C02-
cO 2 (NaDH)
(98%)
HLADH = Horse liver alcohol dehydrogenase
L-LDH = L-Iactic dehydrogenase
11.4 Enzymes Catalysed Hydrolytic Processes

As already stated enzymes have great potential as catalysts for use in synthetic
organic chemistry. The applications of enzymes in synthesis have so far been
limited to relatively small number of large scale hydrolytic processes used in
industry and to a large number of small scale synthesis of products used in
research. Following are given some of the applications of enzymes in hydrolytic
processes.
11.4.1 Enantioselective Hydrolysis of Meso Diesters

Pig liver esterase has been used for the enantioselective hydrolysis of the
following meso substrates (Table 3).
Table 3
Substrate Product ee(%) Ref.
XO~
o~COzMe 77 45
COzMe
CX~M' 96 46,47
CO:1Me
RX
I
MeOzC
2
COzMe
100 48,49,50
R'=OH, CH 3 , H, PhCHPCONH
R2=CH 3 , H, CHlh, N0 2, C6H s' CHMe2, cyc\ohexyl
The enantioselective hydrolysis of the following have been achieved by hog

pancreatic lipase (Scheme 26).51
CH 3 CH 3
~ACO~OH
ee 95%
CH 3 CH 3
~HO~OAC
ee 90%
Scheme 26
11.4.2 Hydrolysis ofN-acylamino Acids

The hydrolytic enzymes 'amidases' are useful for the hydrolysis ofN-acylamino
acids for the synthesis of amino acids and in the formation of amide bonds in
polypeptides and proteins. In fact, this method is the resolution of amino
acids. 52
o R
Acylase
~~CO~
H
•
104 GREEN CHEMISTRY
Some other applications in use of amidases are also given (Table 4):
Table 4
Reaction Ref.
Protease
~
53
Penicillase
II 54,55
NH2 H
A-
~oMe _N S
V 0 +
Ph'
Cyhalospon~
.
Y r--r~
0
0
J--N.... OAc
Acylase C0 2 H
11.4.3 Miscellaneous Applications of Enzymes

(a) A number of commercial applications of Isomerases and Lyases are
recorded. For example, glycosidases are used in large quantity in
conversion of com starch to glucose56 and glucose isomerase catalyses
the equilibration of glucose and fructose. 57
(b) Aspartic acid is prepared by addition of ammonia to fumaric acid in a
reaction catalysed by aspartase. 58
( c) Malic acid is o.btained by hydration of fumaric acid by the· enzyme
fumarase. 59
(d) Enantioselective condensation of HeN with aldehydes is catalysed by
cyanohydrolases from several sources. 60
(e) S-adenosylhomocysteine (or analogues) can be synthesised from
homocysteine and adenosine (or analogues) by adenosylhomocysteine
hydrolase. 61
(f) Ester groups at Sn-l and Sn-2 positions of glycerol moiety can be
hydrolysed by phospholipases Al and ~ respectively.62
(g) L-Phenylalanine synthesised by addition of isotopically labelled ammonia
to cinnamic acid catalysed by phenylalanine ammonia lyase. 63
(h) Using hydrolytic deaminations, L-citraline, L-arginine has been prepared
on a large scale. 64
(i) Acrylamine has been synthesised from acrylonitrile by nitrile hydratases. 65
(j) D-, L- and mesotastaric acids have been synthesised by using
epoxidehydrolases as shown as follows: 66
o<{coo" 9H
G Q
(coo e
.. T
OO~ /-....
l coo cooe
L
E,
e COO
OH
D-Tartarate
Q OH
E2 000coo-
OH
L-Tartarate
meso-tartarate
EI = D-tartarate epoxidase
E2 = L=tartarate epoxidase
E3 = epoxide hydrolysate from rabit liver microsomes
(k) The synthesis of 5-phospho-D-ribosyl-l-pyrophosphate, a key

intermediate in the biosynthesis of nucleotide has been achieved. 67
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12. Aqueous Phase Reactions
12.1 Introduction
The use of water as a solvent for carrying out organic reactions was non-
existent till about the middle ofthe 20th century. In view of the environmental
concerns caused by pollution of organic solvents, chemists all over the world
have been trying to carry out organic reactions in aqueous phase. The advantage
of using water as a solvent is its cost, safety (it is non-inflammable, and is
devoid of any carcinogenic effects) and simple operation. Water has the highest
value for specific heat of all substances. It's unique enthalpic and entropic
properties has led the chemists to use it as a solvent in organic reactions.
Water has an abnormally low volatility because its molecules are associated
with each other by means of hydrogen bonds. In fact, the H bonding is the
main reason why covalent compounds have low solubility in water. Ionic
material become hydrated and polar materials take part in the hydrogen bonding,
so they are soluble.
Under high pressure and temperature, ordinary water behaves very
differently. I The electrolytic conductance of aqueous solutions increases with
increase in pressure. However, for all other solvents the electrical conductivity
of solutions decrease with increase in pressure. This unusual behaviour of
water is due to its peculiar associative properties. 2
Water becomes less dense due to thermal expansion with increase in
temperature. The density of water is 1.0 g Icm3 at room temperature, which
changes to 0.7 g/cm3 at 306 °e. At critical point, the densities of the two
phases become identical and they become a single fluid, which is called
supercritical fluid. The density of water at this point is ~ 0.3 g/cm3 • In the
supercritical region, most of the properties of water vary widely. The most
important of these is the heat capacity' at constant pressure, which approach
infinity at the critical point. Also, the dielectric constant of dense, supercritical
water ranges from 5 to 20 on variation of applied pressure.
As the temperature of water increases to the critical point, its electrolytic
conductance rises sharply independent of the pressure. This is attributed to
decrease in its viscosity over this range. However, near the supercritical point,
the conductance begin to drop off.
Following are given some of the reactions which have been carried out in
aqueous medium.
Aqueous Phase Reactions 109
12.2 Diels-Alder Reaction

The most important method 3 to form cyclic structures is the well-known
Diels-Alder reaction. However, the first Diels-Alder reaction in aqueous media
was carried out in the beginning of the 19 th century.4Thus, furan reacted with
maleic anhydride in hot water to give the adduct (Scheme 1).
Maleic anhydride
~ Hot water
0
O
CO ~C02H
C0 H H2
( 2
+ ~
R.T.
C0 2 H
Furan Maleic acid C0 2H
Adduct
Scheme 1
The product obtained was a diacid (Scheme 1) showing that the reaction
occurred via the formation of maleic acid from maleic anhydride.
A typical reaction of cyclopentadiene with N-sec. butylmaleimide gave
quantitative yield of the adduct (Scheme 2). 5
O
:::::,..., + QN---.A
I
°
o H02
Me(CH,) •.(OCH 2CH 2)2PH

25C, 6 hr stirring
•
~o
Cyclopentadiene
N-Sec. butyl
maleimide
~dduct ~
Scheme 2
However, it was only in 1980 that Breslow6 observed that the Diels-Alder
reaction of cyclopentadiene with butenone in water (Scheme 3) was more
than 700 times faster than the same reaction in isooctane.
Similarly, cyclopentadiene reacted with dimethyl maleate or methyl
melliotei: aque:::di:~;~S:he~ 5)+ , ~

Cyclopentadiene
If
Butenone
~CaCH
~cacH3
3
19 5
Scheme 3
110 GREEN CHEMISTRY
0
C0 Me H 2O
( 2 ~
R.T.
C0 2Me C0 2Me
Cyciopentadiene
Dimethyl
maleate endo+exo
Scheme 4
o +
Cyciopentadiene
I( CO 2Me_H"';"20---l."
Methyl
acrylate
R.T.
~C02Me endo+ exo
Scheme 5
The following two reactions (Schemes 6 and 7) have also been found to
proceed in quantitative yield. 6
(N
0
Cyciopentadiene
+
Acrylo
nitrile
[4+2]
•
~CN exo and endo
Scheme 6
CH20H
+ cl~a [4+2]
~
'-'::0
9-Hydroxymethylanthracene N-Ethyl
rnaleimide
Scheme 7
It has been found that in the Diels-Alder reaction (Scheme 7), the rate
increased 2.5 times if the reaction was carried out in a 4.86 M aqueous solution
ofLiCl. In this case LiCI is a prohydrophobic ('salting out') agent. However,
the rate decreased considerably if the reaction was carried out in presence of
2.0 M aqueous solution of guanidinum perchlorate. In this case, guanidinium
perchlorate is an antihydrophobic ('salting-in') agent.
It has been demonstrated7 that the use of 'salting-out' prohydrophobic
agents considerably increased the yields of cyclo-adduction of the diene
carboxylates with a variety of dienophiles in water at ambient temperature.
Similar results were obtained by using corresponding sodium or ammonium
carboxylates.
It is well known that the conventional Diels-Alder reactions in aprotic
organic solvents are catalysed by Lewis acids. In view of this, the use of
Lewis acids in aqueous Diels-Alder reactions has been investigated and the
reaction was found to occur much faster (Scheme 8). 8
o
Scheme 8
The above reaction (Scheme 8) in aqueous Cu(N03)2 proceeded about

800 times faster than in water alone and 2,50,000 times faster than in acetonitrile.
It is appropriate to state that the reaction between cyclopentadiene and
methyl acrylate (Scheme 5) proceed about four times faster in formamide and
six times faster in ethylene glycol than it does in methanoP Similar results
were reported by Liotta et al. 10 These solvents, viz. formamide and ethylene
glycol are referred to as 'water-like' solvent systems. Also addition of LiCI in
'water-like' solvents led to a further rate increase. In this case, it is noteworthy
that addition of traditional 'antihydrophobic' additives like urea also increased
the rate (rather than retarding the rate) of the Diel-Alder reaction. II
The Diels-Alder reaction in aqueous medium has tremendous synthetic
potentialities. Ita This technique has been used in the field of terpenes, steroids
and alkaloids.
Due to the convenience of conducting Diels-Alder reactions, in aqueous
phase, this methodology has found a number of applications in pharmaceutical
industry. Some interesting applications are:
(i) Synthesis of antifungals based on aqueous Diels-Alder reaction. 12
(ii) Intramolecular version of Diels-Alder reaction with a dienecarboxylate
112 GREEN CHEMISTRY
was used in synthetic study of the antibiotic ilicicolin H.13

(iii) Synthesis of a,ro-alkane dicarboxylic acid by the reaction of cyclooctene
with ozone in H20 at 10° followed by treatment with HP2 in presence of
an emulsifier (Scheme 9).14
AD (I) H 20/10 °C ~ HOOC~ A A A

07 ' 0 (2) HP2 V V v 'C0 2H
emulsifier
Cyc100ctene
Scheme 9
(iv) A hetero-Diels-Alder reaction for the synthesis of heterocyclic compounds

with nitrogen- or oxygen-containing dienophiles are particularly useful. IS
The first example ofhetero-Diels Alder reaction was reported in 1985 by
Grieco. In this reaction an iminium salt (generated in situ under Mannich-
like conditions) reacted with dienes in water to give aza-Diels-Alder reaction
products (Scheme 10) which are useful in the synthesis of alkaloids. 16
RNH2 ·HCl 9~ ~~
~~
Scheme 10
The intramolecular aza-Diels-Alder reaction 17 also occurs in aqueous media.

This reaction gave fused ring system (Scheme 11).
HCHO, Hp
50°C, 48 h, 95%
Scheme 11
For more details, refer to a review on hetero Diels-Alder reactions. 18

(v) A convenient one-pot synthesis of a variety of heterocyclic products by
the reaction of an appropriate oxime with NaOCI in H20/CH 2CI 2
(Scheme 12) has been achieved. 19
Also see Diels-Alder reaction in ionic liquids, which is considered to be
better than in aqueous medium (Chapter 14).
90%
Scheme 12
Diels-Alder reaction can also be performed in the solid phase. Thus,

phenylpropiolic acid derivatives upon heating at 80°C give the products
(anhydrides) in 20-50% yields (Scheme 13).20
~
R2y-=-C02H
R3
Solid
(a) R I, R2 = -OCHp-; R3 = H
(b) RI = R2 = -OCH 3; R3 = H
(c) RI = R2 = -OCH3
R2
Scheme 13
12.3 Claisen Rearrangement

The thermal rearrangement of allyl phenyl ethers to o-allyl phenol and its
mechanism is very well known to organic chemistsY Both the aliphatic and
aromatic Claisen rearrangements involve a 3,3-sigmatropic shift. 22 There are
reviews providing usefulness of this rearrangement reaction.23
The first reported use of water in promoting Claisen rearrangements was
in 1970. 24 The first example of the use of pure water for Claisen rearrangement
of chorismic acid is given (Scheme 14).25
A simple aliphatic Claisen rearrangement, a [3,3 ]-sigmatropic rearrangement
of an allyl vinyl ether in water gave the aldehyde (Scheme 15).26
114 GREEN CHEMISTRY
~R
Cl A _H"-P----.~OO~C02H
heat l)-
: 0 C0 2R
OR OR
Scheme 14
1) 0.01 M pyridine in H20 CHO

ec, 3.5 hr
~(CH,).cO'H
60
2) W 85%
Scheme 15
The corresponding ester also underwent similar rearrangement. Similarly

both allyl vinyl ether and 2-hepta-3,5-dienyl vinyl-ether underwent 3,3-shift.
The best results were obtained in 211 methanol-water; the rates were about 40
times than those in acetone solventY
A special feature of the Claisen rearrangement in aqueous medium is that
it is not necessary to protect the free hydroxyl group (Scheme 19).28
Hp/MeOH 2:5:1
80 ec, 24 hr, 85%
Scheme 16
The above rearrangement for protected analog under usual claisen condition
resulted in elimination of acetaldehyde. 29
Following are given some of the important applications of Claisen
rearrangement in aqueous solution.
(i) Synthesis of fenestrene aldehyde having trans ring fusion between the two
5-membered rings (Scheme 17).30
(ii) The Claisen rearrangement of the allyl vinyl ether (Scheme 18) gave the
aldehyde in 82% yield. 30
y l~
Y
HP, MeOH (3:1) eHO
H
NaOH (1.0 eguiv)
• H ,...... ,,1
90 °e, 8 hr, 48%
H H
Scheme 17
OR
OR
('" 1,-.
IN ag. NaOH
95 °e, 5 hr, 82%
.. ('" 'I .. ,
C0 2 R 0) C0 2 R
CRO
Scheme 18
(iii) Claisen rearrangements of 6-~-glycosylallyl vinyl ether (Scheme 19) and

of 6-a-glycosylalkyl vinyl ether (Scheme 20) has been successful in
aqueous medium. 3 ! In both these reactions NaBR4 was added so that the
formed aldehyde gets converted into the corresponding alcohol.
OR OR OR OR
HP, 80 °e, 1 hr
o R
't""~OR
a- 60%R(40%S)
Scheme 19
116 GREEN CHEMISTRY
OR
OR OR
HP, 60°C, 1.5 hr
RO
R O-{.:. _
O~ ~OR
13-
y-O 60% S (40% R)
Scheme 20
12.4 Wittig-Horner Reaction

The original wittig reaction 32 has been extensively used for the preparation of
olefins from alkylidene phosphoranes (ylids) and carbonyl compounds
(Scheme 21).
@ e
- - . . (C 6HshP-CR2RBr ----i.~
Phosphonium salt
~~~u
----"'--"-----'.~
@ e •
C6Rl - CRR ......I---~~ (C6Rs)3P=CRR---l~
Y1ide Phosphorane
RJCOR2 @
::;;;;
..;:::::::===..~ (C 6R shP-CHR ---'•• (C 6Rs)3P=0
e I
0-CRJR2 Olefin
Scheme 21
In the above reaction the ylide is unstable and is generated in situ for
reaction with the carbonyl compound.
A modification ofthe above reaction, known as the Wittig-Horner reaction
or Horner-Wadsworth-Emmons reaction uses phosphonate esters. Thus, the
reaction of ethyl bromoacetate with triphenylphosphite gives the phosphonate
ester, which on treatment with base (NaH) and reaction with cyc1ohexanone
gives a,l3-unsaturated ester, ethyl cyclohexylidineacetate in 70% yield

(Scheme 22).
(EtO)3P + BrCH 2C0 2Et

Triethylphosphite Ethyl bromoacetate Phosphonate ester
NaH °Il e
--~~ (EtOh-P-CHC0 2Et
Ethyl cyclohexylidineacetate
(70%)
Scheme 22
The above reaction is sometimes performed in an organic/water biphase

system. 33 It is now reported34 that in the above reaction (Scheme 22) in place
of strong base like NaH, a PTC can be used in aq. NaOH with good results. In
the above reaction (Scheme 22) the base used is NaH or any other strong
base. It has been found that the reaction proceeds with a much weaker base,
such as ~C03 or KHCO r Even compounds with base and acid sensitive
functional groups can be used directly. In a typical example, under such
conditions, l3-dimethylhydrazoneacetaldehyde can be obtained efficiently.3S
12.5 Michael Reaction

It is an addition reaction 36 between an a,l3-unsaturated carbonyl compound
and a compound with an active methylene group (e.g., malonic ester,
acetoacetic ester, cyanoacetic ester, nitroparaffins etc.) in presence of a base,
e.g., sodium ethoxide or a secondary amine (usually piperidine).
The first successful report of Michael reaction in aqueous medium was in
the 1970s. 2-Methylcyclopentane-I,3-dione when reacted with vinyl ketone
in water gave an adduct without the use of a basic catalyst (pH > 7). The
adduct further cyclises to give a 5-6 fused ring system (Scheme 23).37
2-Methyl Methyl vinyl

cyclopentane Ketone
1,3-dione
Scheme 23
118 GREEN CHEMISTRY
In this reaction (Scheme 23), use of water as solvent gave better yields
and pure compound compared to reaction with methanol in presence of a base.
Michael reaction of2-methyl-cyc1ohexane-l ,3-dione with vinylketone give
optically pure Wieland-Miescher ketone (Scheme 24).38
#'( Hydroquinone H20

70-80°C,4hr,-100%~
[ ~1
oA o~
o
2-Methyl Methyl vinyl
cyclohexane Ketone
1,3-dione
D-(+) ProHn,
--D";"M":S--O-,R-7---'~ o~
~
6 days, 82%
Wieland-Miescher Ketone
Scheme 24
The Michael addition of 2-methyl-cyc1opentane 1,3-dione to acrolein in

water gave an.adduct (Scheme 25) which was used for the synthesis of 13-
a.-methyl-14a.-hydroxysteroid. 39
H
RT 100"10
2-Methyl Acrolein
cyclopentane
1,3-dione
---i~~ • 13-a-Methyl-14-a-hydroxysteroid
Scheme 25
The rate of above Michael addition (Scheme 25) was enhanced by the
addition of ytterbium triflate [yb(OTf)J
The Michael addition of nitromethane to methyl vinyl ketone in water (in
absence of a catalyst) gave 4: 1 mixture of adducts (A and B) (Scheme 26).40
N0 2
40°, 32 hr ~ ~
CH3N~+~ -- --
H,o - - . 02
100% N +
Nitromethane 0 0 0 0
Methyl vinyl A B
ketone (4 :J)
Scheme 26
Use of methyl alcohol as a solvent (in place ofHP) gave 1: 1 mixture of A

and B. The above reaction does not occur in neat conditions or in solvents like
THF, PhMe etc. in the absence of a catalyst.
A typical synthesis of allylrethrone, an important component of an
insecticidal pyrthroid has been carried out by a combination of michael reaction
ofS-nitro-l-pentene and methyl vinyl ketone in presence of Al 2 0 3 followed by
an intramolecular aldol type condensation (Scheme 27).41
~+y
N0 2
5-Nitro-I-pentene
0
Methyl vinyl
ketone
AI,O,
RTo 7hr
& ~-
0
H,O,
MeOH-H,o
RTo 12 hr
•
OH
t.o 7 hr
Allylrethrone
Scheme 27
The Michael addition of cyclohexenone to ascorbic acid was carried out

in water in presence of an inorganic acid (rather than abase) (Scheme 28).42
The reaction 43 of active nitriles with acetylenes can be catalysed by
quaternary ammonium salts (PTC) (Scheme 29).
6
o
+
HO~O
I 0
RT, 24 hr + 3'- epimer
HO 67%
Cyc1ohexenone HO H
HO
Ascorbic acid H OH
Scheme 28
120 GREEN CHEMISTRY
+ CN
C6HSCH2NEt3Cl-
... I I
C6HSC- CH =CHR
DMSO I
NaOH solid R
R = CH 3 , isopropyl, benzyl
Scheme 29
Very efficient Michael addition reactions of amines, thiphenol and methyl

acetoacetate to chalcone in water suspension have been developed. 44 For
example, stirring a suspension of powdered chalcone in a small amount of
water containing n-Bu2NH and a surfactant, hexadecyltrimethylammonium
bromide for 2 hr gave the adduct in 98% yield. Similarly adducts were obtained
with thiophenol and methyl acetoacetate (Scheme 30).
Surfactant Ph~Ph
+ •
°
n-Bu,NH
water n-&!2N
(98%)
+
Surfactant M:0U) Ph
PhSH
K,CO,/H,O ~
P16
(92%)
°
+ MeCOCH,CO,Me
Surfactant
--------..
K,CO,IH,O Me
0:!h° Ph
C0 2Me
° (98%)
Scheme 30
See also Michael addition in solid state (Sec. 13.2.3).

Asymmetric Michael addition of benzenethiol to 2-cyclohexenone and
maleic acid esters proceeds enantioselectively in their crystalline cyclodextrin
complexes. The adducts were obtained in 38 and 30% ee respectively. In both
cases, the reaction was carried out in water suspension (Scheme 31).45
12.6 Aldol Condensation

The aldol condensation is considered to be one of the most important carbon-
carbon bond forming reactions in organic synthesis in presence of basic
reagents. The conventional aldol condensation involve reversible self-addition
of aldehydes containing a a-hydrogen atom. The formed ~-hydroxy aldehydes
SH
6 D
Cyclohexenone
0
r--w-a-te-r-su-s-p-en-s-io-n~~
PhS
(S)(-)-adduct
ICCOO-octyi
COO-octyl ,(COO~ctyl
Water suspension
P-CD complex of PhS CO O-octyl
benzenethiol
(+)-(- )-adduct
Scheme 31
undergo dehydration to give a,p-unsaturated aldehydes. This has been

extensively reviewed. 46 The reaction can occur either between two identical
or different aldehydes, two identical or different ketones and an aldehyde and
a ketone.
A stereoselective aldol condensation is known as Mukaiyama reactionY
It consists in the reaction of an silyl enol ether of 3-pentanone with an aldehyde
(2-methyl-butanal) in presence of TiCl 4 to yield an aldol product, Manicone,
an alarm pheromone (Scheme 32).48
~osiMe: /VYV o... L'

0
Ti
C(I ..... Cl
Silyl enol ether o Cl
of 3-pentanone Manicone
2-methyl
butanal
Scheme 32
The above reactions are carried out under non-aqueous conditions.

The first water-promoted aldol reaction of silyl enol ethers with aldehydes
was first reported in 1986 (Scheme 33).49
Scheme 33
122 GREEN CHEMISTRY
The above reactions were carried out in aqueous medium without any
acid catalyst. The reaction, however, took several days for completion, probably
because water serves as a weak Lewis acid. The addition of a stronger Lewis
acid (e.g., lanthanide trifiate) greatly improved the yield and rate of such
reactions (Scheme 34).50
o OSiMe3
A ~"
Yb(OTf\
+ R' ~l --R" THF/HP(2:1)
H H ~
RT, 3-12 hr
R'
77-98%
Scheme 34
It has been found that the dehydration of the alcohols can be avoided in
presence of complexes of Zn with aminoesters or aminoalcohols. 51
Using the above methodology, vinyl ketones (Scheme 35) can be obtained
by the reaction of2-alky1-1 ,3-diketones with aqueous formaldehyde (formalin)
using 6-10 M aqueous potassium carbonate as base; the final step involved
cleavage of the intermediate with base. 52
R~R'
R"
o 0
30010 aq. HCHO
~
R,W
0; R" It
----l~~
a
X R"
R'
Vinyl ketone
Scheme 35
The reaction of several silyl enol ethers with commercial formaldehyde

solution catalysed by yb(OTf)3 were carried out and good yields (80-90%) of
the products obtained. 53 Several examples of the aldol condenstion in water
have been cited using various aldehydes and silyl enol ethers. The products
were obtained in good yield (80-90%).54 In all the above reactions the catalyst
could be recovered and used again and again. The above methodology has
been extensively reviewed. 55
An interesting case of aldol condensation is vinylogous aldol reaction.
The y-hydrogen of a,p-unsuturated ketones, nitriles and esters is 'active' and
the electrophilic addition taken place at the y-position. Thus, the reaction of
isophorone with benzaldehyde in water gives only vinylogous aldol addition
but with low conversion. However, in presence of CTACI, the condensation
product, (E)-benzylideneisophorone, is obtained in 80% yield. Use of
tetrabutylammonium chloride (TBACI) gives a mixture of addition and
condensation products (Scheme 36).56
D 0
PheRO
NaOH, RT, 4hr
.. ~+
0
Ph ~Ph
0
Isophorone
Water only 24%
CTACI 80%
TBACI 27% 58%
Scheme 36
Certain aldol condensations have been also carried out in solid state
(Sec. 13.2.5).
12.7 Knoevenagel Reaction

The condensation of aldehydes or ketones, with active methylene compounds
(especially malonic ester) in presence of a weak base like ammonia or amine
(primary or secondary) is known as Knoevenagel reaction. 57•58 However, when
condensation is carried out in presence of pyridine as a base, decarboxylation
usually occurs during the condensation. This is known as Doebner
modification. 59 Some examples are given (Scheme 37).
Base
CH3CHO + CH2(COOH)2 ---~~ CH3CH=C(COOH)2
Acetaldehyde Malonic acid
~ -C02
CH3CH=CHCOOH
Crotonic acid
Pyridine
C6llsCHO + CH2(COOC2HSn ---'-----+~ C6llsCH=C (COOC2HSn
benzene
1) hydrolysis
----~. C6llsCH=C(COOHh --.~ C6llsCH=CHCOOH
2) Hp+ -C0 2
Cinnamic acid
Scheme 37
The Knoevenagel reaction has been carried out between aldehydes and
acetonitrile in water. Thus, salicylaldehydes react with malononitrile at room
temperature in the heterogeneous aqueous alkaline medium to give
124 GREEN CHEMISTRY
a-hydroxybenzylidene malononitriles, which are converted directly to

3-cyanocoumarins by acidification and heating (Scheme 38).60
75-95%
R= H, OH, OMe
Scheme 38
In a similar way, use of substituted acetonitriles in the above procedure

(Scheme 38) give the corresponding 3-substituted coumarins in 66-98% yields
(Scheme 39).
tyYR
~OAO
66-98%
R = CN, C02 Et, N02 , Ph, 2-Py
Scheme 39
In case Of phenylacetonitrile, a catalytic amount of CTABr (0.1 mole/

equiv) is used. The above reaction gives better yields in water compared to in
ethanol.
The reaction of benzaldehyde with acetonitrile does not occur in water
only but requires the presence of catalytic amount of CTACl or TBACl to give
high yields of the corresponding arylcinnamonitriles (Scheme 40).57
Knoevenagel-type addition product can be obtained by the reaction of
acrylic derivatives in presence of a 1,4-diazabicyclo[2.2.2]octane (DABCO)
(Scheme 41).61
CTACI; NaOH Ph>=<CN

RT, 0.5-9 hr
H Ar
85-90%
Scheme 40
_ _ RT/H
--"-_-.-
20 _ PhxOH
~CN + PhCHO DABCO
Acrylo
Benzaldehyde
~ CN
nitrile 90-98%
Scheme 41
12.8 Pinacol Coupling

Ketones are known to react with Mglbenzene to give 1,2-diols by heating with
magnesium in benzene followed by treatment with water. Thus, under these
conditions acetone give pinacol (Scheme 42)
o H3C CH 3
II
CH3-C-CH3 I) Mglbenzene, Il I I
2) Hp ~ CH 3-?-?-CH 3
Acetone OHOH
Pinacol
Scheme 42
This is known as pinacol coupling. The use of Zn-Cu couple to couple

unsaturated aldehydes to pinacols was recorded as early as 1892.62 Subsequently
chromium and vanadium63 and some ammonical-TiCl364 based reducing agents
were used.
It has now been found 65 that pinacol coupling takes place in aromatic
ketones and aldehydes in aqueous media in presence ofTi(III), under alkaline
conditions. However, in presence of acids, only the substrates (aromatic
ketones and aldehydes) having electron withdrawing group like CN, CHO,
COMe, COOH, COOMe, pyridyl (activating groups) only underwent pinacol
coupling66 (Scheme 43). In case of nonactivated carbonyl compounds, it was
necessary to use excess of the substrate as a solvent. 67
126 GREEN CHEMISTRY
THF, RT, 1-7 hr
R, = Ph, 2-Py
R2 = CN, C0 2Me
Scheme 43
The coupling reaction between an a,13-unsaturated carbonyl compound

and acetone using a Zn-Cu couple and ultrasound in an aqueous acetone
suspension (Scheme 44) gave the corresponding product. 68
>-0= _
0 + U
/"""
ZnlCu, Hp
((( 85%
~ "'-
~_OOl-H
/\)(OH
Scheme 44
An interesting example is the coupling of aldimines to give vicinal diamines

(Scheme 45) by indium in aqueous ethanol in presence of small amount of
ammonium chloride, which accelerates the reaction. 69
Scheme 4S
12.9 Benzoin Condensation

It consists in the treatment of aromatic aldehydes with sodium or potassium
cyanide, usually in an aqueous ethanolic solution to give a-hydroxy ketones
(benzoins) (Scheme 46).1°
H o OH
I II I
2Ph-C=0 Ph-C-C-Ph
I
Benzaldehyde H
Benzoin
Scheme 46
Benzoin condensation can be considered to occur through a formal

Knoevenagel type addition (Scheme 47). The key step of the reaction is the
loss of the aldehydic proton, which gives rise to the cyanohydrin anion. In this
case the acidity of the proton is increased by the electron-withdrawing power
of the cyano group.
.. e
..
:0: OH
ArCHO
CN
.. I
Ar-C-H ,
I
... I
Ar-c:e -+-
I
ArCHO
CN CN
HO :0:8 0 OH
I I II I
Ar-C-C-Ar :;;;>cr===="'~ Ar-C-C-Ar
I I I
CNH H
Scheme 47
It is found that benzoin condensation of aldehydes are strongly catalysed
by a PTC (quaternary ammonium cyanide in a two phase system).71 In a
similar way, acyloin condensations are easily effected by stirring aliphatic or
aromatic aldehydes with a quaternary catalyst (PTC), N-laurylthiazolium
bromide in aqueous phosphate buffer at room temperature. 72 The aromatic
aldehydes reacted in a short time (about 5 min). However, aliphatic aldehydes
require longer time (5-10 hr) for completion. Mixtures of aliphatic and aryl
aromatic aldehydes give mixed a-hydroxy ketones. 73
On the basis of extensive work, Breslow found that the benzoin
condensation in aqueous media using inorganic salts (e.g., LiCl) is about 200
times faster than in ethanol (without any salt).74 The addition ofy-cyclodextrin
also accelerates the reaction, whereas the addition of ~-cyclodextrin inhibits
the condensation.
12.10 Claisen-Schmidt Condensation

Normally Claisen-Schmidt condensation involves the condensation of aromatic
aldehydes (without a-hydrogen) with an aliphatic aldehyde or ketone (having
a-hyd!'ogen) in presence ofa relatively strong base (hydroxide or alkoxide) to
form a,~-unsaturated aldehyde or a ketone (Scheme 48).75
NaOH
------,... C6 H sCH=CHCHO
Cinnamaldehyde
Benzalacetophenone
(chalcone)
Scheme 48
128 GREEN CHEMISTRY
A related reaction, known as Mukaiyama reaction76 involves the reaction

of silyl enol ether of the ketone with an aldehyde in an organic solvent in
presence of TiCl4 (Scheme 49) (see also Scheme 32).
0... ,0
'Ti"
Cl.......... 1 'Cl
Cl
o
Manicone
(an alarm pheromone)
Scheme 49
It has been shown77 that trimethyl silyl enol ether of cyclohexanone with
benzaldehyde occurs in water in presence cifTiCl4 in heterogeneous phase at
room temperature and atmospheric pressure (Scheme 50).
Trimethyl silyl
82% ~+~Syn anti
enolether of 3
cyc1ohexanone
Scheme 50
Better yields are obtained under sonication conditions. The reaction is

favoured by an electron-withdrawing substituent in the para position of the
phenyl ring in benzaldehyde.
Claisen-Schmidt reaction of acetophenones with aromatic aldehydes in
presence of cationic surfactants such as cetylarnrnonium compounds, CTACl,
CTABr, (CTA)2S0 4 and CTAOH in mild alkaline conditions give chalcones,
which on cyclisation give flavanols (Scheme 51).
The reaction of cyclohexanone with benzaldehyde in water gives high
yield of a 1: 1 threo-erythro mixture of the ketol. However in presence of
CTACI, the bis-condensation product in obtained quantitatively (Scheme 52).78
Rl
JOC' 0
R
+ ArCHO
Surfactant NaOH
--------------~••
RT, 0.3-16 hr, 61-94%
~O
Rl
~
R
Ar
l
Chalkone
R=H, OH, OMe
R\ = H, OMe
Ar = X-C6H5 80° C R=OH
20min H2 0 2
(X = H, p-CI, p-NMe 2, m-NO)
R~:~ 70%
Flavanol
Scheme 51
_P_hC_H_O_,_R_T~.~ Mph
6 NaOH,3hr
Water only
V ~Ph
V
91%
+
9%
+
with CTACI 100%
Scheme 52
12.11 Heck Reaction

The Heck reaction, a synthetically used palladium catalysed reaction involves
the coupling of an alkene with a halide or triflate in presence ofPd(O) catalyst
to form a new alkene (Scheme 53).
H Pd(O) ~ R~ 1 + HX
RX+ ~l base R
R
R = aryl, vinyl or alkyl group without p-hydrogens on a Sp3 carbon atom

X = halide or triflate (OS02CF3)
Scheme 53
Heck reaction uses mild base such as Et3N or anions like OH-, -OCOCH3,
CO/- etc. Some other applications of Heck reaction are also given
(Scheme 54).
130 GREEN CHEMISTRY
PhCl+ ~ Pd(OAc)/Phl
NEt" 80 DC
~
Ph~
Ph
6l+ Br
/
Ph Pd(OAc)/Phl
NEt" 100 DC
~
~ Ph
O-Br+~
S ~N
Pd(OAc)2
100 DC, 96 hr
~
Scheme 54
The traditional technique for carrying out the Heck reaction is to use
anhydrous polar solvents (eg., DMF and MeCN) and tert. amines as bases.
Recently it has been found that the Heck reaction can proceed very well in
water. In fact, the role of water in the Heck reaction, as well as other reactions
catalysed by Pd(O) in presence of phosphine ligands is: (i) transformation of
catalyst precursor into Pd(O) species and (ii) the generation of zero-valent
palladium species capable of oxidative addition by oxidation of phosphine ligands
by the Pd(II) catalyst precursor can be affected by water content of the
reaction mixture.
It has been found that the Heck reaction can be accomplished under PTC
conditions 79 with inorganic carbonates as bases under mild conditions at room
temperature. Such conditions can be used in case of substrates, like methyl
vinyl ketone, which do not survive the usual conditions of Heck arylation
(action of base at high temperature). Subsequently, it has been shown that the
Heck reaction can be carried out in water and aqueous organic solvents,
catalysed by simple palladium salts in presence of inorganic bases like ~C03'
Na2 C0 3, NaHC0 3, KOH etc. 80
An interesting application of the Heck reaction is the synthesis of cinnamic
acid by the reaction of aryl halides with acrylic acid (Scheme 55).
Use of acrylo nitrile in place of acrylic acid in this method (Scheme 55)
yield the corresponding cinnamonitriles. Most of the products obtained in
Heck-reactions are almost exclusively (E) isomers. However, the reaction of
acrylonitrile give a mixture of (E) and (Z) isomers with ratio 3: 1, close to that
observed under conventional anhydrous conditions. 81
The Heck reaction can also be performed under milder condition by addition
of acetate ion as given in (Scheme 56).
R ~ x+ :::::.,... COzH
~ . DMF-Hp, or HMPA-HzO
PdCI 2' Na2CO3
~ R
~COOH
Aryl halide Acryhc aCId or Hp (100°C) Cinnamic acid
x = I, Br
R = H, p-CI, p-OMe, p-Me-, p-Ac, p-NO z' p-CHO, p-OH, m-COOH etc.
Scheme 55
°
HOzC'©r X
o + ~
:::::.,... COzH
PdCI H
z' z
HOzC~COzH
KZC0 3, 80°C, 2 hr (97%)
~
0
KZC0 3, KOAc, 50°C, 1 hr (98%)
Scheme 56
A number of other application ofthe Heck reaction have been described in

literature. 82
The Heck reaction has also been performed in ionic liquids (for details see
Sec. 14.3.3).
12.12 Strecker Synthesis

This method is used for the synthesis of amino acids by the reaction of an
aldehyde with ammonia followed by reaction with HCN to give a-aminonitrile,
which on hydrolysis give the corresponding amino acid (Scheme 57).83
NH2 NH2
+ I
PhCH2CHO NH3IHCN ~ PhCH2tH-CN 0
H3 .. PhCH2CH-COOH
Scheme 57
The a-aminonitrile can also be obtained by the treatment of the aldehyde

with HCN followed by reaction of the formed cyanohydrin with ammonia.
This method is known as Erlenmeyer modification. 84 A more convenient route
is to treat the aldehyde in one step with ammonium chloride and sodium cyanide
(this mixture is equivalent to ammonium cyanide, which in tum dissociate into
ammonia and HCN). This procedure is referred to as the Zelinsky-Stadnikott
modification. 85 The final step is the hydrolysis ofthe intermediate a-arninonitrile
under acidic or basic conditions.
Using strecker synthesis, disodium iminodiacetate (DSIDA) an intermediate
for the manufacture is Monsantos' Roundup (herbicide) was synthesised. 86
132 GREEN CHEMISTRY
NH3 + 2CH20 + 2HCN - NC./""'-..N./""'-..CN 2NaOH~ Na02C./""'-..~./""'-..C02Na

H
DSIDA
Strecker Synthesis of DSIDA
In the above synthesis hydrogen cyanide, a hazardous chemical is used

and this requires special handling to minimise the risk to workers and the
environment. An alternative green synthesis of DSIDA was developed by
Monsanto.
HO~~OH 2NaOH ~ NaOz~N"""""""'COzNa + 4Hz

eu catalyst H
H
DSIDA
Diethanolamine
Alternative Synthesis of DSIDA
The new method avoids the use ofHCN and CHP and is safer to operate.
12.13 Wurtz Reaction

It involves coupling of alkyl halides with sodium in dry ether to give
hydrocarbons. 87 An example is the synthesis of hexane (Scheme 58).
Na
CH 3 CH 2 CH 2 Br CH 3(CH 2)4 CH 3
ether
Propyl bromide Hexane
Scheme S8
It has been shown88 that the Wurtz coupling can be carried out by ZnlHP
(Scheme 59).
I~CI ZnlH 2 0 Cl
--.......---i.~ Cl
Scheme S9
12.14 Oxidations
One of the most widely investigated process in organic chemistry is oxidation.
A large number of reactions involving oxidation are used in industries besides
being of interest in the laboratory. A number of oxidizing agents with different
substrates have been described. 89
Oxidations have been known to be carried out in aqueous medium for a
long time. The well known oxidation of arenes with KMnO 4 in aqueous alkaline
medium is very well known. 90 However, the yields are considerably increased
by using KMn04 in presence of a phase transfer catalyst particularly in the

oxidation of toluene. Also, HP2 in water has been used quite frequently in
many organic solvents. It is environment-friendly since it forms water as a
secondary product.
In the present unit, some innovative and recent oxidations by chemical
reagents in aqueous media are given. Enzymatic oxidations have also been
known to occur in water. However, this subject will be discussed in a separate
section. Following are given some of the important reactions in aqueous medium.
12.14.1 Epoxidation
Peracids are known to react with alkenes to give stable three-membered rings
containing oxygen atom, called epoxides or oxiranes (Scheme 60) .
. . . . . c4) H~ ..........C/ o
II
II + 0/;:.. ~) ---..~ 1.......... 0 + R-C-OH
/C--¥'O~C-R C/
Peracid
/'\.
Alkene Epoxide
(oxirane)
Scheme 60
A number of peracids can be used. The reaction takes place in nonpolar

solvents such as dichloromethane and benzene. The above epoxidations are
stereoselective and take place by syn addition to the double bond, as established
by x-ray analysis of the products obtained. As the cis alkene gives only cis
epoxide and trans alkene gives trans epoxide, the reaction must be concerted,
i.e., the one step mechanism retains the stereochemistry of the starting alkenes.
It has now been found 91 that epoxidation of simple alkenes with
m-chloroperoxybenzoic acid in aqueous solution of NaHC0 3 (pH ~ 8.3) at
room temperature proceeds well and gives good yields of the epoxides. Using
this procedure some of the alkenes like cyclopentene, cyclohexene,
cycloheptene, cyclooctene, methyl cyclohexene, (+)-3-carene have been reacted
with m-chloroperbenzoic acid at 20°C for 30 min to give 90-95% of the
epoxide. Styrene could be epoxidized at 20°C (1 hr) giving 95% yield.
a-Methylstyrene and trans-~-methylstyrene could be epoxidized at 0 °C in
1 hr giving 63% and 93% respectively yields of the epoxides. In aqueous
medium, the reaction occurs in heterogeneous phase, but this does not effect
the reactivity, which sometimes is higher than in homogenous organic phase.
For direct epoxidation of simple alkenes by HP2' the peroxide must be
activated (Scheme 61). This is done in buffered aqueous tetrahydrofuran
(THF), 50% HP2 activated by stoichiometic amounts of organophosphorus
anhydride.
134 GREEN CHEMISTRY
xAlkene Epoxide
60-100%
Scheme 61
Using this method a variety of alkenes could be epoxidized. 92 The
epoxidation of electron-deficient olefins can be achieved with HP2 in presence
of sodium tungstate as a catalyst. 93 The epoxidation of alkene has also been
effected with a variety of oxidizing reagents such as Ph10 4, NaC10, 02' HP2'
ROOH, KHSO s etc. in aqueous medium in presence ofmetalloporphyrins. 94
On an industrial scale, epoxidation of alkenes is generally carried out by
using hydrogen peroxide, peracetic acid or t-butyl hydroperoxide (TBHP).9s
A novel safe and cheap method for epoxidation has been developed. 96 It consist
in using nacent oxygen generated by electrolysis of water at room temperature
by using Pd black as an anode. Using this method cyclohexene could be
epoxidized in good yield. In this illustration, water is used as a reaction medium
as well as a reagent.
Regioselective epoxidation of allyl alcohols in presence of other C=C bonds
by using monoperphthalic acid (MPPA) in presence of cetyltrimethyl ammonium
hydroxide (CTAOH) (which controls the pH of the aqueous medium)
(Scheme 62).97
I I MPPA L _ 1 _
~OH H20/CTAOH~ /~~f>/"'OH
92% 0
Scheme 62
It is interesting to note how the epoxidation takes place at different double

bonds in the terpenoids viz. geraniol (I), nerol (II), farnesol (III) and linalool
(IV) with MPPA by carrying out the reaction at different pH.
Geraniol Nerol Famesol Linalool

I II ill N
It has been found 98 that 2,3-epoxidation takes place in I, II and III with
MPPA in aqueous medium at pH 12.5 and in about 90% yields. In I, II and IV
6,7-epoxidation takes place in aqueous medium at pH 8.3 in about 60-90%

yields. The 10,1l-epoxidation takes place at pH 12 in 88% yield. In case of
linalool (IV), 1,2-epoxidation does not take place. It is appropriate to state that
6,7-epoxidation of geraniol (I) has been reported earlier with t-C4 HPOHIVO
(acac)z in benzene (refluxing) and 2,3 -epoxidation achieved by using
m-chloroperbenzoic acid. 99
It is interesting to note that attempts to epoxidise linalool and its analogues
with MPPA in organic solvents give the tetrahydrofuran and tetrahydropyran
derivatives.
Epoxidation of a,~-unsaturated carbonyl compounds in aqueous media
can be achieved traditionally by Michael reaction with alkaline hydroperoxides. 100
It has been reported that the epoxidation of a,~-unsaturated carbonyl compound
can be conveniently accomplished 101 by using sodium perborate (SPB) in
aqueous media at pH 8 to give a,~-epoxyketones (Scheme 63).
The epoxidation of a,~-unsaturated carbonyl compounds with hydrogen
peroxide under basic biphase condition, known as the Weitz-Scheffer
epoxidation (Scheme 64)102 is a very convenient and efficient method for giving
the epoxides.
The reaction (Scheme 64) has been used for the epoxidation of a number
of a,~-unsaturated aldehydes, ketones, nitriles, esters and sulfones etc.
The epoxidation of a,~-unsaturated carboxylic acid is difficult. However,
the epoxidation can be achieved with H 20z in presence of Na2W0 4 at pH 5.8-
6.8 (Scheme 65).
o
SPB, 57-80°C Rl~COMe
Hp-THF or Hp-dioxane R2 H
65-100%
R, = H, Me
R z = Me, Ph
o
SPB, 75°C 19 hr
~
Scheme 63
~
-OH-.. xH
o 0
o
Scheme 64
136 GREEN CHEMISTRY
R 1>===<C0 2H
R2 R3 pH 5.8-6.8; 60-65 °C
1.5-3 hr
Scheme 65
The above reaction is known as Payne's reaction l03 using the modified
procedure of sharpless. 104
Alternatively the above epoxidation of a,p-unsaturated carboxylic acids
can be achieved by using ozone-acetone system and buffering the reaction
with NaHC0 3 105 in 75-80% yield.
Epoxidation of fumaric acid can be achieved by using ozone in water at
neutral pH in quantitative yield. 106
The epoxidation of chalkones with NaOCI (commercially available) in
water suspension proceeded very efficientlyI°7 in presence of a PTC
hexadecyltrimethylammonium bromide in excellent yields (50-100%)
(Scheme 66).
R2 C 16 H"NMe,Br- II
NaOCI/H,O
10 hr to 2 days
o
Chalcone Chalcone epoxide
R =R =H R, = p-MeO; R, = H
R'I =p:Br' 'R2 =H R, =p-Me; R, = H
R =RR =p·Br R, =H; R,=p-Me
,
R'=~M~'R .,
' . =H
R, = p-CI; R, = H
R =R =p-CI
R:= R: =p-Me
Scheme 66
12.14.2 Dihydroxylation
In case of aIkens, one can get either syn- or anti-dihydroxylation.
12.14.2.1 Syn-Dihydroxylation
One of the earliest known method of syn-dihydroxylation of alkenes is by
treatment with dilute KMnO 4 solution in presence of sodium hydroxide
(Scheme 67). In fact the change in purple colour is the basis for the presence
of double bond and this is known as Baeyer's test for unsaturation.
This method is used for syn-hydroxylation of oleic acid and norbornene
(Scheme 68).
dil. aq. KMnO 4 HO, . . . . OH

-C-C-
NaOH /'" ...........
Scheme 67
oleic acid 1,2-diol (erythro)
aq.KMn0 4
---~.~
~H
dil. NaOH OH
Norbomene HO H
Diol
Scheme 68
There are numerous other examples of syn-dihydroxylation of alkenes in

the literature.
Osmium tetroxide in dry organic solvent 108 was subsequently used for
syn-dihydroxylations of alkenes. In fact, only a catalytic amount of osmium
tetraoxide was needed; the reaction was done in presence of chlorate salt as
primary oxidant. The reaction is normally carried out in water-tetrahydrofuran
solvent mixture (Scheme 69). Silver or barium chlorate gave better yields.
Scheme 69
The syn-hydroxylation of alkenes can also be effected by hydrogen peroxide

in presence of catalytic amount of OS04' This procedure was used earlier in
solvents such as acetone or diethyl ether.109 By this. method allyl alcohol is
quantitatively hydroxylated in water (Scheme-70).110
OH
~OH
HP,100%
HO~OH
Allyl alcohol 1,2,3-Trihydroxy propane
(glycerol)
Scheme 70
138 GREEN CHEMISTRY
Following are given some other methods used for syn-diliydroxylation of

alkenes:
(i) Osmium-tetroxide-tertiary amine N -oxide system. III The reaction is carried
out in aqueous acetone in either one or two phase system.
(ii) K3 Fe(CN)6 in presence of K2C0 3 in aqueous or tertiary butyl alcohol
provides a powerful system for the osmium-catalysed dihydroxylation of
alkenes (Scheme 71 ).112 Using this method even alkene having low reactivity
or hindered alkenes could be hydroxylated.
HO OH
~OH OsO/Kle(CN). ~ ~Y."l ./'... ./'... ~OH
K2CO/aq. t-BuOH T""""" I . . . . .,
88%
Scheme 71
Syn-hydroxylation of olefins has also been carried out with KMn04solution

using a PTC catalyst under alkaline conditions. Thus, under alkaline conditions,
cyclooctene gives 113 50% yield of cis 1,2-cyclooctane diol compared to an
O
yield of about 7% by the classical technique (Scheme 72).
o
Cyc100ctene
"'R
",~R
OR
cis, 1,2-cycIooctane diol
50%
Scheme 72
J2.14.2.2 Anti Dihydroxylation

Hydrogen peroxide in presence of tungsten oxide (W0 3) or selenium dioxide
(Se0 2) react with alkene to give anti-dihydroxylation products (Scheme 73).114
W03 (50-70°C)
•
Scheme 73
Using the Sharpless dihydroxylation different types of compounds (having

C=C) have been transfonned to diols with high enantiomeric-excess levels.
This is known as asymmetric dihydroxylation and has a wide range of synthetic
applications. A representative example is dihydroxylation used as the key step
for the synthesis of squalestatin (Scheme 74).115
A one pot procedure for the antihydroxylation of the carbon-carbon double
bond can be achieved as shown below (Scheme 75).116
OCOt-Bu
OCOt-Bu
OsO., Kle(CN)6
K2C0 3, MeS0 2NH 2
...." ...... OCOt-Bu t-BuOH-H 20

~ DHQD-CLB
RT, 3.5 days, 65%
OH
H°ftC
~
- CO,H
Ph 0 CO,H
OAc "'0 ":::::,... L 1 ./
HO (('6"""" ......".
Squalestatin-I
Scheme 74
1) HP, MCPBA, 20°C, 0.5-8 hr

2) H+, 20-100 °c, 1-10 hr
75-95%
Scheme 75
12.14.3 Miscellaneous Oxidations in Aqueous Medium
12.14.3.1 Alkenes
The oxidation of alkenes with aqueous solution of KMnO 4 in presence of a
phase transfer catalyst (e.g. CH3(CH)15N+(CH3)3CI-) or a crown ether (e.g.
I8-crown-6) gives 79% yield of the carboxylic acid. Some examples are given
(Scheme 76).
An interesting example is the oxidation of n-octane to I-octanol
(Scheme 77) using Psuedomonas oleovorans.1l7 This procedure is used for
the commercial production of I-octanol (>98% pure )."8
140 GREEN CHEMISTRY
aq. KMn04
CH3(CH2)s CH=CH2 ~ CH3(CH2)4CH2COOH
+
l-octene CH3(CH2)15N(CH3)3CI- Heptanoic acid
Qa-Pinene
KMnO/H..20
Dicyclohexano-18-crown-6
~ G:0 C02H
cis-pinonic acid
Scheme 76
Pseudomonas
CH 3(CH 2)6 CH3 oleovorans H2O • CH3(CH2)6CH20H
n-Octane l-Octanol
Scheme 77
12.14.3.2 AlI'Ynes
Alkynes can be oxidised with KMnO 4 in aqueous medium to give a mixture of
carboxylic acids. Some examples are given below (Scheme 78).
KMnO
R-C=C-R' + 4[0] 4 ~ RCOOH + R'COOH
00
aq. KMn04 II II
CH3(CH07C=QCH2hCOOH pH 7.5 • CH3(CH0,C-C-(CH2h-COOH
alk. KMn04
L.....-_ _--'-.~ CH3(CHihCOOH + HOOC(CH2hCOOH
Scheme 78
12.14.3.3 Oxidation of Aromatic Side Chains and Aromatic Ring System

Some examples are given (Scheme 79).
12.14.3.4 Oxidation of Aldehydes and Ketones

A number of procedures are available for the oxidation of aldehydes to the
corresponding carboxylic acids in aqueous and organic mediaY9
Aromatic aldehydes have been conveniently oxidized by aqueous performic
acid obtained by addition ofHP2 to HCOOH at low temperature (0-4 0C).120
alk. KMnO/~
Cetyltrimethyl ammonium chloride

4hr
Toluene Benzoic acid
>78%
[0]
KMn04 reflux
PTC
6T
~ACOOH
COOH
Quinoline Quinolinic acid

Scheme 79
The carboxylic acids precipitate out of the reaction mixture and can be
isolated by filtration. Even the hetroaromatic aldehydes like formyl pyridines,
formyl quinolines and formylazaindoles can be oxidised by the above procedure
to the corresponding carboxylic acids; in this procedure, the formation ofN-
oxides is avoided.
Chemoselective oxidation of formyl group in presence of other oxidizable
groups can be carried out in aqueous media in presence of a surfactant. For
example, 4-(methylthio)benzaldehyde is quantitatively oxidised to 4-
(methylthio)benzoic acid with TBHP in a basic aqueous medium in presence
of cetyltrimethyl ammonium sulphate. 121
Aromatic aldehydes having hydroxyl group in ortho or para position to the
formyl groups can be oxidised with alkaline HP2 (Dakin reaction) in low
yields. 122 This reaction has been recently carried out in high yields using sodium
percarbonate (SPC; Na 2C0 3 , 1.5 HP2) in H 20-THF under ultrasonic
irradiation. 123 Using this procedure following aldehydes have been oxidised in
85-95% yields: o-hydroxybenzaldehyde; p-hydroxybenzaldehyde; 2-hydroxy-
4-methoxybenzaldehyde, 2-hydroxy-3-methoxybenzaldehyde and 3-methoxy-
4-hydroxybenzaldehyde.
The Baeyer-Villiger oxidation 124 is well known for the conversion of aromatic
ketones (e.g., acetophenone) into the corresponding esters (Scheme 80).
The common peracids used are perbenzoic acid, performic acid and m-
chloroperbenzoic acid. The reaction is generally carried out in organic solvents.
The Baeyer-Villiger oxidation of ketones has been satisfactorily carried out in
aqueous heterogeneous medium with MCPBA at room temperature. 125 Some
examples using the above methodology are given (Scheme 81).
142 GREEN CHEMISTRY
6~CHJ_P_h_C_OO_O_H_'_C_H_CI_3
// 25°C
--.
..
Acetophenone Phenyl acetate
Scheme 80
MCPBA, 20°C .. R~o 0

Hp,lhr ~r
R = Me, t-Bu 95%
MCPBA, 80°C .. R-{)\-OCOMe

R--©-COMe Hp,0.5-1.5hr ~
R=H, CI, OMe 70-90%
Scheme 81
Using the above procedure, ketones, which are reactive (e.g. anthrone
which usually gives anthraquinone) and ketones, which are unreactive or give
the expected lactones in organic solvents with difficultyI26 can also be oxidised
(Scheme 82).
MCPBA, 80°C
---------i..
~
Hp, 3 hr
>000 27%
Scheme 82
Some Baeyer-Villiger oxidation of ketones with m-chloroperbenzoic acid

proceed much faster in the solid state than in solution. In this method, a
mixture of powdered ketone and 2-mole equivalent of m-chloroperbenzoic
acid is kept at room temperature to give the product. 127 The yields obtained in
solid state are much better than in CRel}" Some representative examples are
given as follows (Scheme 83).
Bu'Do + m-CPBA RT,30min

Solid state
~
Bu'-Cf
95%
(94% in CHCl)
MeOC-\ I-Br + m-CPBA RT, 5 days

Solid state
~
MOOCO--\ I-Br
64%
(50% in CHCI 3 )
RT, 24 hr
PhCOCHlh + m-CPBA -------i~
.. PhCOOCH 2 Ph
Solid state
97%
(46% in CHCI 3 )
RT, 24 hr
PhCOPh + m-CPBA PhCOOPh
Solid state
85%
0\ 0\\
(13% in CHCI 3 )
RT, 24 hr
PhOC '1_ '\ Me + m-CPBA ----+~ PhOCO '1_ '\ Br
Solid state
50%
(72% in CHCI 3)
Scheme 83
12.14.3.5 Oxidation of Amines into Nitro Compounds

Alkaline KMnO 4 oxidises tertiary alkyl amines into nitro compounds
(Scheme 84).128
I 300C I
-C-NH2 + 2MnO~
I I
--=..:....-..:::...--,1... --C-N0 2
MgS04
tertiary alkyl amine
85%
Scheme 84
Primary and secondary alkyl amines remain uneffected under above conditions.
Aromatic amines containing a carboxylic or alcoholic groups can be oxidised
144 GREEN CHEMISTRY
to nitro compounds by oxone (potassium hydrogen peroxymonosulfate triple

salt, 2KHS0 3 , KHSO 4' K2SO 4) in 20-50% aqueous acetone at 18°C in 73-84%
yield. 129
It is of interest to note that aminopyridine N-oxides are obtained under
acidic conditions in organic solvent and usually requires protection of the
amino group by acetylation and final deprotection. 130 It has now been possible
to obtain N -oxide in good yield from aminopyridine directly by using oxone in
water under neutral or basic conditions at room temperature. 131 The selectivity
of the reaction depends on the position of the amino group.
12.14.3.6 Oxidation of Nitro Compounds into Carbonyl Compounds

Alkaline KMnO 4 oxidises primary and secondary nitro groups into the
corresponding carbonyl compounds (aldehydes and ketones respectively)
(Scheme 85).
-
KMn04,OH
~ R-CHO
H20, 0-5 °C
85%
~N02 ____________
KMn0 4) OH
H O
- ~
• 2
cf°
95%
Scheme 8S
12.14.3.7 Oxidation of Nitriles
The conversion ofnitriles into amides was first reported in 1968 132 by heating
the nitrile with alcoholic KOH (Scheme 86).
fX
Ph
CONH2
ale. KOH (20%)
------..~
I"
reflux 5 hr h
Ph N H2
2-Amino-3-cyano- 2-Amino-3-carbamoyl-
4,6-diphenylpyridine 4,6-diphenylpyridine
Scheme 86
It is now well known that the conversion of nitriles into ami des can be
carried out under a variety of conditions in presence of metal catalyst. 133
A convenient method 134 has been developed. It involves in using urea-hydrogen

peroxide adduct (UHP, H2NCONH2, HP2) in presence of catalytic amount of
~C03 in water-acetone at room temperature (Scheme 87).
UHP, K 2C0 3
R-CN - - - -..............:---.. R-CONH2
Hp-acetone, R.T.
Scheme 87
Using the above method following nitriles have been converted into
corresponding amides in 85-95% yield: benzonitrile, methyl cyanide and
chloromethyl cyanide.
Nitriles can also be converted into amides by using sodium perborate
(SPB; NaB03, nHp, n = 1 to 4) in aqueous media such as Hp-MeOH13S;
Hp-acetone l36 and Hp-dioxan 137. An interesting application of this reaction is
the synthesis of quinazolin-4-(3H)-ones 138 (Scheme-88).
~HCORI SPB
~CN
Hp-dioxane, 24 hr
R\ = Me, Ph, NMe2

25-67%
Scheme 88
The quinazolin-4-(3H)-ones are interesting systems to build pharmaceutical

compounds.
It has been reported139 that the CN group of 4-(methylthio)benzonitrile is
quantitatively and selectively oxidised to amide by tertiary butyl hydroperoxide
(TBHP) in strong alkaline aqueous medium in presence of cetyltrimethyl
ammonium sulfate [(CTA)2S04] (Scheme 89). TBHP does not oxidise the CN
group at pH 7 (even at 100 0q, however in the absence of (CTA)2S04' only
the methylsulfenyl group is oxidised to methylsulfinyl. But under basic
conditions, TBHP converts both groups into amide and sulfonyl groups
respectively (Scheme 89).
12.14. 3. 8 Oxidation of Sulphides

A number of reagents (e.g. Hp/acetic acid) are available for the oxidation of
sulphides to sulfoxides and sulphones. These methods are useful only for
small scale preparations. On a large scale, an oxidant like oxone in aqueous
acetone, buffered to pH 7.8-8.0 with sodium bicarbonate is used. 140 This
procedure is economical and environmentally benin. The formation of the
146 GREEN CHEMISTRY
oxidation products, viz. sulfoxides or sulphones depend on the equivalent of

oxone used, temperature and reaction time. In aqueous medium at pH 6-7
(buffered with phosphate), the reaction is very fast and excellent conversions
to sulfoxides and sulphones are obtained. 141
NC--@-SMe
1BHP (CTA)2S0 4 1BHP HP, 100°C, 1BHP H,O, 70°C,

pH > 13 HP, 70°C, pH 7 20 hr pH> 13 - 20 hr
20 hr
H2NoC-@-SMe NC-@-SOMe H 2NOC-@- S02Me
100010 98% 98%

Scheme 89
Another cheaply available industrial chemical, sodium perborate (SPB) in

aqueous methanolic sodium hydroxide oxidises sulphides into sulphones in
very good yield. 142 Sulphides can be oxidised to sulphoxides exclusively by
using commercial 70% aqueous TBHP in water in the heterogeneous phase at
20-70 °C.143 Using this procedure some of the sulphides like Et2S, PhSMe,
PhSPh, p-OHC6H4 SMe can be oxidised quantitatively into the corresponding
sulfoxides at 20°C.
The SMe group of 4-(methylthio)benzaldehyde can be selectively oxidised
to the sulfinyl group in water at 70°C at pH 7 with tertiary butyl hydroperoxide
(TBHP) (Scheme-90).144 However, under strong basic condition both the CHO
and SMe groups are oxidised to -COOH and -S02Me respectively. By using
MCPBA under basic conditions, oxidation of -CHO group is prevented and
SMe group is oxidised to S02Me in good yield.
oHC-@-SMe
TBHP HP, 70°C TBHP H 20, 70 °C MCPBA HP, I-3°C

pH7 5 hr pH>13 2 hr pH>13 2 hr
OHc--©-soMe OHC--©-SChMe
96% 100% 98%
Scheme 90
12.14. 3. 9 Oxidations with Hypochlorite

Hypochlorite is a well known oxidizing agent in the haloform reaction for the
oxidation of methyl ketones to carboxylic acids. It has been shown 14s that the
hypochlorite anion can be transferred into organic solutions by PTC (quaternary
cations). Some of the applications of this technique are given as follows
(Scheme 91).
+ -
Bu4NX
RCH20H + NaOCl ----'-----.~ (RCHO) - - . RC0 2H
Slow reaction
Aliphatic
0
alcohol
Bu 4NX
+-
+ NaOCI----~----~.~ 0
EtOAc (solvent)
1.2 hr
Cycloheptanone
Cycloheptanol
(89%)
+ -
Bu4NX
C6HSCH-NH2 + NaOCI-----=------.~ C6HsCOCH3
I EtOAc (solvent)
CH 3 1.4 hr 98%
a-Methyl benzyl amine
+ -
Bu4NX
n-C7HlSCH2NH2 + NaOCI -------:.----~.~ n-C 7H 1S CN
EtOAc (solvent)
l-Octylamine 0.5 hr l-Cyanoheptane
(60%)
Scheme 91
12.14.3.10 Oxidation with Ferricyanide

Potassium ferri cyanide oxidises 1,2-disubstituted hydrazines in presence of
2,4,6-triphenyl phenol (as PTC) in presence ofNaOH146 to give 1,2-disubstituted
azo compounds (Scheme 92).
148 GREEN CHEMISTRY
TPP
---~~ RN=NR
NaOH
63-98%
Scheme 92
Besides what has been mentioned above, a number of oxidations can be

performed in aqueous phase in the presence of a phase transfer catalyst
(see Chapter 8).
12.15 Reduction
12.15.1 Introduction
Like oxidation, reduction of organic molecules has played an important role in
organic synthesis. A number of reducing agents with different substrates have
been described. 147
During the past 10 years, there has been considerable progress with respect
to the types of bonds which can be reduced and also with respect to regio-
and stereo-selectivity of the reduction processes. The only reducing agent
which could be used in aqueous medium is sodium borohydride. From a point
of view of industrial application reduction in aqueous medium is of paramount
importance. It is interesting to note that hydride reductions which at one time
seemed impossible to be carried out in aqueous medium have now been
accomplished by the development ofa number of water-soluble catalysts which
give higher yields and selectivities. Even the hydrogenation of aromatic
compounds have been accomplished in aqueous media.
In the present unit, some examples of a few novel reduction performed in
aqueous medium are described. Enzymic reduction have also been known to
occur in water. However, this subject will be discussed in a separate section.
Some important reductions in aqueous media are given as follows:
12.15.2 Reduction of Carbon-Carbon Double Bonds

Organic compounds containing carbon-carbon double bond (e.g. alkenes)
can be reduced to the corresponding saturated compounds (eg., alkanes) by
PtO/H 2 , Pd/H 2 or Raney Ni/H 2 • Even diimide is useful for reducing carbon-
carbon double bond in compounds like p-nitrocinnamic acid, cyc10hexene
1,2-dicarboxylic acid and oleic acid.
The reduction of carbon-carbon double bonds by the use of water soluble
hydrogenation catalysts has received attention. 148 Thus, hydrogenation of
2-acetamidoacrylates with hydrogen at room temperature in water in the
presence of water soluble chiral Rh(I) and Ru(II) complexes with
(R)-BINAP (S03Na) [BINAP is 2,2'-bis( diphenylphosphino-l, 1'-binaphthyl]
(Scheme 93).149
Rl.>==<NHcoMe M/LIH2 (l atm) .. Rl>--< NHCOMe

H C02R2 HP, RT H C~R2
2-Acetamidoacrylates L = BINAP (S03Na)4
R,
H
H
Ph
Scheme 93
Ruthenium complexes are found to be more stable than the corresponding
rhodium analogue; the ee of the final reduced product is found to be 68-88%.
The carbon-carbon double bond of a,p-unsaturated carbonyl compounds
is conveniently reduced by using ZnlNiCl2 (9: 1) in 2-methoxyethanol (ME)-
water system (Scheme 94).150 Sonication increases the yield.
~
~
___ __ z_n~iC~12(_9:~I)
ME-Hp, 30°C, 2 hr
__••
C0 2Et ))))
Scheme 94
The above procedure (Scheme-94) has been used to selectively reduce

(-)-carvone to (+) dihydrocarvone and carvotanacetone in 95% and 83 % yields
respectively by variation of experimental conditions (Scheme-95).151
ME-Hp, 30°C, 2 hr
+
))))
(+)-Dihydro Carvotanacetone
(-)-Carvone
carvone
Scheme 95
150 GREEN CHEMISTRY
Carvone was earlier reduced to dihydrocarvone by using homogeneous

hydrogenation technique with hydridochlorotris(triphenylphosphine) ruthenium
(Ph3P)3 RuCIH.152
Hydrogenation of3,8-nonadienoic acid (a compound containing an terminal
as well as an internal double bond) gives different products depending on the
reaction conditions. ls3 For example, half hydrogenation of 3,8-nonadienoic
acid in anhyd. benzene with RhCI[P(P-tolyl)313 gives major amount (66%) of
3-nonenoic acid (A). However, addition of equal amount of water to the reaction
medium gives an inversion of selectivity giving 8-nonenoic acid as the major
product (85%). The use of aqueous KOH retards the hydrogenation rate
(Scheme 96).
8 H2 (1 attn) 30 °c
A B C
3,8-Nonadienoic 3-Nonenoic acid 8-Nonenoic acid Decanoic acid
acid (capric acid)
C6Ht; (4 hr) 66% 10% 20%
C6Ht;-H20 (2 hr) 0.7% 85% 8%
C6Ht;-KOH aq.(20 hr) 6% 18% 39%
Scheme 96
The carbon-carbon double bonds can also be reduced by samarium

diiodide-Hp system. IS4
Chemoselective hydrogenation of an unsaturated aldehyde by transition
metal catalysed process lSS (Scheme 97) has been achieved.
12.15.3 Reduction of Carbon-Carbon Triple Bonds

It is very well documented that the carbon-carbon triple bonds (e.g., alkynes)
on catalytic hydrogenation gives the completely reduced product, viz. alkanes.
Alkynes can also be reduced partially to give z-alkenes by palladium-calcium
carbonate catalyst which has been deactivated (partially poisoned) by the addition
of lead acetate (Lindlar catalyst) or Pd-BaS04 deactivated by quinoline. The
lead treatment poisoned the palladium catalyst, rendering it less active and the
reaction is more selective. Some examples are given (Scheme 98).
An example of reduction of carbon-carbon triple bond in water is the
reaction of disubstituted alkynes (which are electron deficient) with water-
soluble monosulfonated and trisulfonated triphenylphosphine (Scheme 99).IS6
RU/tpps (1/10)
H2 (20 bar), 80°C I
r----to-lu-e-ne-ffi-2-0-(-I-:I-)--~ ~OH
pH 7
100% Conversion
Selectivity 99%
~o
Ru/tpps (1/10)
~o
H2 (20 bar), 80°C
tolueneffi 20 (I: I)
90% Conversion
Selectivity 95%
Scheme 97
H2 CH3(CH2h....... ==e:«CHzhCOz H
CH3(CH2hCEC(CH2hC02H -L-in-d-la-r~ca-ta-ly--is~~ w C H
(Z) alkene
Scheme 98
Phl(m-C6H4-S03Na), 1.2 eq.

I HP, RT5 min
~
Ph-C=C-COMe
IPhzP(nrC614-S03Na), 0.9 eq.

Hp,RT3 min
.. Ph H
H'>==<COMe
Scheme 99
In the above procedure (Scheme 99), the water acts both as a

solvent as well as a reactant, and the amount of phosphine controls the
152 GREEN CHEMISTRY
cis/trans ratio of the formed alkenes since it catalyses the cis-trans olefin
isomerisation.
12.15.4 Reduction of Carbonyl Compounds

A variety of reagents are available for the reduction of carbonyl compounds.
Some of the common reagents are Na-C 2HpH, PtO/H2, LAH, NaBH4'
Na2BH3CN, HC0 2H1EtMgBr, (EtP)SiH.Me, B2H6.157
Some of the more common reductions using NaBH4 are gIven
(Scheme 100).
00 NaBJ4/MeOH ~ OOH
o-0tl-Q ~_
NaBJ4/MeOH
~
Q-L00H
°HC---Q>-CO2Et
N0 2
@-CHO NaBHJMeOH. @-CH,oH
Scheme 100
Using sodium borohydride in aqueous medium, 2-alkylresorcinols have

been prepared (Scheme 10 1).158
The entire process (Scheme 101) could be carried out as one pot reaction.
The reduction of carbonyl compounds in aqueous media has been carried
out by a number of reagents under mild conditions. The most frequently used
reagent is sodium borohydride, which can also be used using phase-transfer
catalysts l59 or inverse phase transfer catalyst 160 in a two phase medium in the
presence of surfactants.
The carbonyl compounds can be quantitatively reduced regio- and stereo-
selectively by NaBH4 at room temperature in aqueous solution containing
glycosidic amphiphiles like methyl-p-D-glactoside, dodecanoyl-p-D-maltoside,
sucrose etc. 161 By using this procedure, a,p-unsaturated ketones give
1,2-reduction product (corresponding allylic alcohols) and cyc1ohexanones

give the more stable alcohol.
H0yY0H
~C-R
II
R = Me, Ph °
54-80%
Scheme 101
Reduction of ketones with NaBH4 also proceeds in the solid state. 162 In
this method a mixture of powdered ketone and 1O-fold molar amount ofNaBH4
is kept in a dry box at room temperature with occasional mixing and grinding
using an agate mortar and pestle for 5 days to give the reduced product.
Following ketones were reduced by this procedure (Scheme 102).
Enantioselective hydrogenation of ~-ketoesters has been achieved by
using a ruthenium catalyst derived from (R,R)-1,2-bis(trans-2,5-
diisopropylphospholano )ethane [(R,R)-i-Pr-PPE-Ru] to give ~-hydroxy esters
with high conversion and high ee under mild conditions (Scheme 103).163
The reduction of aldehydes like benzaldehyde and p-tolualdehyde with
Raney Ni in 10% aqueous NaOH give the corresponding benzyl alcohols in
17-80% yields 164 along with the corresponding carboxylic acids as byproducts
obviously by cannizzaro reaction. It has been found that in aqueous NaHC0 3
under sonication conditions give the corresponding alcohols in good yields.
Another interesting reagent used for reduction of carbonyl compounds is
cadmium chloride-magnisum in Hp-THF system (Scheme 104).165
Certain other reagents like samarium iodide in aqueous THf1 66 , sodium
dithionite in aqueous DMf1 67 , sodium sulfide in presence of polyethylene glycoP68
and metallic zinc along with nickel chloride. 169 Using the latter reagent
(ZnJNiCI 2), a,~-unsaturated carbonyl compounds can be very readily reduced
under ultrasound conditions 170 (Scheme 105).
154 GREEN CHEMISTRY
NaBH 4
Ph2 CO ---....,~~ Ph2 CHOH
(100%)
NaBH4
trans PhCH=CHCOPh - - -.... trans PhCH=CH CHPh
I
+ OH
(I: I)
Yield 100%
~CH(OH)Me
VV (50%)
NaBH4
PhCHCOPh --~.~ PhCHCHPh
I I I
OH HO OH
meso (62%)
But - o 0 NaBH4 .. But -0 OH
(92%)
Scheme 102
o 9H
R
~ C02RJ---------=----=--··
(R,R)-i-Pr-PPE/RuBr2' H2
MeOH-Hp; 35 DC, 20hr
R A
"'-""
. . C02R 1
ee> 98%
R = RI = Me, Et, i-Pr, t-Bu
(R,R)-i-Pr-PPE
Qo~~
i-Pr i-Pr
Scheme 103
--=-----
CdClz-Mg
HzD-THF
OCOCHMe2 OCOCHMe2
RT, 15 min, 85% HO
o o
Scheme 104
o o
ZnlNiCI2
1M NHPH-NH 4CI
pH 8, 1.5 hr, 30°C, 95%
(C(e
Scheme lOS
Ketones can also be reduced in an aqueous medium by SmI2-HpJ71

(Scheme 106).
PhCH2> = O 1) SmI2-H 20 PhCH2...........

--~~----------~~ ~CHOH
PhCH 2 THF, room temperature, PhCH2~
10 min
2) Quenching in HCI 94%
Scheme 106
12.15.5 Reduction of Aromatic Ring

The hydrogenation ofbenzenoids to cyclohexane derivatives is very useful for
various methodologies. Aromatic hydrocarbons require drastic conditions for
reduction (for example PtO/H/CH3COOH; Raney NiIH/Pr/~, Rh-AIP/H2).
It is now possible to reduce aromatic ring in aqueous medium at 50 atm
of H2 and at room temperature with ruthenium trichloride stabilized by
trioctylamine (RuCI/TOA).172 One such example is given (Scheme 107).
In the given procedure (Scheme 107) the rate of the reaction is 10-12
times the rate in organic solvent and in the aqueous medium, in comparison to
cis, the trans isomer is the major product.
The heterocyciic compounds, viz. pyridine, 2-phenylpyridine and
3-methylpyridine can be reduced to the corresponding hexahydro product by
Sm-20% HCI in 90-95% yields. 173 However in the reduction of 4-aminopyridine
by the above method, the 4-amino group is eliminated giving piperidine as the
156 GREEN CHEMISTRY
major product (60%). The heterocyclic compounds can also be reduced in

70-94% yield by SmI2-Hp system at 0 DC for 2.5 hr.174 Using this method
2-amino-, 2-chloro-, and 2-cyano-pyridine on reduction give piperidine, the
substituent groups are eliminated.
MeOH-Hp, RT, 1.2-10 hr
80~90%
RI = OMe, COzMe cis-trans 6: 15
R2 = H, Me, NH z
Scheme 107
12.15.6 Miscellaneous Reductions -

(i) Reductive removal of halogen from a-halo carbonyl compounds in aqueous
medium can be effected by using sodium dithionite 175 , zinc 176 , chromous
sulfate 177 and sodium iodide. 178
(ii) 2,3-Epoxyallyl halides can be transformed readily into allylic alcohol
(Scheme 108) by zinc-copper couple in Hp under sonication.
Zn(Cu)
EtOH/HP
))))
89-94%
Scheme 108
(iiii) Reductive dehalogenation in aryl halides can be effected in aqueous

alkaline media in presence ofPdCl 2 with NaHl02 as a hydrogen source
(Scheme 109).179
C1-r6 50-70 cC, 6-8 hr
15-94%
Scheme 109
The above method (Scheme 109) does not work in case of nitrogen
containing heterocyclic compounds and the yield in case of m-substituted
aryl halides is low.
However, m-bromobenzoic acid can be converted into benzoic acid in

90% yield by using water soluble tris[3-(2-methoxyethoxy)propyl]
stannane in presence of 4,4'-azobis (4-cyanovaleric acid) (ACVA) or
sunlamp as initiator in aqueous NaHCO r 180 Above debromination can
also be effected by using [bis(potassium propanoate)n (hydroxystannate),
which in presence ofN aBH4 and ACVA affords reductions and free radical
cyclisation of aryl and alkenyl bromides (Scheme 110).
©t CO'H
Br
(OH)nSn(CH,CH,CO,Klz.
NaBH., ACY A, KOH, 90°C

©COOH
90%
EtO
(OH)nSn(ClhCH2C02Kh. /\
NaBH., ACY A, KOH, 90 °C ~OR
Scheme 110 62%
The hydrogenolysis ofhalopyridines can be convenient when carried out

with 15% aqueous TiCl 4 in presence of acetic acid. 181 Aqueous titanium
trichloride quantitatively removes cyano group from cyanopyridines.
Reductive dehalogenation is also catalysed by SmI 2.
(iv) Groups like azide, sulfoxide, disulphide, activated C=C bond and nitroxide
can be effectively reduced by using sodium hydrogen telluride (NaTeH)
(prepared in situ by the reaction of tellurium powder with aqueous
ethanolic solution ofNaBHJ 182
(v) Groups like aldehydes, ketones, olefins, nitroxides and azides can be
reduced by sodium hypophosphite buffer solution. 183
(vi) Vinyl sulphones can be stereospecifically reduced to the corresponding
olefins with sodium dithionite in aqueous medium (Scheme 111).184
RS02~
R'/-"""'R" R'~R"
52-88%
R'
~R"
Scheme 111
158 GREEN CHEMISTRY
(vi) Diaryl and dialkyl sulphides can be reduced by triphenylphosphine in

aqueous solvents (Scheme 112)}85
~R
f+ Ph.3P:
\
Scheme 112
12.16 Polymerisation Reactions
12.16.1 Polymers
It is well known that most ofthe polymers are not biodegradable. This problem
can be approached in two ways. One way is to recycle the polymer and the
other way is to convert it again into the monomers and recycle them again.
However, the best way is to make polymers which are biodegradable.
12.16.1.1 Recycling of Polymers

Let us now consider recycling, taking the example of the polyester,
polyethyleneterephthalate (PET). It is known that PET is obtained by the
polymerisation of dimethylterephthalate and ethylene glycol and is used in
different products like beverage and food containers, nonfood containers,
trays, luggage, boat parts, tapes etc. Fibres of PET are also used in clothing,
carpets, blanckets, cord, rope etc. The recycled PET cannot be reused for
food containers, as the impurities present are not sanitized at the temperature
used in the melt process. Some of the products made of PET are mixtures
with other polymers and contain dyes and other materials. These have to be
disposed off by only incineration or land-filled. Also, during incineration the
products obtained cause atmospheric pollution.
12.16.1.2 Conversion of PET Materials into Monomers

The process for the conversion of scrap PET into monomers is known as the
P~trette process. 186 The flow sheet of the Petrette process for the recovery of
monomers from PET scrap is given (Scheme 113).
The monomers (DMT and ethylene glycol) are purified and again
polymerised to give PET.
I) Dissolution in DMT > 220°C

2) CHpH (260-300 0c)
340-65° KPa
O~O ~OH
n~n + HO
H3C-O O-CH3 Ethylene glycol
(DMT)
Scheme 113
12.16.1.3 To Make Polymers which are Biodegradable

One of the commonly used biodegradable polymer Thermal Polyaspartate
polymer (TPA). Prior to the synthesis of TPA, polyacrylate polymer (PAC)
was used as scale inhibitor in water handling processes. If not inhibited, the
scale formation lead to loss of energy, non-functioning of pumps, boilers and
condensers.
CH:2-CH
I
c=o
6-
PAC
n
Though PAC is relatively non-toxic and environmentally benign, it is not

biodegradable. This causes a disposal problem in waste water treatment facilities,
where the PAC must be removed and land filled. The problem for it's disposal
has been solved by Donlar Corporation, which has developed a method for the
production ofTPA(thermalpolyaspartate),abiodegerable alternative toPAC.187
The Donlar's synthesis 188 consists of heating the aspartic acid followed by
hydrolysing the formed succinimide polymer with aqueous base (Scheme 114).
The above synthesis is 'green' because it uses no organic solvent, produces
little or no waste and the yield is better than 97%.
12.16.1.4 Manufacture of Polycarbonates

Polycarbonates were earlier prepared by the polymerisation of phenols (e.g.,
bisphenol-A) using phosgene and methylene chloride. A new process has been
developed by Asahi Chemical Industries using solid state polymerisation 189 for
producing polycarbonate without phosgene and methylene chloride. 190
160 GREEN CHEMISTRY
In this process bisphenol-A and diphenyl carbonate directly give low molecular
weight prepolymers, which are converted into high molecular weight polymers
by crystallisation followed by further polymerisation (Scheme 115).
H
I ~O
H.........
N-C-C
H/ I 'OH
~ tHCt~'Nt
H-C-H
~C,
o
I
OH
Ll HC_{ 2
2H 0 + 2
Aspartic acid o
Succinimide polymer
n m
(TPA)
Scheme 114
HO -Q-fO-
f' f' _
CH3
_
OH + Ph,
0
0
)l..... 0 ..... Ph - - + [Prepolymer] - - +
1 r <}-oJ,~
CH3
--+ --+ 0 -{ ) 1
CH3
Polycarbonate
Scheme 115
12.16.1.5 Emulsion Polymerisation

Earlier attempts at emulsion polymerization of norbomenes in aqueous solution
using iridium complexes as catalysts gave poor yields (10%).190 However, it
was subsequently found that 7 -oxaborane derivatives could be rapidly
polymerised in aqueous solution in presence of air using some group VIII
coordination complexes as catalysts giving a quantitative yield of a ring-opening
metathesis polymerisation product (Scheme 116).191
n ~R Ru(HP)6(tOS)2
H 2O
30-35 min
~
R= H, Me
Scheme 116
Using the above methodology norbomene could also be polymerised. 192,193

The ruthenium catalyst required for the above polymerisation were obtained
by the procedure of Berhard-Ludi. 194 The aqueous catalyst solution could be
reused; it was found to be more active. Another Ru(IV) catalyst 19S could also
be used for emulsion ring-opening polymerisation of norbomene. The polymers
obtained by the later catalysts had very high molecular wieght and had high
cis-selectivity. Using this method, neogylcopolymers were synthesised
(Scheme 117).
o~o}o 55°C,72%
o
HO~O OO~OH HO~O
OH
OH OH
HO 0 HO 0
o OH
HO
Scheme 117
A non-metallic conducting polymer was synthesised (Scheme 118).196

A helical polymer was prepared by using palladium-catalysed coupling
between aryl halides with acetylene gas (Scheme 119).197
Solid state polymerisation of a-amino acids has been achieved giving rise
to high molecular weight polypeptides.
162 GREEN CHEMISTRY
COOH
Br
HOOC
COOH
Scheme 118
=
OMe
cat. Pd(OAc)/PPhJ
+ H H •
MeCN/Hp EtJN
OMe
n
Scheme 119
12.17 Photochemical Reactions

The importance of photochemical reactions can hardly be overemphasized.
The earliest known photochemical reaction is the photosynthesis of sugars by
plants using sunlight, CO 2 and Hp in presence of chlorophyll. Some of the
common examples of routine photochemical reactions are:
(i) Photochemical cyc1oaddition of carbonyl compounds and olefins (Patemo-
Buchi reaction) to give four membered ether rings (Scheme 120).198
H CH 3
I I
o H 3C........ .,/H O-C-CH3 O-C-CH 3
II C hv I I I I
R-C-R' + \I • R-C-C-CH3 + R-C-C-H
C I I I I
H 3C""""" ........CH 3 R' CH 3 R' CH 3
Scheme 120
(ii) Photo fries rearrangements. The phenolic esters in solution on photolysis

give a mixture of 0- and p-acylphenols. 199
There are numerous other examples. Most of the photochemical reaction
are carried out in solvents like benzene.
In view of the scare ofthe medium dependence of photochemical reactions,
attempts were made for carrying out the reactions in water as a solvent. 20o
It has been reported in 1980's that the photochemical reactions can be
conveniently carried out in aqueous phase. Thus, the photodimerisation of
thymine, uracil and their derivatives could be carried out in water giving
considerably better yields than in other organic solvents (Scheme 121).201
Water 27.8% 63.1% 9.1% 0=0.015

Acetonitrile 24.9% 68.2% 6.7% 0 = 0.0047
Methanol 31.4% 68.6% 0=0.004
Scheme 121. Data taken from reference 201
Organic substrates having poor solubility in water (e.g., stilbenes and

alkyl cinnamates) also photodimerize efficiently in water (Scheme 122). The
same reaction in organic solvents such as benzene gives mainly cis-trans
isome".'"' hv .. ~~ + l~h
24h ~Ph ~
Ph Ph
Benzene 0% 0%
Water 12% 10%
Water + Liel 25% 17%
Water + guanidinium chloride 8% 6%
164 GREEN CHEMISTRY
The addition of LiCI (decreasing the hydrophobic effect) increases the

yield of dimerisation (Scheme 122), whereas the addition of guanidinum chloride
(decreasing the hydrophobic effect) lowers the yield of the product.
Similar results were obtained with alkyl cinnamates. 203
An interesting example is the photodimerisation of coumarin in water
(Scheme 123).
( I ~
( hv~
) 24h +
~
o 0
o
Solvent Quantum Yield

Benzene < 10-5
Methanol < 10-5
Water 2 X 10-3
Scheme 123
The yield of the dimerisation of coumarin in water (Scheme 123) is toO

times more than that in benzene or methanol.
It has been found that the micelles (formed by carrying out the reaction in
presence of a surfactant/water) have a pronounced effect on regio- and stereo-
selectivity of photochemical reactions.
The photodimerisation of anthracene-2-sulphonate in water gives four
products A, B, C, D (Scheme 124). However, if the reaction is carried out in
presence of p-cyc1odextrin, only the isomer A is obtained. 204 Some other
examples of photochemical reactions are:
(i) Photoirradiation of dibenzoyldiazomethane in CH3CN-HP in presence
of an amino acid derivative gave the addition product (Scheme 125) via
theformation of a carbene. 205
(ii) The photoirridation of o-fluoroanisole in KCN-Hp gave o-substitution
product (catechol monomethyl ether) as the major product along with
o-cyanoanisole as the minor product. Similar reaction with p- fluoroanisole
gave p-cyanoanisole as the major product along with amount minor of
hydroquinol monomethyl ether (Scheme 126).206
SO~
hv
A SO~ SO~
B
SO~
SO~
c D SO~
Medium Product (A: B : C : D)

Water 1 : 0.8 : 0.4 : 0.05
Water + ~-CD A only
o 0 hv
•
Ph~Ph
N2
Dibenzoyldiazo
Carbene
methane
o
~h·~O NU-BOC-L-Lys-OMe.. 0 0 ~HBoC
Ph' T 85% PhVN~C02Me
Ph
Ph H
Scheme 125
166 GREEN CHEMISTRY
0>
I~
o-Fluoro
hv, KCN
H 2O
~
&CN &OH
I
~
o-Cyano
anisole
+ I~
Catechol
monomethyl ether
anisole
(major)
0' F
P-Fluoro
hv, KCN
H 2O
~
0' 0'eN
p-Cyano anisole
+
OR
Hydroquinol
anisole (major) monomethyl ether
Scheme 126
In the above reaction (Scheme 126), the use of water influences the
chemoselectivity in photochemical substitution reactions.
(iii) Photochemical oxidative dimerisation of capsacin in aqueous ethanol
gave dimer in 60% yield within 20 min of irradiation (Scheme 127).207
o
CH30)y' ~ hv, air
I ~ EtOH-Hp (9:1)
H0 ~ Capsacin 20 min, 60%
0
CH30
.. HO
HO
CH30
0
dimer(60%)
Scheme 127
(iv) Photooxidation of phenol is of interest in environmental chemistry.20s

Photochemical reactions have also been studied in solid state. Thus the
photodimerisation of cinnamic acid to truxillic acid has been achieved in the
solid state (Scheme 128).209
Hooe hv
solid
eOOH
Truxillic acid
Cinnamic acid (single cyrstal)
(single cyrstal)
Scheme 128
The photodimerisation of cinnamic acid can be controlled by irradiation

of its double salts with certain diamines in the solid state. Thus, the double salt
crystal of cinnamic acid and o-diaminocyc1ohexane gave upon irradiation in
the solid state, 13-truxinic acid as the major product (Scheme 129).210
CX NH3 +
NH 3 +
-ooe~Ph
-ooe~Ph
hv
----~~~
solid HOOe
Ph
Hooe:tr:Ph
/3-Truxinic acid
Double salt of cinnamic acid
with o-diamino cyclohexane
Scheme 129
Similar irradiation of naphthoic acid-derived cinnamic acid (A) in solid

state on irradiation for 20-50 hr afforded a single cyclobutane product in
100% yield (Scheme 130).211
The photocyc1isation of coumarin and its derivatives has been extensively
studied. 212 Thus, irradiation of coumarin for 48 hr in the solid state gives a
mixture of A, B and C in 20% yields. However, irradiation of an aqueous
168 GREEN CHEMISTRY
solution of coumarin for 22 hr affords only the syn-head to head dimer (D) in
20% yield (Scheme 131).
hv
Solid
20-50 hr
Cyc10butane product
(A) (100%)
Scheme 130
(Xl bOO
hv
H20, 22 hr
20%
~
t
Coumarin
solid, 48 hr
hv 20%
+ SO-Ao 0
I: "0 I
0
+ 0
Syn-HH anti-HH Syn-HT

(A) (B) (C)
Scheme 131
It is well recorded that benzopinacol can be obtained quantitatively on

photoirradiation of 4,4'-dimethyl benzophenone in isopropylalcohol. However,
in the solid state photoirradiation gives the dimeric compound (Scheme 132).2J3
Besides the representative example of photochemical reactions in solid phase a
large number of illustrations are available. 214
o
hv
aq. solution
~
iso PrOH
Me Me
4, 4 '-Dimethyl
benzophenone Me
1
Benzopinacol derivative
hy So!;d ,"'"
Me Me
Dimeric
product
Me
Scheme 132
12.18 Electrochemical Synthesis
12.18.1 Introduction
The earliest electrochemical synthesis is the so-called Kolbe reaction involving
the oxidation of carboxylic acids in forming decarboxylated coupling products
(alkanes). At present, the electrochemical synthesis has become an independent
discipline. A large number of organic reactions (synthesis) have been achieved
by this technique. The essential requirement for conducting an electrochemical
reaction is the conductivity of the reaction medium. The most commonly
170 GREEN CHEMISTRY
used solvent is water, though organic solvents have also been used. However,
there is a distinct advantage in using aqueous solutions over organic solvents.215
In case of organic solvents, during electrolysis, a complex mixture of products
get accumulated in the electrolyte, which leads to loss of expensive solvent.
On the other hand, electrolysis of water yield O/H+ and H/OH-. In view of
this, the electrolysis of water can be performed at a maintained level of pH
without contaminating the electrolytic system.
The electrochemical synthesis are oftwo types: anodic oxidative processes
and cathodic reductive processes. During anodic oxidative processes, the
organic compounds are oxidised. The nature of the product of anodic oxidation
depends on the solvent used, pH of the medium and oxidation potential.
In cathodic reductive processes, the cathode of electrolysis provide an
electron source for the reduction of organic compounds. Generally the rate of
reduction increases with the acidity of the medium. Electroreduction of
unsaturated compounds in water or aqueous-organic mixtures give reduced
products - this process is equivale'nt to catalytic hydrogenation.
An electrochemical process uses a anode made of metal that resists
oxidation, such as lead, nickel or most frequently platinum. The anode is
usually in the shape of a cylinder made of wire guage. The usual electrolytes
are dilute sulphuric acid or sodium methoxide prepared in situ from methanol
and sodium. The direct current voltage is 3-100 V, the current density is
10-20 Aldm3, and the temperature of the medium is 20-80 °e.
Electrochemical reactions are practically as diverse as non-electrochemical
reactions. Thus, the combination of electrochemical reactions with catalysts
(electrochemical catalytic process), enzymatic chemistry (electroenzymatic
reactions) are quite common. The readers may refer to the following references:
• A.N. Frumkin, in Advances in Electrochemistry and Electrochemical Engineering,
P. Delahay and c.w. Tobias, eds., Interscience, New York, Vol. 3.
• Topics in Current Chemistry, E. Steckhan, ed., Springer-Verlag, Berlin, 1987, Vol. 142.
• E. Steckhan, in Topics in Current Chemistry, E. Steckhan, ed., Springer-Verlag, Berlin,
Vol. 170.
• O.K. Kyriacou, Basics of Electroorganic Synthesis, Wiley, New York, 1981.
• H. Lund and M.M. Baizer, eds., Organic electrochemistry, Marcel Dekker, New York,
1991.
Following are given some representative examples of electrochemical synthesis.
12.18.2 Synthesis of Adiponitrile

Adiponitrile is used as an important synthon for hexamethylene diamine and
adipic acid, which are used for the manufacture of Nylon-66.
It is obtained commercially by the electroreductive coupling of acrylonitrile.
By this process about 90% of adiponitrile is obtained.216 In this process a
concentrated solution of certain quaternary ammonium salts (QASs), such as
tetraethylammonium-p-toluene sulfonate is used together with lead or mercury

cathode (Scheme 133).
2e-
~CN + 2H 20 --..-.,.~
QASs
NC~ ./"-..../"-...
..........."..........." ...... CN
+ 20H
Acrylonitrile
Scheme 133
It will be appropriate to mention here that selective hydrocyanation of
butadiene catalysed by Ni(O)/triarylphosphite complexes give adiponitrile
(Scheme 134).217
HCN ~ HCN
-----~. ~== CN
Ni(O)
~
N~CN
Butadiene
Adiponitrile
Scheme 134
12.18.3 Synthesis ofSebacic Acid

Sebacic acid is an important intermediate in the manufacture of polyamide
resins. It is obtained on a large scale by saponification of castor oil. 218 It is
now obtained by electrochemical process involving the following three steps
(Scheme 135).
CH 3 0H
H02C-(CH2)4C02H ---"----1~. CH302C(CH2)4C02H -------c~~
esterification
Adipic acid Monomethyl ester of
adipic acid
Hydrolysis
--------.~ H02C(CH2)SC02H
Dimethyl ester of Sebacic acid
sebacic acid
Scheme 135
In the above process, anodic coupling of the monomethyl ester of adipic

acid takes place. The electrolyte is a 20% aqueous solution of monomethyl
adipate, neutralised with sodium hydroxide. The anode is platinum-plated with
titanium and the cathode is of steel.
12.18.4 Miscellaneous Electrochemical Reactions

(i) Electrochemical reduction of glucose for the manufacture of sorbitol and
mannitol. 220
172 GREEN CHEMISTRY
(ii) Electrochemical reduction of phthalic acid to the corresponding

dihydrophthalic acids. 22I
(iii) Electrochemical coupling of acetone to yield pinacol. 222
(iv) Electrochemical oxidation of l,4-butynediol to acetylene dicarboxylic
acid. 223
(v) Electrochemical oxidation of furfural to maltol,224
(vi) Electrochemical epoxidation ofalkenes.225
(vii) Electrochemical conversion of alkenes into ketones. 226
(viii) Electrochemical oxidation of aromatic rings and side chains to carboxylic
acids.227
(ix) Electrochemical oxidation of primary alcohols to carboxylic acids.228
(x) Electrochemical oxidation of secondary alcohols to ketones.229
(xi) Electrochemical oxidation of vicinal diols to carboxylic acids. 230
(xii) Electrochemical hydroxylation or dehydrogenative coupling of phenols. 231
(xiii) Electrochemical Kolbe synthesis ofhydrocarbons. 232
12.19 Miscellaneous Reactions in Aqueous Phase
12.19.1 Isomerisation of Alkenes

Alkenes are known to isomerise in presence of transition metal complexes. It
has been found that isomerisation of allylic alcohols (or ethers) can be performed
in aqueous media in presence of Ru(II)(HP)6(tos)2 (tos = p-toluene sulfonate)
(Scheme 136).233
Ru(II)(H 2O)6(toS)2
(lOmol %)
~OH
HP, RT>90% ~O
H
Scheme 136
In the above reaction the initially formed enols and enolethers are unstable
and are instantaneously hydrolysed to give the corresponding carbonyl
compounds.
Some other examples are given as follows (Scheme 137).234
OH RuCI2(PPh3)3 (2-4 mole %) OH

XPh~ HP, air atmosphere 49-75% • XPh ~
OH
OH RuCI 2(PPh 3)3 (cat. amount)
• Ph~
Ph~ HP, air atmosphere 61%
Scheme 137
In both the given examples (Scheme 137) the substrates undergo structural
reorganisation involving reshuffling of both the hydroxyl group and the olefin
in water. These reactions can be considered as olefin migration followed by an
allylic rearrangement.
12.19.2 Carbonylation
Carbonylation is a very important process for the preparation of carboxylic
acids (and their derivatives), aldehydes and ketones. It was earlier carried out
in presence of transition metal catalysts. 235
The aryl halides can be converted into the corresponding carboxylic acid
by carbonylation in presence of water. The use of PTC is a well established
technique for carbonylation of organic halides. 236 Carbonylation of organic
halides using various types of phase transfer techniques has been extensively
reviewed. 237
Aryl halides can be carbonylated to give the corresponding carboxylic
acids (Scheme 138) under very mild conditions in presence of inorganic bases
(like alkaline metal hydroxides, carbonates, acetates etc.) and certain palladium
catalysts (like Pd(OAc)2' KldCI, Pd(NH)4CI, PdCI 2(PPh3)2 etc.). Best results
are obtained with simple palladium salt using ~C03 as base (Scheme 138).
Pd(OAc)2 (I mole %), CO, K2CO)

ArX ----=-------='---'~
DMF-Hp (2:1) 25-50 °c
... ArCOOH
Ar = p-ZC6 H4 (Z = N02, Cl, CN, Me, NH2 etc.)
Scheme 138
Water soluble aryl iodides can be carbonylated in Hp in presence of

soluble palladium salt or complexes and K 2 C0 3 as base at 25-50 °C
(Scheme 139).
R-©-I Hp, 25-50 °c

----;.~ ~COOH
__P_d_(II_),_C_O_,_bas_e
R
~
R = m-, p--COOH
0-, m-, p--OH
Scheme 139
Ortho-iodobenzoic acid cannot be carbonylated under the above conditions

(Scheme 139). It, can, however be carbonylated in presence of excess iodide
ion to give-phthalic acid (Scheme 140).
174 GREEN CHEMISTRY
Scheme 140
In case of water insoluble aryl iodides, the iodine atom is first oxidized to
the iodyl group by NaCI0 3, the fonned iodyl derivative (having slightly enhanced
solubility in water) are readily carbonylated under mild conditions to give
carboxylic acids (Scheme 141).238
NaldCl4, NaOH
ArI ------~~------~~~ ArCOOH
co (l atm), H 0, 40-50 °C
2
Scheme 141
Carbonylation of allylic and benzylic chlorides was carried out by transition-

metals (as catalysis) to give p,y-unsaturated acids.239 However, the above
method gave low yields. It is found that carbonylation of benzyl bromide and
chloride could be carried out by stirring with an aqueous sodium hydroxide
and an organic solvent using a PTC and a cobalt catalyst. Even benzylic
mercaptan could be carbonylated to give esters under high pressure and
temperature (Scheme 142).240
X=ClorBr
ArCH 2SH + CO + R'O H Co 2(CO)g, Hp

----~--~~--~~~
A r CH 2COOR'
850-900 psi (Ib/in 2)
190°C, 24 hr, 25-83%
Scheme 142
Carbonylation of allyl bromides and chlorides has been achieved in presence

of a nickel catalyst in aqueous NaOH at atmospheric pressure. 241 Subsequently
it is found that Palladium-catalysed carbonylation of allyl chloride proceeded
smoothly in two-phase aqueous NaOHlbenzene under atmospheric pressure
at room temperature (Scheme 143).242
Pd
19-98% ~ CH2=CHCH2COOR
Scheme 143
In the above method shown in Scheme 143, addition of surfactants (e.g.,

n-C 7H 1S S03Na or n-C 7H 1S C02Na) accelerate the carbonylation. 243
Some other carbonylation reactions are:
(i) Carbonylation of I-perfluoroalkyl-substituted 2-iodoalkanes in presence
of transition metal catalysts in aqueous media give p-perfluoroalkyl
carboxylic acid (Scheme 144).244
Pd, Co, or Rh cat.
-------~~ R r-CH2CHR'C0 2H
base 42-89%
Rf = perfluoroalkyl group
Scheme 144
(ii) y-Lactones have been obtained by the carbonylation of terminal alkynes

in water in presence of rhodium carbonyl (Scheme 145).245
HP,CO
Rh 6 (CO)16' Et3N
60-99%
Scheme 145
(iii) The reaction of styrene oxide with carbon monoxide is catalysed

by a cobalt complex in presence of methyl iodide to give enol
(Scheme 146).246
+ 2CO
PTClNaOH, R.T., 1 atm, 65%
Ph)Q
I °
HO
Scheme 146
o
-(iv) Carbonylation of methane under acidic conditions by oxygen and CO in
water, catalysed by palladium, platinum or rhodium catalysts gives acetic
acid. 247
(v) 5-Hydroxymethyl furfural can be selectively carbonylated to the corres-
ponding acid by using a water soluble palladium catalyst (Scheme 147).248
176 GREEN CHEMISTRY
Scheme 147
(vi) Carbonylation of 1-(4~isobutylphenyl)ethanol gives ibuprofen

(Scheme 148).249
OH Pd/cppts C~H
+co •
Ibuprofen
Scheme 148
12.19.3 Hydroformylation of Olefins

Hydroformylation of olefins is a chief industrial process for the manufacture
of aldehydes and alcohols by reaction with CO and H2 in presence of a
catalyst. 250
Carbon monoxide and hydrogen have been known to be used for the
manufacture of methyl alcohol. Also, the first product to be manufactured by
the hydroformylation of propene is butyraldehyde (Scheme 149).25J
ZnO, cr03
CH 30H
300°C
Methyl alcohol
CH 3CH=CH 2 + CO + H2
Propene
Scheme 149
A number of catalysts were tried for the hydroformylation of olefins. Main

among these are:
(i) Rhodium combined with phosphorus ligand
(ii) Attachment of a normally soluble catalyst to an insoluble polymer support.
(iii) Transition-metal complexes with water soluble phosphine ligands and
water as immiscible solvent for the hydroformylation. Most of the
catalysts had a problem arising out of leaching of the catalyst into the
organic phase.
Finally a variety of l-alkenes were hydrofonnylated with a highly water-

soluble tris-sulphonated ligand, P(m-PhS0 3 Na).252 Some more effective
catalysts involving the use of other sulphonated phosphine ligands have also
been developed.253
Another unique approach is the concept of support aqueous phase (SAP)
catalysisY4 In this approach, a thin, aqueous film containing a water soluble
catalyst adheres to silica gel with a high surface area. The reaction occurs at
the liquid-liquid interface. Using this technique, hydrofonnylation of alkenes
like octene, dicyclopentadiene is possible. Through SAP approach,
hydroformylation of acrylic acid derivatives is of considerable industrial
applications (Scheme 150).255
/
COOR H2, CO, [HRh(CO)~] ~-<.
COOR
+
CHO OHC
r CO OR
Scheme 150
The major product obtained (Scheme 150) is fonnylpropionic acids, which

are precursors of methacrylate monomers and can be used for a number of
important pharmaceuticals. A number of other applications ofhydrofonnylation
have been reviewed. 256
12.19.4 Homologation ofl,3-dihydroxyacetone

In aqueous medium, it is not necessary to protect functional groups. Thus
homologation of 1,3-dihydroxyacetone with fonnaldehyde in presence of base
gives the homologated derivatives A and B (Scheme 151).257
A
OR OR
1,3-dihydroxy
HCHO
NaOH, RT, 105 min
acetone (A) (75%) (B) (17%)
HCHO
J
Ca(OH)2' RT, 30 min
46%
Scheme 151
The above reaction is known as Tollens reaction.

178 GREEN CHEMISTRY
12.19.5 Weiss-Cook Reaction

The reaction of dimethyl3-oxoglutarate with glyoxal in aqueous acidic solution
gives [3.3.0] octane, 3,7-dione-2,4,6,8-tetracarboxylate; and on acid catalysed
hydrolysis followed by decarboxylation it gives cis-bicyclo[3.3.0] octane-3,7-
dione (Scheme 152).258 The reaction is believed to involve a double Knoevenagal
reaction that gives an a,j3-unsaturated y-hydroxycyclopentenone, which reacts
with another molecule of dimethyl 3-oxoglutarate by Michael addition.
12.19.6 Mannich Type Reactions

The original Mannich reaction consisted in the reaction of a compound
containing at least one active hydrogen atom (ketones, nitroalkanes, j3-ketoesters,
j3-cyano acids etc.) with formaldehyde and primary or secondary amine or
ammonia (in the form of its hydrochloride) to give products, p-aminoketone
derivatives, known as mannich base (Scheme 153).259
A new approach (or modification) using preformed iminium salts and
imines has been developed. The imines react with enolate (especially
trimethylsilyl ethers) to give p-amino ketones. In this reaction TiCl4 was used
as a promoter. 260 The general scheme for the synthesis of p-aminoketones is
given in Scheme 154.
M~~~
Me02C
Dimethyl 3-
+
( ° H2O,H+
0
Glyoxal
~
:W:
Me02C C02Me
I) hydrolysis
2)-CO,
~
oWo
H
H
cis-bicyc1o [3.3.0]
oxoglutarate octane-3,7-dione
OO'T$~M'
CO 2 Me
a,~-unsaturated
y-hydroxycyclopentenone
Scheme 152
0
II II
0 + 0_ II +
CJf,c-CH3 + H-C-H + (CH3)2NH2CI _ CJf,c-CH2CH2NH(CH3hCI- + H2 0
Acetophenone Formaldehyde Dimethylamine ~-N,N-Dimethylamino ketone
hydrochloride (HCI salt)
Scheme 153
Yb(OTt))
(5 mole%)
Imines Silyenolate
p-amino ketone
(60-97%)
Scheme 154
Vinyl ethers also reacted with imines and amines in presence of catalytic
amount of Yb(OTf)3 to give corresponding p-amino ketones (Scheme 155).261
R2
Yb(OTt)) (10 mole %) 'NH 0
~ I II
RI~R3
60-95%
p-amino ketones
Scheme 155
The Mannich type reaction was also used for the synthesis of p-amino
esters from aldehydes using Yb(OTf)3 as catalyst (Scheme 156).262
2
4
3
R1CHO +R2NH2+ R>=<.oSiMe
5)
Yb(OTt)) (5-10 mole %)
~
vXNH
R,
°
R R CH 2CI 2, RT in presence of R R5
MgS04 R3 R4
p-amino esters
(75-90%)
Scheme 156
12.19.7 Conversion of o-nitrochalcones into Quinolines and Indoles

Reduction of o-nitrocha1cone under WGSR conditions 263 followed by the
cyclisations give rise to the formation of quinolines and indoles (Scheme 157).264
12.19.8 Synthesis ofOctadienols

The aqueous isomerization of butadiene gives octadienols (Scheme 158).265
180 GREEN CHEMISTRY
Ar CO (30 bar), RU2 (CO)l2

EtOH-HP, 170 °C
o-Nitrochalcones
r()r6I
~AAr
+ ~Ar
~rf~O
H
Quinolines Indoles
Scheme 157
~ + ~+H20
surfactants
OH + Isomers
Scheme 158
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P. Bourdauducq, J.L. Couturier, J. Kervennel and A. Mortreux, Appl. Catal. A-Gen.,
1995,131,167.
13. Organic Synthesis in Solid State
13.1 Introduction
The earlier belief that no reaction is possible without the use of a solvent is no
more valid. It has been found that a large number of reactions occur in solid
state without the solvent. In fact in a number of cases, such reactions occur
more efficiently and with more selectivity compared to reactions carried out
in solvents. Such reactions are simple to handle, reduce pollution, comparatively
cheaper to operate and are especially important in industry. There is some
literature available on different aspects of organic synthesis in solid state. 1-9 It
is believed that solvent-free organic synthesis and transformations are
industrially useful and largely green.
In the present discussion, the organic synthesis will be presented in two
parts:
1. Solid phase organic synthesis without using any solvent.
2. Solid supported organic synthesis.
13.2 Solid Phase Organic Synthesis Without Using Any Solvent

The earliest record of an organic reaction in dry state is the Claisen
rearrangement lO of allyl phenylether to o-allylphenol (Scheme 1).
o~
6
Allyl phenyl ether o-Allylphenol
Scheme 1
The following gives a brief account of solid phase organic synthesis without
the use of any solvent.
13.2.1 Halogenation
Solid phase bromination is known II since 1963 but systematic work was done
in 1987. It was found 12 that crystalline cinnamic acid on bromination (gas-
190 GREEN CHEMISTRY
solid phase) gives exclusively the erythro isomer, but its chlorination gives the
threo and erythro isomers in 88 and 12% yields, respectively (Scheme 2).
( }-CH=CH-COOH
gas-solid
Cinnamic acid
x = Br erythro isomer
X = CI threo and erythro isomer
(88 and 12%)
Scheme 2
In a similar way bromination of powdered (E)-o-stilbene carboxylic acid

with bromine vapour or with powdered pyridine. HBr.Br2 complex in solid
state at room temperature gave 12 selectively erythro-l ,2-dibromo-l ,2-dihydro-
o-stilbene carboxylic acid. However, bromination with bromine in solution
gives 12 4-bromo-3-phenyl-3,4-dihydroisocoumarin as the major product
(Scheme 3).
Br I ~
(Yy~ Br, I~ ~ # __B.....
r, _ _.. I
~d '--I ~ # H or C,H,N.HBr.Br,
o (E)-o-stibene carboxylic acid Erythro-I,2-dibromo-
1,2-dihydro-o-stibene
trans-4-bromo-3-phenyl carboxylic acid
3,4-dihydroisocoumarin
Scheme 3
Bromination of 4,4'-dimethylchalcone with bromine (gas-solid reaction)
gave 13 optically active erythro-dibromide (6% ee) along with minor amount of
a product (Scheme 4).
4,4'-Dimethylchalcone
Br,
gas-solid
.Me~Br
V
Br
)-eo-o-' -
Me
erythro-dibromide (major) (6% ee)
Br +
~co-O->& minor
Scheme 4
Organic Synthesis in Solid State 191
13.2.2 Hydrohalogenation (addition ofHBr)

The only example recorded is the gas-solid phase reaction of hydrogen bromide
with u- and /3-cyc1odextrin complexes of ethyl trans-cinnamate to give l4 (R)-
(+)-3-bromo-3-phenyl propanoate (46% ee) and (S)-(-)-3-bromo-3-phenyl
propanoate (31 % ee) (Scheme 5).
HBr
gas-solid
EtO
u- and l3-cyc1odextrin Mixture of(R)-(+) and S-H-

complexes of ethyl 3-bromo-3-phenylpropanoate
trans-cinnamate (ee 46% and 31 % respectively)
Scheme 5
13.2.3 Michael Addition

A number of 2'-hydroxy-4',6'-dimethylcha1cones undergo a solid state
intramolecular Michael type addition to yield l5 the corresponding flavonones
(Scheme 6).
Me Me R
R 50-600C
Solid
Me Me
2'-hydroxy-4',6'-dimethylchalcones 5,7-Dimethyl flavones
R=H, CI or Br
Scheme 6
The Michael addition of chalcone to 2-pheny1cyc1ohexanone under PTe

conditions give l6 2,6-disubstituted cyclohexanone derivative in high
distereoselectivity (99% ee) (Scheme 7).
192 GREEN CHEMISTRY
Ph
COPh KO Bu' Ph
+ Ph~ --------.~
n-Bu 4NBr
2-Phenyl Chalcone
cyclohexanone
Scheme 7
The enantioselective Michael addition of mercapto compounds with an

optically active host compound derived from 1: 1 inclusion complex of 2-
cyclohexenone with (-)-A derived from tartaric acid l7 and a catalytic amount
of benzyltrimethyl ammonium hydroxide on irradiation with ultrasound for
1 hr. at room temperature gave the adduct in 50-78% yield with ee 75-80%
(Scheme 8).
(R,R)-(-)-
O=rr: 6 Ph2COH
(R,R)-(-)A
Cyclohexenone
ArSH
Solid
»» (+)-adduct
Scheme 8
Using the above procedure (Scheme 8) following adducts were obtained:
Ar Reaction time Adduct

(hr) Yield %ee
0- 24 51 80
()- 36 58 78
Mt
Me
~-:)--- 36 77 74
The Michael addition ofthiols to 3-methyl-3-buten-2-one in its inclusion

crystal with (-)-A also occurred enantioselectively (Scheme 9).
(R,R}(-)A + Me
ye0
Ar-SH
Solid •
Me
~e
3-Methyl-3-buten-2-one »» Adduct
SAr
Scheme 9
Using different thiols following adducts were obtained:
Ar Product
Yield %ee
() 76 49
C)-
)-
93 9
Me
Me
t 89 4
N
(}-s 78 53
S
Michael-addition of diethyl(acetylamido) malonate to chalcone using

asymmetric phase transfer catalyst (ephedrinium salts) in presence ofKOH in
the solid state has been carried OUt. 17a The yield is 56% with ee of 60%
(Scheme 10).
194 GREEN CHEMISTRY
o
/C0 2 Et Ephedrinium salt (A)
+ H-C,C0 2 Et ~
KOH, solid state
NHCOMe
Chalcone" Diethyl acetylamidomalonate
Yield 66%
56%ee
(-)-adduct
A= H
+
H NMe 2CH 2
Me
H-N-methyl-N-
benzylephedrinium bromide
Scheme 10
13.2.4 Dehydration of Alcohols to A1kenes

The dehydration of alcohols proceed efficiently in the solid state. 18 In this
reaction, alcohols of the type PhRIC(OH)CH2R2 give on dehydration alkenes,
PhRIC=CHR2. The dehydration is carried out by keeping the powdered alcohol
in a disiccator filled with HCI gas for 5-6 hr. Using this method l8 the following
alcohols were dehydrated (Scheme 11).
HCIgas
PhRiCCH R2 ~ PhR i C=CHR2
I 2 Solid
OH
R' RZ Yield (%)
Ph H 99
Ph Me 99
Ph Ph 97
Scheme 11
Use of benzene as solvent in the above reaction gave much lower yields
(65-75%). The dehydration proceeded much faster by using Cl3CC02H as
catalyst.
13.2.5 Aldol Condensation

The aldol condensation of the lithium enolate ofmethyI3,3-dimethylbutanoate
with aromatic aldehydes gives l9 (the reaction is carried out by mixing freshly
ground mixture ofthe lithium enolate and powdered aldehyde in vacuum for 3
days at room temperature) a 8:92 mixture of the syn and anti products in 70%
yield (Scheme 12).
-../OLi
/~-" + RCHO ---=;=---
Solid VOH ° +
OH °
t-8u OMe 3 days vacuum R OMe RYoMe
room temprature t -Bu
t-Bu
Lithium enolate of methyl
3.3-dimethyl butanoate syn anti
R = 2-0CH,C,H,-. 4-Cl-C,H,
4-NO,C,H.-. 3-NO,C,H,-. 2-NO,C,H,-
4-NO,-2-thienyl
Scheme 12
In the absence of any solvent, some aldol condensation proceed20 more

efficiently and stereoselectively. In this method, appropriate aldehyde and ketone
and NaOH is grounded in a pestle and mortar at room temperature for 5 min.
The product obtained is the corresponding chalcone. In this method the initially
formed aldol dehydrates more easily to the chalcone in the absence of solvent
(Scheme 13).
196 GREEN CHEMISTRY
ArCHO + Ar'COMe
NaOH
---.~
Solid
[6 ArC HCH2 COAr'
H 1
-----;~~
Ar,
-==--....
- - C OAr'
Aldehyde Ketone Chalcone
Aldol
Scheme 13
Using the above method following chalcones were prepared:

Ar Ar' Reaction time Yield (%) of
(min) aldol chalkone
Ph Ph 30 10
p-MeC 6 H4 Ph 5 97
p-MeC 6 H 4 p-MeC 6H4 5 99
p-C1C 6 H4 Ph 5 98
p-C1C 6 H4 p-MeOC6 H4 10 79
p-C1C 6 H4 p-BrC 6H4 10 81
--0--
p-BrC 6 H4 10 91
o ~ ;}
Hi,o
Use of alcohol as a solvent in the above method using conventional
procedure gave only the aldol in poor yields (10-25%). The only exception
was the first case, where solid state reaction gave aldol in 10% yield.
13.2.6 Dieckmann Condensation

Dieckman condensation reactions of diesters have been carried oue l in solid
state in presence of a base (like Na or NaOEt) using high-dilution conditions in
order to avoid intermolecular reaction. It has been found 22 that the Dieckman
condensation of diethyl adipate and pimelate proceed very well in absence of
the solvent; the reaction products were obtained by direct distillation of the
reaction mixture. In this method the diester and powdered ButOK were mixed
using a pestle and mortar for 10 min. The solidified reaction mixture was
neutralised with p-TsOH.Hp and distilled to give cyclic compounds
(Scheme 14).
Any of the bases like BuI()K, ButONa, EtOK or EtONa could be used in
the above reaction.
13.2.7 Grignard Reaction

The results obtained by carrying out the usual Grignard reaction are different
than that obtained in the solid stateY Thus the reaction of ketone (e.g.
benzophenone) with Grignard reagent (the reaction carried out by mixing ketone
and powdered grignard reagent, obtained by evaporating the solution of the

Grignard reagent (prepared as usual) in vacuo) in solid state gives more ofthe
reduced product of the ketone than the adduct (Scheme 15).
Base
Solvent
Diethyl adipate (n = 2) 60-70%

Diethyl pimelate (n = 3)
Scheme 14
0.5 hr
Ph2CO + RMgX Ph2RCOH + P~CHOH
Solid Adduct Reduced product
(A) of ketone (B)
Scheme 15
Following results are obtained:

Grignard reagent % products obtained
RMgX in solid state
R X (A) (B)
Me No reaction
Et Br 30 31
i-Pr Br 2 20
Ph Br 59
13.2.8 Reformatsky Reaction

Treatment of aromatic aldehydes with ethyl bromoacetate and Zn-NH 4Cl in
the solid state give the corresponding Reformatsky reaction products 24
(Scheme 16).
13.2.9 Wittig Reaction

The well known Wittig reaction has been reported 25 to occur in solid phase. In
this procedure a 1: 1 mixture of the finely powdered inclusion compound of
cyclohexanone or 4-methyl cyclohexanone and (-)-B (derived from tartaric
acid'7 and a catalytic amount of benzyltrimethyl ammonium hydroxide) was
heated at 70°C with Wittig reagent carbethoxymethylene triphenylphosphorane
to give optically active 1-(carbethoxymethylene) cyclohexane (Scheme 17) or
198 GREEN CHEMISTRY
the corresponding 4-methyl compound.
Zn-NHP. RCH(OH)CH2C0 2Et

Solid state
3 hr 80-90% yields
Scheme 16
(-)-B
6 R
R=HorCH3
Solid, 70°C, 4 hr
R
(-)-product
45% ee 73% yield
Scheme 17
In a similar way inclusion compound of 3,5-dimethylcyclohexanone and

(-)-A (derived from tartaric acid J7 and a catalytic amount of benzyltrimethyl
ammonium hydroxide) on reaction with the Wittig reagent gave optically active
15
3 ,5-dimethyl-l-(carbethoxymethylene) cyclohexane (Scheme 18).
D
H C0 2Et
P~COH 0
(R,R)-(-)- OO~ H • Phl=CHC02Et ~
O~ Solid, 70°C, 4 hr
P~COH Me Me Me Me
(-)-product
57%ee
Yield 58%
Scheme 18
13.2.10 Armoatic Substitution Reactions
13.2.10.1 Nuclear Bromination

Nuclear bromination of phenols with N-bromosuccinimide (NBS) is
accomplished J8 in the solid state. Thus, the reaction of 3,5-dimethylphenol
with 3 mol equivs of NBS in the solid state for 1 min gave the tribromo
derivative in 45% yield. However, if the reaction is conducted in solution a
mixture of mono and dibromo derivatives is obtained (Scheme 19).
OH
_ _B r * B r
~
D+
Me Me
Br
Tribromo dervative
NBS
Me ~ Me
3,5-dimethyl phenol
,---S_olu_tio_n----.. ~ + &B'
Me~Me Me~Me
Br Br
Monobromo Dibromo
derivative derivative
Scheme 19
13.2.10.2 Nitration
The nitration of aromatic compounds with stoichiometric quantity of nitric
acid and acetic anhydride (in absence of solvent) at 0-20 0 C in presence of
zeolite beta catalyst gave 26 the nitration product as given (Scheme 20).
R R
Q ¢
R
6
R
(rN~
HNO/Ac 2O
• I +
Zeolite beta ~ ~ NO;
N02
o-nitro m-nitro p-nitro
R Yield Ratio of
(%) o- m- p-
Me >99 18 3 79
t-Bu 92 8 trace 92
Cl >99 7 0 93
N0 2 13 92 7
Scheme 20
200 GREEN CHEMISTRY
13.2.10.3 Synthesis ofAmines

The halogen in an aromatic compound (e.g., 4-chloro-3,5-dinitrobenzoic acid)
can be made to react with amino group (e.g., p-aminobenzoic acid) in solid
state at 1800 C to give 27 the corresponding amine (Scheme 21).
COH
O~iJ
-0
NOz
HOOC~Cl
\'1. ISO°C
+ HN
2
'I
_
'1 COOH- HOOC-o' N,
Solid NOz
- H
NOz p-amino amine
4-chloro-3,5- benzoic acid
dinitrobenzoic acid
Scheme 21
13.2.11 Pinacol-Pinacolone Rearrangement

Pinacol-pinacolone rearrangements proceed28 faster and more selectively in
solid state. A 1:3 molar ratio of the pinacol and p-toluene sulphonic acid
(p-TsOH) (powered mixture) on keeping at 60 0 C give the products (A) and
(B). It is found that the hydride migrates more easily than the phenyl anion
and the yield of A is higher than that of B in all the reactions (Scheme 22).
H Ph Ph Ph
H+
Ph++R ~
Ph~R + H-rt-R
OHOH 0 H 0 Ph
Pinacol (A) (8)
Piancol Time(hr) Yield

R for reaction (A) (B)
Ph 2.5 89 8
o-MeC6H4 0.5 45 29
m-MeC6H4 OJ 70 30
p-MeC6H4 0.7 39 19
p-MeOC6H4 0.7 89 0
p-CIC6H4 1.0 54 41
Scheme 22
However, pinacol-pinacolone rearrangement in presence ofCCl3C0 2H (in

place ofTsOH) gives major amount of the isomeric product (B). The reaction
is considerably enhanced if the water formed during the reaction is continuously

removed under reduced pressure.
13.2.12 Benzil-Benzilic Acid Rearrangement

Normally the above rearrangement has been carried out by heating benzil and
alkali metal hydroxides in aqueous organic solvent. It is found that the
rearrangement proceeds more efficiently and faster in the solid state 29
(Scheme 23). The reaction takes 0.1 to 6 hr and the yields are 70-93%.
oII °II
Ar-C-C-Ar'
Benzil
KOH
Solid
~
- - - - I.. Ar + Ar'
OH
COOH
Benzilic acid
Ar=Ar' = Ph
Ar = Ar' = p-ClC 6 H4
Ar = Ar' = P-N0 2 C 6 H4
Ar = Ph; Ar' = p-ClC 6 H4
Ar = Ph; Ar' = P-N0 2 C 6 H 4
Ar = Ph; Ar' = p-MeOC 6 H4
Scheme 23
The effect of the reaction efficiency of the above rearrangement

(Scheme 23) in the solid state increases in the following order:
KOH > Ba(OH)2 > NaOH > CsOH
13.2.13 Beckmann Rearrangement

Usually, Beckmann rearrangement of oximes of ketones are converted into
anilides by heating with acidic reagents like PCls' HCOOH, SOCl2 etc. However,
solid-state Beckmann rearrangement has been reported. 30 In this method oxime
of a ketone is mixed with montmorillonite and irradiated for 7 min in a
microwave oven to give corresponding anilide in 91 % yield (Scheme 24).
-Mont. KID
- -...
Microwave
~ Me-C-N
II H
-0'\ '/
_
'\
IDmin 0
Acetophenone oxime Acetanilide (91 %)
Scheme 24
202 GREEN CHEMISTRY
However, conventional heating gives only 17% yield.

Another interesting example is the preparation31 of (-)-5-methyl-E-
caprolactam of 88% ee by heating 1: 1 inclusion compound of (-)-1, 6-bis(o-
chlorophenyl)-1,6-diphenylhexa-2,4-diyne (A) and oxime of p-
methylcyclohexanone in ether-petroleum ether with conc. sulphuric acid gave
(-)-5-methyl-E-caprolactam. In place of oxime of p-methylcyclohexanone,
use of the oxime of 3,5-dimethyl cyclohexanone gave the corresponding (+)-
4,6-dimethyl-E-caprolactam (Scheme ·26).
Cl Cl
. (-)-
H 2S0 4
Solid!:i
. 0°
..
NH
OH OH Me
(A) Me
(-)-5-methyl-
I: 1 inclusion compound of
E-caprolactam
(-)-1, 6-bis(o-chlorophenyl)-
80%ee
1,6-diphenylhexa-2,4-diyne-l, 6-diol
and 4-methyl cyclohexanone oxime
Cl (-)- AOH ~~~~ "fIrtH

OR OR
MeMMe MW Me
I: 1 inclusion compound of (+)-4,6-dimethyl-
(-)-1, 6-bis(o-chlorophenol)- E-caprolactam
1,6-diphenylhexa-2,4-diyne-l, 6-diol 59%ee
and 3,5-methyl cyclohexanone oxime
Scheme 26
13.2.14 Meyer-Schuster Rearrangement

Propargyl alcohols on keeping (2-3 hr) with p-toluene sulphonic acid (TsOH)
rearranges to give 1B a,p-unsaturated aldehydes (Scheme 27).
13.2.15 Chapmann Rearrangement

5-Methoxy-2-aryl-l,3,4-oxadiazoles on heating in solid state undergo
rearrangement to give 32 the corresponding oxadiazole-5-ones (Scheme 28).
TsOH
Solid (3-5 hr)
cr,p-unsaturated aldehydes
(58-94% yield)
Proparglyalcohols
R' = R2 = Ph
R' = Ph; R2 = o-ClC 6 H4
R' = R2 = 2,4-Me2C6 H3
Scheme 27
_-... R--0
~'\\
Solid
~ Dyo
N-N.....
Ar
R = H, Cl, OMe, N0 2
Scheme 28
The same type of rearrangement also occur with methyl cyanurates and
thiocyanurates in the solid state33 (Scheme 29).
XMe XMe XMe X

N.J.--N .J.-- .J.--
~ ;l J:Me ~ ~ J:Me ~-~ ~-Me
)l..
A )l.
MeX N XMe MeX:""N X XAN x ~AN.AX
I I
Methylcynurates X = 0 Me Me
Methylthiocynurates X = S
Scheme 29
13.2.16 Miscellaneous Reactions
13.2.16.1 Coupling Reactions
(i) Coupling of salts of crotonic acids

Sodium crotonate on heating in solid state gave hex-I-ene-3,4-dicarboxylate
(A). On the other hand, potassium crotonate on heating at 320°C for 4 hr
gives (A) along with the isomeric dimers (B) .and (C) (Scheme 30).34
204 GREEN CHEMISTRY
Sodium crotonate M = Na (A)

Potassium crotonate M = K
- + - +
MeCH=C-COO K H2C=C-CHZ-COO K
I. _+ + 1_+
Me-CH-CH2COO K Me-CH-CH2-COO K
(B) (C)
Scheme 30
In a similar way, cross thennal coupling of binary salts of but-3-enoic

acid and methacrylic acid (the salts were obtained by mixing equimolar amounts
of the two acids with an equimolar amount of metal or alkaline metal earth
salts) on heating gave 3S the coupled product, which was isolated as the methyl
ester, i.e. (E)-methyl-hex-l-ene-l,5-dicarboxylate (Scheme 31).
-OOC~ + ==< COO-

~ -OOC,•./""-..../""-...
';" -
' / --.
T
COO
but-3-enoate Methacrylate
--. OOC~ Esterification. Me02C~
COO- C02Me
(E)-Methylhex-l-ene-
1,5-dicarboxylate
Scheme 31
(ii) Pinacol coupling

Aromatic aldehydes and ketones undergo pinacol coupling in solid state by
Zn-ZnCI2 reagent to give 36 a mixture of the reduced product (0-2%) along
with major amount (45-80%) of the coupled product (glycol) (Scheme 32).
However, coupling of aromatic ketones under the above solid state
conditions (Scheme 32) give only the coupled product (Scheme 33).
Aromatic Coupled product (glycol)

aldhydes product
(45-80%)
(0-2%)
(ratio of meso/dl product is
X=H,Me, C~ Br, Ph 60:40 to 80:20)
Scheme 32
Zn-ZnCI 2
ArCOAr' ArC-C-Ar'
Solid I I
3 hrRT OHOH
30-90% Yield
Ar'
Ph
p-CIC6H4
p-CIC6 H4
Scheme 33
(iii) Oxidative coupling of phenols

Oxidative coupling of phenols in presence of FeCI3.6H20 proceed much faster
in the solid state37 than in solution. The reaction is carried out by mixing the
phenol and FeCI3 .6Hp in powdered state and leaving the mixture for 2 hr
at 50°C. Some of the coupling products of phenols are given in the following
(Scheme 34).
(iv) Oxidative coupling of acetylenic compounds
Oxidative coupling of acetylenic compounds proceeds more efficiently in the
solid state38 than in water. In this procedure, powedered cuprous aryl acetylide
and CuCI2.2Hp was kept for 3 hr to give the coupled product in 40-75% yield
(Scheme 35), compared to 10-30% in water.
In a similar way prop argyl alcohols could be coupled38 in solid state
(Scheme 36).
(v) Dimerisation of [60J fullerene
Due to extremely very low solubility of fullerens in organic solvents, its chemical
transformations is very difficult. The dimerisation reaction of [60] fullerene in
presence ofKCN proceeded in solid state (Scheme 37) to give39 [2+2] adduct
in 18% yield (Scheme 37).
206 GREEN CHEMISTRY
OH
# # Solid, 50 °C, 2 hr , OH
OH
p-Naphthol
bis p-naphthol
(95%)
[Fe(DMF)JCI2] [Feq]
Solid )))) , 50 °C, 2 hr

•
9,9' -bis(phenantherol)
68%
C1n
Me
CI
Me
FeCl J,6H 2O Me OH
~
Me I # OH
Solid Me OH
CI
Me
30%
Scheme 34
CuCl~.2H2Q
ArC=C-Cu ----~~~.~ ArC=C--C=C--Ar
Solid
Cuprous aryl Diaryldiacetylene
RT 48 hr
acetyl ide
Scheme 35
CuCl 2.2 Pyridine

RR'CC=CH -----:--..,.,-,...-----i~~ RR'CC=CC=CRR'
I So1id,~ I I
OH OH OH
Substituted 30-70%
propargyl alcohols Coupled products
R= R = Ph
R = Ph·, R' = o-CIC6 H4
R = R = p-MeC 6H4
R = Ph; R = 2,4-(Me)2-C6H3
R = 2,4-(Me)2-C6H3; R = o-ClC6H4
R=Ph; R =Me
Scheme 36
KCN
2 ~
solid
Scheme 37
It is appropriate to mention here that [60] fullerene reacted with ethyl

bromoacetate in presence ofZn dust (the reaction was carried out by vigorously
agitating the mixture for 20 min at room temperature) and the adduct (A) was
208 GREEN CHEMISTRY
obtained40 in 17.2% yield along with some by products (designated B, C and

D) (Scheme 38).
(A) (B)
Zn + BrCH,CO,Et
Solid ~
CH,COCH,CO,Et
H
(C) (D)
Scheme 38
13.2.16.2 Solid Phase Synthesis oJOxazolidines

The reaction of aldehydes with (-)-ephedrine or (+ )-pseudoephedrine by
keeping powered reaction mixture at room temperature give41 quantitatively
the corresponding oxazolidines (Scheme 39).
, H H
H H
R-C
~o
~
+ Me-C-C-OH R.T..
HRVN°,}-Ph +
....\ ~1t. :'i~Ph
'H 1 ,
MeNHPh Me" H Me Me" H Me
Aldehyde (-)ephedrine Oxazolidines
R -C'
~O ¥¥
+ Me-C-C-OH RT
.. ~
'H 1 ,
PhNHPh
Aldehyde
(+ )-pseudoepheridine Oxazolidines
R= PhCH=CH
R = H (Paraforrnaldehyde)
R = 4-0H-3-0MeC6H3
R = CsHleCsH4
R = 4-N02C6H4 Scheme 39
13.2.16.3 Synthesis ofAzomethines

Solid state reaction of anilines and aromatic aldehyde (by grinding the reactants)
give42 quantitative yield of various azomethines (Scheme 40).
ArNH2 + Ar'CHO
Aromatic
Mix
Solid
. ArN=CH-Ar'
Aromatic Azomethines
amine aldehyde
Ar = 4-MeC6 H4 Ar = 4-CIC.H 4
4-MeOC 6H 4 4-BrC.H4
4-N0 2C 6H 4 4-N02C.H4
4-ClC.H4 4-0HC6 H4
4-BrC.H4 4-0H, 3-0MeC.H3
4-HOC.H4
I-Naphthyl
Scheme 40
13.2.16.4 Synthesis of Homoallylic Alcohols

Treatment of aldehydes with 3-bromopropene and Zn-NH4CI in absence of
any solvent gave43 the corresponding homoaUylic alcohols in 85-99% yields
(Scheme 41).
Zn-NH.CI
RCHO + BrCH2CH=CH2 ----!----.
.. RCH(OH)CH2CH=CH2
Aldehyde 3-Bromopropene Homoallylic alcohol
R = Ph, ~-naphthyl, n-pentyl or trans CH 3CH=CH2
Scheme 41
13.2.16.5 Synthesis of Cyclopropane Derivatives

The reaction of chalcones and trimethylsulphonium iodide and KOH in the
solid state gave" the corresponding cyclopropanes (Scheme 42).
The same cyclopropane derivative was also obtained" by the reaction of
chalcone with (+)-S-methyl-S-phenyl-N-(p-tolyl)sulfoximide and tert. BuOK
at room temperature in 94% yield (Scheme 43).
210 GREEN CHEMISTRY
o
Ph>=<H 11+_ KOH. PhAH
-- + Me2S -Mel
H COPh H COPh
Chalcone trans-I-benzoyl-2-
phenyl cyclopropane
79%
Scheme 42
Ph
~COPh+
H
o
II
(+)Ph-S-Me
II
N-Tol
tert. BuOK
PhAH
H COPh
Chalcone (+)-form
24%ee
Scheme 43
The y-CD complex ofphenylmethyldiazirine (obtained by treatment ofy-

CD solution with the phenylmethyldiazirine) on heating in inert atmosphere
gave45 trans-l,2-diphenyl-l-methylcyclopropane (Scheme 44).
f.l200 °C
Argon atmosphere H3 C
Solid
trans-I,2-diphenyl-
I-methyl cyclopropane
y-C-CD complex
Scheme 44
13.2.16.6 Synthesis ofOxirazies

The reaction of cyclohexanones with trimethylsulfonium iodide and KOH in
the solid phase gave44 gave the oxirazines (Scheme 45).
13.2.16.7 Synthesis ofAziridines

The reaction of imines with trimethylsulfonium iodide in solid state in presence
of KOH gives 44 the corresponding aziridines (Scheme 46).
KOH
Solid state
CycIohexanone
R
trans
+ R~ cis
Oxirazine
R YieJd(%) Ratio
(trans + cis) trans: cis
t-Bu 83 97: 1
Me 33 91:9
Et 75 92: 8
Ph 82 97: 3
Scheme 4S
o
Ar>=
H
N
Imine
......... Ar'
11+
+ MezS -Mel
_ KOH
50°C, 3 hr
~
~~N'Ar' Aziridine
(36-56%)
Ar= Ar' = Ph
Ar = Ph; Ar' = p-MeOC6H4
Ar = p-CIC6 H4; Ar' = p-MeOC6H4
Ar = p-MeC6 H4 ; Ar' = p-MeOC6H4
Scheme 46
13.2.16.8 Synthesis ofDisulphides

Disulphides have been obtained46 by the solid state reaction of benzyl halides,
alkyl halides and acyl halides at room temperature in the presence of
benzyltriethylammonium tetrathiomolybdate. For example, butyl iodide, benzyl
bromide and benzoyl chloride give the corresponding disulphides in 70-74%
212 GREEN CHEMISTRY
yield. The 1-bromo-6-iodohexane reacted with benzyltriethylammonium

tetrathiomolybdate to give exclusively the dibromodisulphide. However, the
same reaction in solution give eight membered cyclic disulphide (Scheme 47).
+
I(CH2)6-Br + PhCH2-NEt3MoS~ --.~ Br(CH2)6-S-S-(CH2)6-Br
I-Bromo-6-iodo Dibromodisulphide
hexane
Cyclic disulphide
Scheme 47
13.2.16.9 Synthesis of Thiocarbonylimidazolide Derivatives

The title compounds can be prepared 47 by grinding together
thiocarbonyldiimidazole and alcohols (Scheme 48).
R-OH
Solid
grinding RO~\\
Alcohol
Thiocarbonyl
~N
Thiocarbonylimidazolide
diirnidazole
derivative
Scheme 48
13.2.16.10 Synthesis ofSecondary and Tertiary Halides

These can be prepared48 from the corresponding secondary and tertiary alcohols
on exposing the powdered alcohol to Hel gas in a desiccator (Scheme 49).
13~2.16.11 Formation of Ethers from Alcohols

Treatment of alcohols with p-toluene sulphonic acid (TsOH) in solid state by
keeping the powdered mixture (1: 1) at room temperature for 10 min give 48 the
corresponding ethers in 94-98% yields (Scheme 50).
The formation of ethers in benzene solution gave 40-73% yields while in
methanoic solution gave 1-50% yields.
PhR 1CR2 HClgas PhR 1CR2

I ------i~~ I
Solid Cl
OH 1-10 hr
Alcohol Halides
(2 or 3° C) (2 or 3°C)
(92-94% yield)
R' = Ph; R2=H

R' = Ph; R2=H
RI = o-ClC6H4 ; R2 = H
Scheme 49
Ph-CH-R1 _T_sO_H-.~ R1-CH-O-CH-Ph

I Solid I I
OH Ph Rl
Alcohol Ether 94-98%
Scheme SO
13.2.16.12 Synthesis of High Molecular Weight Polypeptides

N-carboxy anhydrides of a-amino acids, viz. L-Ieucine, L-alanine, y-benzyl-
L-glutamine and glycine undergo solid state polymerisation49 by using butylamine
as an initiator in a hexane suspension at 20-50 °C (Scheme 51).
13.3 Solid Supported Organic Synthesis
13.3.1 Introduction
In these reactions, the reactants are stirred in a suitable solvent (for example,
water, alcohol, methylene chloride etc.). The solution is stirred thoroughly
with a suitable adsorbent or solid support like silica gel, alumina, phyllosilicate
(Mn+ -montomorillonite etc.). After stirring, the solvent is removed in vacuo
and the dried solid support on which the reactants have been adsorbed are
used for carrying the reaction under microwave irradiation.
214 GREEN CHEMISTRY
o
o R
BuN~ :Y{O II I
Bu-N-C-C-N-COOH
-C02
HN-<.
~
H H H
o
N-carboxy
anhydrides of
a-amino acids
o R [ R~:l
HN-4 0 R
Bu-N.J:!:-t-NH2 ____ O_n~~ Bu-N1J!_t-Nl +nC0 2
H I Polymerisation H \ '-" H H J
H ~
High molecular weight
polypeptide
Scheme 51
Some of the important applications of solid support synthesis are given as

follows.
13.3.2 Synthesis of Aziridines
Dry media synthesis under focussed microwave irradiation (MWI) by Michael

addition has resulted in various substituted aziridines, though elimination
predominates over the Michael addition under MWI when compared to classical
heating under same condition (Scheme 52).50
R++X
H H
Br Br
Bentonite
R'NH2 MWI
H
R~X
\/
N
R'
H + >v<: N
R'
x = electron withdrawing group + RCH= C (X) Br + RCH= N-R'
Scheme 52
13.3.3 Synthesis of ~-lactams

In a preliminary report, Bose et al. 50• had described an efficient and rapid
synthesis of number of p-Iactams under microwave irradiation (MWI). Further
in closed Teflon vessels using KF and phase transfer catalyst (PTC), p-lactams
have been synthesized in few minutes from ketene sHyl acetal and aldimines
(Scheme 53).51
M~OSiMe3+
HOMe Ph--N =< Ph KF-18Crown6
• H
H MW (300 W), 7 min Me
Phj={H
N/
0
Ph
93% (anti/syn = 65/35)

Scheme 53
N (4-hydroxycyclohexyl)-3-mercaptolcyano-4-aryl-azetidine-2-one has
been synthesized from N -(4-hydroxycyclohexyl)-arylaldimine by reacting with
ethyl a.-mercapto/a.-cyanoacetate on basic alumina under microwaves
(Scheme 54), wherein not only the reaction time were brought down from
hours to minutes in comparison to conventional heating but also yields were
improved. 52
HO"""o-N=CH~
~
EtOOC-CH 2 X.
Basic alumina
HO""o-N-~
I
......;r:\\
I ~
R MWI
o-:.C-C;:~
; .."X R
X= SH, CN;R = H, 4-0H, 4-0CH 3 , 2-0H, 3-N02, 4-CI H
Scheme 54
Deacylation of cephalosporins, a growing class of p-Iactam antibiotics,

has been investigated using enzymatic and microwave activated solid phase
techniques. The de acylation was achieved in less time with better yields
(Scheme 55).53
_::::runa" ~o
MWI
;)
~
OH
eOOH
Scheme 55
Reaction of 7-amino-3-[5'-methyl-l ',3',4'-thiadiazol-2'-ylthiomethyl]

cephalosporanic acid with heterocyclic amines using basic alumina under
microwave irradiation (MWI) afforded new cephalosporin analogs in shorter
reaction time with improved yield as compared to conventional heating
(Scheme 56).54
216 GREEN CHEMISTRY
! Bru;k Alunri.. MWI
Scheme 56
An environmentally friendly safe method developed for the preparation

of 3-carbamoyl cephalosporin derivative such as cefuroxime uses
o-transcarbomylase, an enzyme of microbial origin for the conversion of
3-hydroxy function to the desired 3-carbomyl group. This new synthesis
replaces the conventional chemical route, which employs hazardous isocyanates
such as dichlorophosphenyl isocynate or chlorosulfinyl isocyanate to achieve
the same conversion (Scheme 57).55
R-N:±±) OH
o-trans
~~
_ca_r_bo_m..:.'y_las--,e R-N:j
tI
r
H:6
A' 0 NH,
ot:::
R = H, acyl group
o OR'
R' = H, or carboxyl protecting group
Scheme 57
13.3.4 Synthesis of Pyrroles

A simple and fast synthesis of a tetrapyrrolic macrocycle under dry media
conditions with microwave activation was performed. Pyrrole and benzaldehyde
adsorbed on silica gel afforded tetrahydroporphyrin within 10 min, whereas
conventional method needed 24 hr (Scheme 58).56
H©O
C
+ __ NH
----....
Silcagel
--';;"-'-l~~
MWI
Scheme 58
Synthesis of substituted pyrrole over silica gel under microwave irradiation

has been reported (Scheme 59).57
Scheme 59
13.3.5 Synthesis of Furans

Naturally occurring, pharmacologically important 2-aroyl-benzofurans are easily
obtainable in the solid state from a-tosyloxyketones and salicylaldehydes in
the presence of a base such as KF doped alumina using microwave irradiation
(Scheme 60).58
13.3.6 Synthesis of Pyrazoles

Diarylnitrilimine on cyclocondensation with alkynes and disubstitued alkenes
gave the corresponding pyrazoles when irradiated with microwaves. The
218 GREEN CHEMISTRY
nitrilimine was generated in situ and thus was a one pot reaction ofhydrazonyl
chloride over alumina (Scheme 61).59
TsO
R'''rAY CHO
R
~+
OH
R o
Scheme 60
ArC=N-NH AlP3 JAr-cr-x -}

I
CI
I
Ph MWI
..
l Ar-C=N-X-
I R'CH=CHZ
~
M-Ph
R y Y R
Ar
:t)-Pb N
+
Ar N
Scheme 61
13.3.7 Synthesis oflmidazoles

Benzimidazoles are prepared readily by condensation reaction of ortho-esters
with o-phenylenediamines in the presence of KSF clay under solvent free
conditions using focused microwave irradiation (Scheme 62).60
.. {=©
EtO
KSF Clay
EtO)C-H
MWI
EtO
I
H
Scheme 62
4-Alkylidene-lH-imidazol-5(4H)-ones are obtained in good to excellent

yields by 1,3-dipolar cycloaddition, in solvent-free condition under focussed
microwaves from an activated imidate and aldehydes in the presence of catalytic
amounts of anhydrous acetic acid (Scheme 63).61
Me /"-...
?N COOMe + R-CHO
EtO
Scheme 63
An expeditious solvent-free synthesis of pyrazolino/iminopyrimidinol

thioxopyrimidino imidazoline derivatives from oxazolones on solid support
using microwaves has been described. The reaction time was brought down
from hours to minutes with improved yield as compared to conventional heating
(Scheme 64).62
H2Nif-NHCN
~_ _
NC
H 'N---"u
N_H_ _ _ Ar
>Q
NH
;,N
Neutral alumina N-N

NyN'Z~
Ph s CH3
(cis and trans)
Basic 1PhNHNH
s HH~'N--fS
alumma 2
NHr.~-NH2 Ar ;, N
~-----. N-N
N ....... I/ \\
Neutral alumina N
Y Z;....
Ph S CH3
(cis and trans)
Scheme 64
13.3.8 Synthesis of Azoles

Oxazolines are readily prepared from the carboxylic acids and 0.,0.,0.-
tris(hydroxymethyl) methylamine under MWI (Scheme 65).63
220 GREEN CHEMISTRY
o OR
MWI,2-5min. ~J<;
80-95% ::-..
R
OR
Scheme 65
1,3-Dipolar cycloaddition ofN-methyl-C-phenyl nitrone to methyl acrylate

to yield isooxazolidines has been studied in the presence of several inorganic
solid supports (silica gel, alumina) using microwave irradiation (Scheme 66).64
Scheme 66
The solid supported synthesis of azoles and diazines by using ~C03 as a

solid support has been reported. This novel technique involves aqueous work
up (Scheme 67).65
Scheme 67
Thiazole and its derivatives are obtained by reaction of a-tosyloxyketones,

which are generated in situ from aryl-methyl ketones and [hydroxy (tosyloxy)
iodo] benzene with thioamides in the presence of KIO clay using MWI
(Scheme 68).58
;grCo~
R
Scheme 68
Amidoximes on reaction with isopropenyl acetate in presence of KSF

clay under MWI gave 1,2,4-oxadiazoles in good yield (Scheme 69). The 1,2,4-
oxadizaoles were also obtained by MWI from O-acylamidoximes adsorbed on
alumina (Scheme 70).66
~-OH KSF, MWI

R-C ~
""'NH 2
Scheme 69
O-N
R-C/ ~-R'
II I MWI
o NH2
Scheme 70
A general method for solid phase synthesis ofN-arylated benzimidazoles,

imidazoles, triazoles and pyrazoles has been demonstrated utilizing copper (II)
mediated coupling of aryl boronic acids under MWI (Scheme 71).67
Microwave accelerated solid state synthesis of spiroindole derivatives has
also been described. The products were obtained in few seconds in good
yield. 68
Reaction of aromatic aldehydes with phenyl nitromethane under microwave
irradiation (MWI) on basic alumina afforded excellent yields (90-96%) of
isoxazoles within 2-3 minutes (Scheme 72).69
222 GREEN CHEMISTRY
CU(OAC)2
R~~/x'
N 'X
11
- - - - i...
MWI \
xrx
x = CH orN R2
Rl, R2 = substituents
Scheme 71
2RN0 2 +
Basic alumina
ArCHO _~.
MWI
Ar
h/I
I
~
R
N
R 0/
Scheme 72
13.3.9 Synthesis of Pyridines

A rapid and high yielding protocol for the synthesis of l,4-dihydropyridine in
the presence of silica gel under microwave irradiation (MWI) has been
described (Scheme 73).70
ORO
o 0 ___
Silica gel---.. Et0)X:1 OEt
R-CHO
+AAOEt Urea, MWI · M N Me
H
Scheme 73
13.3.10 Synthesis ofChromenes and Flavones

Isoflav-3-enes possessing chromene nucleus are well known estrogens. There
is a great demand for the development of ecofriendly synthetic methods for
these derivatives. A facile and general method for the one pot synthesis of
isoflav-3-enes have been described (Scheme 74).71
A solvent-free synthesis of flavones which involves the MWI of
o-hydroxydibenzoyl methanes absorbed on montmorillonite K10 clay for 1 to
1.5 min has been achieved. Rapid and exclusive formation of cyclized flavones
occurs in good yields (Scheme 75).72
+f
Ph
R
N140Ac
MWI, 2-8 min
~
Ph
(73-88%)
Scheme 74
Xl KIO Clay
~
MWI, 1-1.5 min
x X
o o o
Scheme 7S
13.3.11 Synthesis of Quinoline

KSF clay catalyzed Friedlander condensation of2-aminoarylaldehyde or ketones
with carbonyl compounds containing a-methylene group has been achieved
in solvent free condition under MWI to give polycyclic quinoline derivatives
(Scheme 76).73
Clay, MWI
2-5 min •
Scheme 76
In yet another solventless cyciisation reaction using montmorillonite K 10

clay under MWI condition, readily available 2'-aminocha1cones provide easy
224 GREEN CHEMISTRY
access to 2-aryl-l,2,3,4-tetrahydro-4-quinolones which are valuable precursor

for the medicinally important quinalones (Scheme 77).74
KIO clay
~
MWI,1-2min
o
o x = el, Br, Me, OMem NO z
Xl=H
Scheme 77
In an alumina-supported synthesis of antibacterial quinolines using

microwaves wherein the reaction times were brought down from hours to
seconds with improved yield as compared to the conventional heating
(Scheme 78).7S
F1AfJ(H
Cl~N I Me
Acidic alumina
MWI
Me
Me
1
H
Basic
alumina
Me
Me
Scheme 78
13.3.12 Synthesis of Pyrimidines

A one pot synthesis of pyrano [2,3-d] pyrimidines from thiobarbituric acids
under microwave irradiation using basic alumina has been reported. A significant
reduction in reaction time and enhancement in the yield was observed

(Scheme 79),76
R
I
SY:;tN0
.... N
R
o
Scheme 79
Pyrimidino [1 ,6-a] benzimidazoles (Scheme 80) and 2,3-dihydroimidazo

[1 ,2-c] pyrimidines (Scheme 81) under focused microwave irradiation have
been synthesised,77
MWI, 15-30 min

~
Scheme 80
o
EtO II
>=N-C-R1
R2
Scheme 81
13.3.13 Synthesis of Oxadiazines

Three component condensation ofN,N' -dimethyl urea, paraformaldehyde and
primary amines using montmorillonite Kl 0 clay in dry media under microwave
irradiation (MWI) lead to the formation oftriazones whereas condensation of
dimethyl urea and paraformaldehyde supported on montmorillonite K1 0 using
MWI gave 4-oxo-oxadiazinone (Scheme 82),78
An efficient synthesis of benzopyranopyrimidines using three different
solid supports viz" acidic alumina, montmorillonite, silica gel has been carried
out. The products were obtained with improved yields as compared to
conventional heating (Scheme 83),79
226 GREEN CHEMISTRY
~° + (CH20 )n
Montmorillonite
KlO, MWI
~
MelIN NHMe
1
RNHz
Montmorillonite KIO
MWI
°
)(
Me-N N-Me
l.N)
I
R
Scheme 82
rAl°yO +
©yO~ ~ .... RCHO
OH
°
1 *
H2N-C-NH2
Acidic solid support
Scheme 83
13.3.14 Synthesis of Thiadiazepines

An environmentally benign synthesis of the 1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazepines from substituted triazoles and chalcones on basic alumina under
MWI is reported (Scheme 84).80
R~y(~SH
N-N
N-N H, C6J4-R' )( \L
//~
.A + ~CH Basic alumina
.. I
R SH 0=<:( MWI HN C6J4R'
I C6J4-X --
~
2 C6J4X
H
Scheme 84
13.3.15 Miscellaneous Reactions

Scandium tri-fluoromethane sulfonate microencapulated (Lewis acid) have
replaced traditional monomeric Lewis acid reactions like Michael, Fridel Craft,
Mannich and immino Aldol reactions (Schemes 85_88).81-84
o OSiMe3 MC Sc (OTf)3 0 Ph 0
Ph~Ph + ~OMe CH3CN, RT, 6 h Ph~OMe
Scheme 8S
MC Sc (OTf)3
@-OMe+ Ac,O ~
CH3N02, IiCI04
50°C,6 h
Scheme 86
OSiMe3
PhCHO + PhNH2 + Ph~ MC Sc (OTf)3

~
Scheme 87
OSiMe3 MC Sc (OTf)3
+Ph~
Scheme 88
228 GREEN CHEMISTRY
Industrial applications of basic catalysts are in the allylation of phenol,

side chain allylation and isomerization reaction (Scheme 89).85
Zeolite
Scheme 89
The problems associated with waste disposal of solvents and excess

chemicals has been overcome by performing reaction without a solvent under
microwave. The use of~C03 not only eliminate the need for external base to
netralize HCI evolved but also enables aqueous workup (Scheme 90).86
!'RLH ~ H--@
YS:!rN-C-N +
R R
Basic Alumina
R = H, o-OMe, p-OMe, p-CI, p-Br

Scheme 90
An interesting example is the solvent-free Michael addition reaction of

nitromethane to chalcone in the presence of alumina under microwave
irradiation condition that gives the adduct in 90% yield (Scheme 91).87
MWI
Alumina
solid state
Chalcone methane Adduct
Scheme 91
The previous reaction (Scheme 91) takes about 15 days under conventional
conditions. 88
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52. M. Kidwai, R. Venkataramanan and S. Kohli, Synth. Commun., 2000, 30(6), 989.
53. M. Kidwai, B. Dave, K.R. Bhushan, P. Misra, R.K. Saxena, R. Gupta, R. Gulati and
M. Singh, Biocatalysis and Biotransformation, 2002, 20(5), 377-379.
54. M. Kidwai, P. Sapra, K.R. Bhushan, P. Mishra, R.K. Saxena, R. Gupta and M. Singh,
Bioorg. Chemistry, 2001,29,380.
55. I.D. Flemeng, M.K. Turner and SJ. Brewer, US 4075061, 1978; Chem. Abstr., 1978,
88,168488.
56. A. Petit, A. Loupy, P. Maillard and M. Momenteau, Synth. Commun., 1992,22, 1137.
57. B.C. Ranu, A. Hajraand U. Jana, Synlett., 2000, 75.
58. R.S. Varma, D. Kumar and P.J. Liesen, J. Chem. Soc. Perkin Trans. 1, 1998,4093.
59. K. Bougrin, M. Soufiaoui, A. Loupyand P. Jacquault, NewJ. Chem., 1995,19,213.
60. D. Villemin, M. Hammadi and B. Martin, Synth. Commun., 1996,26,2895.
61. G. Kerneur, J.M. Lerestif, J.P. Bazureau and J. Hamelin, Synthesis, 1997,287.
62. M. Kidwai, P. Sapra, K.R. Bhushan and P. Misra, Synthesis, 2001, 10,1509.
63. A.L. Marrero-Terrero and A. Loupy, Synlett., 1996,245.
64. A. Padwa, L. Fisera, K.F. Koehler, A. Rodriguez and G.S.K. Wong, J. Org. Chem., 1984,
49,276.
65. M. Kidwai, R. Venkataramanan and B. Dave,J. Heterocycl. Chem., 2002, 39,1-3.
66. B. Oussaid, L. Moeini, B. Martin, D. Villemin and B. Garrigues, Synth. Commun., 1995,
25(10), 1451.
67. A.P. Combs, S. Saubern, M. Rafalski and py.s. Lam, Tetrahedron Lett., 1999,40,1623.
68. M. Kidwai and P. Misra, Oxidation Communications, 2001, 24, 287.
69. M. Kidwai and P. Sapra, Org. Prep. Proced. Int., 2001, 33, 381.
70. J.S. Yadav, B.V.S. Reddy and P.T. Reddy, Synth. Commun., 2001,31(3),425.
71. R.S. Varma and R. Dahiya, J. Org. Chem., 1998,63,8038.
72. R.S. Varma, R.K. Saini and D. Kumar, J. Chem. Res. (s), 1998,348.
73. G. Sabitha, R.S. Babu, B.V.S. Reddy and J.S. Yadav, Synth. Commun., 1999,
29(24), 4403.
74. R.S. Varma and RK. Saini, Synlett., 1997,857.
75. M. Kidwai, K.R Bhushan, P. Sapra, RK. Saxena and R. Gupta, Bioorg. Med. Chern.,
2000,8,69.
76. M. Kidwai, R. Venkataramanan, RK. Garg and K.R. Bhushan, J Chern. Res. (S), 2000,
586.
77. M. Rahmouni, A. Derdour, J.P. Bazureau and J. Hamelin, Tetrahedron Lett., 1994,
35,4563.
78. S. Balalaie, M.S. Hashtroudi and A. Sharifi, J Chern. Res. (S), 1999,392.
79. M. Kidwai and P. Sapra, Synth. Commun., 2002, 32(11),1693.
80. M. Kidwai, P. Sapra, P. Misra, RK. Saxena and M. Singh, Bioorg. Med. Chemistry, 2001,
9,217-220.
81. S. Kobayashi, I. Hachya, H. Ishrleni and Araki, Synlett., 1993,472; S. Kobayashi and
S. Nagayama,J Am. Chern. Soc., 1998,120,2985.
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84. S. Kobayashi, M. Arcki and S. Hachiya, Synlett., 1995,233.
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88. M.e. Kloetzel, J Am. Chern. Soc., 1947,69,2271.
14. Versatile Ionic Liquids as Green
Solvents
14.1 Green Solvents

The commonly used solvents like benzene, toluene, methylene chloride etc.
for organic synthesis, particularly in industrial production, are known to cause
health and environmental problems. In view of this, the search for alternatives
to the damaging solvent is of highest priority. This is particularly important as
solvents are used.in huge amounts (in industrial production) and these are
mostly volatile liquids, which are difficult to contain.
The ionic liquids, comprising entirely of ions were and mainly of interest
to the electrochemists. I It is possible, by careful choice of starting materials,
to prepare ionic liquids that are liquid at and below room temperature. Different
aspects of ionic liquids have been reviewed by a number of authors. 2 The first
ionic liquid [EtNH3] [N0 3] (m.p. 12°C) was discovered in 1914. 3
Broadly speaking, ionic liquids are oftwo types: simple salts (made up of
a single anion and cation) and binary ionic liquids; the latter are salts where an
equilibrium is involved. It is the binary ionic liquids that are used as green
solvents. Some examples of simple salt are given (Scheme 1).
Scheme 1
An example of a binary ionic liquid system is a mixture of aluminium (III)

chloride and 1,3-dialkylimidazolium chloride. It contains several different ionic
species and their m.p. and properties depend upon the mole fractions of AICl3
Versatile Ionic Liquids as Green Solvents 233
and 1,3-dialkyl imidazolium chloride present. For the binary systems, the m.p.
depends upon the composition4 and is designated as [emin]CI-AICIJ , where
[emin]+ is I-ethyl-3-methyl imidazolium.
The above binary system, [emin]CI-AICIJ can be basic, acidic or neutral in
nature. The composition of the binary ionic liquid is described by the apparent
mole fraction of AICl 3 [X(AICI3 )] present. Ionic liquids with X(AICI 3) < 0.5
contain an excess of Cl- ions over [AI2 CI7]- ions are called 'basic'. On the
other hand, those with X(AICI 7) > 0.5 contain an excess of (AI 2CI7>- ions over
Cl- and are called 'acidic'. Mixtures with X(AICI3) = 0.5 are called 'neutral'.
These ionic liquids (basic, acidic or neutral) are used in different types of
reactions. Thus, the properties such as m.p., viscosity and hydrophobicity
and misicibility with water can be varied by changing the structure and
composition of the ions.
The most commOn salts in use are those with alkylammonium,
alkylphosphonium, N-alkylpyridinium and N,N' -dialkyl imidazolium cation
(Scheme 1).
The reactions in ionic liquids are easy to perform and need no special
apparatus or methodologies. Also, the ionic liquids can be recycled and this
leads to reduction of the costs of the processes.
14.2 Reactions in Acidic Ionic Liquids

The chloroaluminate (III) ionic liquids (where X(AICI) > 0.50) behave like
powerful Lewis acid and promote reactions that are usually promoted by AICI3 •
In fact, chloroaluminate ionic liquids are powerful solvents and can be prepared
by mixing the appropriate organic halide salt with AICl 3 and heating to form
the ionic liquid. This synthesis should be performed in inert atmosphere.
The well known Friedel-Crafts reaction works very well with the
chloroaluminate (III) ionic liquids. s Thus, using this methodology, traseolide
(5-acyl-I,I,2,6-tetramethyl-3-isopropylindane) and tonalid (6-acetyl-
1,1,2,4,4,7-heaxmethyltetralin have been synthesised in high yield in the ionic
liquid [emin]CI-AICI3 (X = 0.67) (Scheme 2).
Similarly Friedel-Crafts reaction of naphthalene gives I-acetyl derivative
as the major product (Scheme 3).
Another interesting application in the use of ionic liquids is in the
hydrogenation of polycyclic aromatic hydrocarbons, 'which are soluble in
chloroaluminate (III) ionic liquids to form highly coloured paramagnetic
solutions6 , which on treatment with a reducing agent such as an electropositive
metal and a proton source results in selective hydrogenation of the aromatic
compound. Using this method, the anthracene can be reduced to
perhydroanthracene at normal temperature and pressure to give the most stable
isomer (the sequence of reduction of anthracene is depicted in Scheme 4).7
234 GREEN CHEMISTRY
CH3COCl[emin]Cl-AlCI3(X=O,67)
5 min, °C° •
1,1,2,6-tetramethyl- traseolide (99%)

3-isopropylindane
CH3COCl[emin]Cl-AlCI3(X=O,67) _
5 min, ° °C
o
1,1,2,4,4,7-hexamethyltetralin tonalid
Scheme 2
CH3COCl[emin]Cl-AlCI3(X=O,67) •
5 min, °C°
Napthalene 1-Acetylnapthalene
80%
+ (2% 2-acetylisomer)
Scheme 3
_[_emI_'n_]C_l_-A_lC-,13,-(X_=_O,_67_)---.. ~
ZnlHCl(g) ~
-.·cco
.
Anthracene
fI
Perhydroanthracene
90% (single product)
Scheme 4
The above reduction is in contrast to catalytic hydrogenation reaction,

which requires high temperature and pressure and expensive platinum oxide
catalyst and gives a mixture of products. 8 In the above case (Scheme-4) the
sequence of chemical reduction can be determined by careful monitoring of
the reduction in ionic liquid.
Using the above procedure (Scheme-4) pyrene can be reduced to perhydro
pyrene.
14.3 Reactions in Neutral Ionic Liquids

As already stated, chloroaluminate (III) ionic liquids are excellent solvents in
many reactions. The main problem arises due to their moisture sensitivity and
difficulty in separation of products (containing heteroatoms) from the ionic
liquid. In view of this, water-stable ionic liquids have been developed. One
example of this is the ionic liquid [bmin][PF61 [(bminY = I-butyl-3-
methylimidazolium)].9 The ionic liquid [bmin][PF61 forms triphasic mixture
with water and alkanes, which makes it useful for clean synthesis. Such ionic
liquids can be used without any special conditions needed to exclude moisture
and the isolation of the reaction products is convenient.
Some applications in the use of neutral ionic liquids are discussed here.
14.3.1 Hydrogenations
The most important advantage of using neutral ionic liquids is that the reaction
products can be easily separated from the ionic liquids and the catalyst. 10
Using the neutral ionic liquids, cyclohexene can be reduced to cyclohexane. II
Even benzene could be reduced to cyclohexane. 12 An interesting asymmetric
hydrogenation using a chiral catalyst [RuCI2-(S)-BINAP12,NEtz has enabled
the synthesis of (S)-Naproxen (Scheme 5).13
(S)-Naproxen
Scheme S
14.3.2 Diel's-A1der Reaction

The neutral ionic liquids are excellent solvents for the Diels-Alder reaction l4
and are better than the conventional solvents and even water (see Section
12.2). Addition of a mild Lewis acid like ZnI2 increases the selectivities in this
reaction. A special advantage of this system is that the ionic liquid and catalyst
can be recycled and reused after extraction or direct distillation of the product
from the ionic liquid. A typical Diel's-Alder reaction is given (Scheme 6).
236 GREEN CHEMISTRY
o 0
[bmin][PF6]5moleo/~ ~+~
6hr,20°C N -V
Isoprene But-3-en-2-one Major Minor
Scheme 6
14.3.3 HeckReaction
Neutral ionic liquids are excellent solvents for the palladium catalysed coupling
of alkyl halides with alkenes (Heck reaction). The special advantage of using
neutral ionic liquids is that many palladium complexes are soluble in ionic
liquids 15 and that the products or product of the reaction can be extracted with
water or alkane solvents. So the expensive catalyst can be recycled compared
to the routine Heck reaction in which the catalyst is lost at the end of the
reaction (see Section 12.11). A typical Heck reaction is given (Scheme 7).
OI
o
X
Pb(OAc)2 OEt
+
ionic liquid, basic
•
R ~ R
R=H,OMe +[H-Baset + x-
X = Br, I
Scheme 7
An alternative Heck reaction uses aromatic anhydrides as a source of the

aryl group (Scheme 8).
cro~
Scheme 8
In the above method (Scheme 8) the by-product of the reaction is benzoic

acid (which can be converted back to the anhydride for reuse) and the halide
containing waste is not formed.
14.3.4 O-Alkylation and N-alkylation

A common reaction in organic synthesis is the nucleophilic displacement
reaction. Thus 2-naphthol undergoes alkylation to give O-alkyl ether on
treatment with a haloalkane and base (NaOH or KOH) in [bmin][PFJ 16

Similarly indol undergoes N-alkylation. Though both the above 0- and N-
alkylations occur with similar rates to those carried out in dipolar solvents
(e.g. DMF or DMSO), but the advantage of ionic liquid process is that the
reaction products can be extracted into an organic solvent such as toluene
leaving behind the ionic liquid, which can be recycled after separation from
sodium or potassium halide by extraction with water.
14.3.5 Methylene Insertion Reactions

Aldehydes and ketones are known to react with sulphur ylides to give
epoxide (Scheme 9).
~
0 Base
/V + [),,]' I ~
~~"r ~
0 Base
~
~
0 0
0
+ [),,]' Base
~
Scheme 9
The methylene insertion reactions have been found to proceed better in

ionic liquids such as [bmin] [PF6 ] or [bmin] [BF4] on treatment with sulphur
ylides. Sulphur ylides are obtained in situ by the reaction of alkyl halides with
sulphides. The reaction works equally well with preformed sulphonium salts
(Scheme 10).
Preformed or
generated in situ
[bmin] [PF 6 ]/KOH
~
cr
~
~ I +
H
K[
Scheme 10
238 GREEN CHEMISTRY
It is also possible to carry out asymmetric methylene insertion reaction

in good enantiomeric excess by using a chiral sulphide such as 2R,5R-
tetrahydrothiophene (Scheme 11).
~B'_[_bm_l_.n_][_p~F6~]I_K_OH~.
Benzaldehyde Benzyl bromide II••••• ~ Stilbene oxide
Scheme 11
14.3.6 Miscellaneous Applications
14.3.6.1 Synthesis ofPharmaceutical Compounds

Ionic liquids have been extensively used in the synthesis of pharmaceutical
compounds. A representative example is the synthesis of pravadpline. 17 The
method consists the alkylation of 2-methylindole with 1-(N-morpholino)-2-
chloroethane in [bmin] [PF6] to give 95% yield of the corresponding N-alkyl
derivative. Subsequent Friedel Craft reaction with p-methoxybenzoyl chloride
in chioro aluminium (III) ionic liquid gives pravadoline (Scheme 12).
Base
ionic liquid [bmin] [PF6]
2-Methylindole
+
CI~
(j.He)
l-(N-morpholino )-2-
chloroethane hydrochloride
~
OCH3
CI
..... C
I d·
II
o
ionic liquid N
~
N)
Pravadoline
CO
Scheme 12
References
1. C.L. Hussey, Adv. MoltenSaltChem., 1983,S, 185.

2. T. Welton, Chem. Rev., 1999,2071-2083; 1. Ho1brey and K.R. Seddon, Clean Prod.
Proc., 1991,1,223-236; K.R. Seddon, J. Chem. Tech. Biotech., 1997,68,351-356;
K. Sheldon, Chem. Commun., 2001,2399-2407; M.J. Earle and K.R. Seddon, Pure Appl.
Chem., 2000, 72, 1391-1398; P. Wasserscheid and W. Keirn, Angew. Chem. Int. Ed.
English, 2002, 3773-3784.
3. P. Walden, Bull. Acad. Imper. Sci. (St. Petesburg), 1914, 1800.
4. C.L. Hussey, 1.B. Scheffler, 1.S. Wilkes and A.A. Fannin, Jr.,J. Electrochem. Soc., 1986,
133,1389.
5. J.A. Boon, 1.A. Levosky, J.L. Pfung and 1.S. Wikes, J. Org. Chem., 1998,51,480.
6. P. Tarakeshwar, J.Y. Lee and K.S. Kim, J. Phys. Chem., 1998, 102A, 2253.
7. C.J. Adams, M.J. Earle and K.R. Seddon, Chem. Commun., 1999, 1043.
8. D.K. Dalling and D.M. Grant, J. Am. Chem. Soc., 1974,96, 1827.
9. J.D. Huddlesten, H.D. Willauer, R.P. Swatioski, A.E. Visser and R.D. Rogers, Chem.
Commun., 1998, 1765.
10. T. Welton, Chem.Rev., 1999,99,2071-2083.
11. PAZ. Suarez, 1.E.L. Dullius, S. Einloft, R.F. de Souza and 1. Dupont, Inorg. Chim.
Acta., 1997,225,207.
12. P.J. Dyson, D.J. Ellis, D.G. Parker and T. Welton, Chem. Commun., 1999,25.
13. A.L. Monterio, K.F. Zinn, R.F. de Souza and 1. Dupont, Tetrahedron Asymmetry, 1997,
8,177.
14. M.J. Earle, P.B. McCormac and K.R. Seddon, Green Chem., 1999, 1, 23; T. Fisher,
A. Sethi, T. Welton and 1. Woolf, Tetrahedron Lett., 1999,40,793.
15. w.A. Herrmann and v.P.w. Bohn,J. Organomet. Chem., 1999,572,141.
16. M.1. Earle, P.B. McCormac and K.R. Seddon, Chem. Commun., 1998,2245.
17. M.J. Earle and K.R. Seddon, Pure Appl. Chem., 2000, 7, 1397.
15. Synthesis Involving Basic Principles of
Green Chemistry: Some examples
15.1 Introduction
Since the beginning of the twenty-first century it was considered of paramount
importance to reduce the impact on the environment caused basically by
pollutants (including waste products) generated by the chemical industries.
Thus there was urgent need to develop environmentally benign or green
synthesis. We already know that a number of ways are available to reduce the
impact on the environment of a large scale process. These include carrying
out reactions in safer aqueous systems instead of hazardous organic solvents.
The reactions, as far as possible, should be carried out at ambient temperature
instead of using heat energy. If possible, the materials should be recycled.
The pathways for synthesis be selected so as to avoid the generation of toxic
materials. All these may reduce the impact of the process on the environment
in terms of pollution or consumption of resources.
It is most advantageous to carry out reactions iIi aqueous media. The
most important factor for industrial process is the economic value of the
process. In view of this, water is the cheapest abundantly available solvent.
Also when water is used as a solvent, the final product can be separated (or
isolated easily) and there is least waste generation. Also the reactions carried
out in aqueous medium are comparatively much more safer compared to
reactions conducted in organic solvents. However, the most important thing is
that reactions in aqueous medium are generally environmentally benign.
The objective of green chemistry is not only to design new green synthesis
(environmentally benign synthesis) but also to devise green methods for the
synthesis of already existing molecules (products) whose known synthesis
are responsible for environmental pollution.
Following are some typical examples of green synthesis.
15.2 Synthesis of Styrene

The chemical industry consumes styrene, the monomer used for the
manufacture of polystyrene in large quantities each year. The cortunonly used
Synthesis Involving Basic Principles of Green Chemistry 241
industrial method for making it converts benzene into styrene by a Friedal-

Crafts alkylation followed by dehydrogenation (Scheme 1).
oBenzene Styrene
(90-92%)
Scheme 1
A new synthesis developed by Chapman uses a single step to convert

mixed xylenes (compounds that are noncarcinogenic) into styrene. This new
method eliminates the use of ton quantities of benzene each year (details of
this process are not available).
15.3 Synthesis of Adipic Acid, Catechol and 3-Dehydroshikimic

Acid (a Potential Replacement for BHT)
Adipic acid is required in large quantities (about 1 billion kg a year) for the
synthesis of nylon, plasticizers and lubricants. Conventionally, adipic acid is
made from benzene (Scheme 2).
oBenzene
H2
NiorPt
~ 0
Cyclohexane
02
Catalyst
Cyclohexanone Cyclohexanol
HN0 3 ~
HOOC-(CH2)4-C00H + N20
Cu, HN4N03
Adipic acid
Scheme 2. Conventional synthesis of adipic acid
Like adipic acid, catechol is also manufactured using benzene as the starting
material. The procedure is given (Scheme 3).
As seen, both adipic acid and catechol are obtained from benzene, which
causes environmental and health problem. Also, benzene is produced from
non-renewable source. In addition, in the synthesis of adipic acid, nitrous
oxide is generated as a byproduct, which contributes to the greenhouse effect
as well as destruction of the ozone layer.
242 GREEN CHEMISTRY
H'OH' OR
0 6
CH 3-CH=CH 2
Propene
~ ~I °2 ~ ~
Friedel craft ~
alkylation
Cumene
(y0H
Benzene Phenol
OR OR
H 20
Catalyst
2
~
I~ ¢
Catechol
+
OR
Hydroquinone
Scheme 3. Conventional synthesis of catechol
BHT is obtained from toluene (which unlike benzene is not carcinogenic

but is toxic in nature) as shhown (Scheme 4).
¢ ¢
CH2
6
II CH3
CH'-C-CH'~
Cl 2
.. OH
.. isobutylene ~ -::? I
FeCI 2, S2CI 2 H2 O H2 S04 ~
Toluene CI OH OH
p-chloro
2
p-cresol BHT
101=, ~
CH3-CH=CH2
Propene
AICl) 0,
H3C CH3
p-cymene
Scheme 4. Conventional synthesis of BHT

An environmentally benign (or green) synthesis of adipic acid, catechol

and BHT (a potential replacement for BHT) has been developed by John W.
Frost and Karen M. Draths starting with glucose and using a biocatalyst
(genetically altered E. coli bacteria)1.2 (Scheme 5).
P' o
9H
..'",OH
OH
E.coli ~
(genetically altered)
o
Ii C0 2H
~ OH
OH OH OH
D-glucose 3-dehydroshikimi.: acid
0
HO~
H
-----. ~
:O~
__ -.~
HOOC'
~
'==/--
f OOH
cis, cis-muconic acid
--~~~
OH OH
Protocatechuic acid Catechol
(PCA)
Adipic acid
Scheme 5. Green synthesis of catechol and adipic acid
The above environmentally benign synthesis of catechol and adipic acid

uses D-glucose (a non-toxic and a renuable resource) as the starting material.
Also the synthesis is conducted in water instead of organic solvents. The
reaction can also be used to stop at either catechol stage or at the adipic acid
stage by using another genetically altered E. coli. 2
It may be appropriate to say that in the above synthesis, use of unmodified
E. coli gives the amino acids, L-phenylalanine, L-tyrosine and L-tryptophan
via the formation of shikimic acid from dehydroshikimic acid (Scheme 6).
15.4 Synthesis of Methyl Methacrylate

Methyl methacrylate is used in large quantities for manufacture of polymers.
It was earlier synthesised as shown in Scheme 7.
244 GREEN CHEMISTRY
~
COOH ~COOH ----+
D-Glucose - - . . . ~ ----+ --.
o OH HO OH ----+
OH OH L-Phenyl alanine
DHS Shikimic acid
OH L-Trytophan
L-Tyrosine
Scheme 6
HCN . . . .'OH
• CH3-C .......
I CN
Acetone CH3
Acetone Methyl methacrylate
cyanohydrin
Scheme 7. Conventional synthesis of methyl methacrylate
A very convenient synthesis of methyl methacrylate, developed by the

shell corporation is given (Scheme 8).
Pd
-----'... CHrC-COOCH3
II
Propyne CH 2
Methyl methacrylate
Scheme 8. New synthesis of methyl methacrylate

This new synthesis3 employs a palladium catalyst and enjoys 100% atom
economy compared to the conventional synthesis, which besides using an
extremely poisonous HeN enjoys only 47% atom recovery.
15.5 Synthesis of Urethane

Urethane is required in large quantities for the manufacture of polyurethanes,
a class of important polymers which are used for a number of commercial
applications.
Urethane was synthesised earlier using phosgene, an extremely hazardous
chemical (Scheme 9).
R'OH
RNH z + COClz -----,~~ RNCO + 2HCI ---l.~ RNHCOzR'
Amine Phosgene Isocyanate Urethane
Scheme 9. Synthesis of urethane using phosgene
Monsanto company has developed a method for the synthesis of urethanes,

eliminating the use of phosgene4 (Scheme 10).
R'OH
RNHz + COZ --~~ RNCO + HzO ----I.~ RNHCOzR'
Amine Carbon Isocyanate Urethane
dioxide
Scheme 10. New synthesis of urethane without using phosgene
15.6 An Environmentally Benign Synthesis of Aromatic Amines

The usual synthesis of aromatic amines involve chlorination of benzene
followed by nitration and nucleophilic displacement of the chlorine with a new
substitution group. This process is illustrated by the following synthesis
of 4-aminodiphenylamine (Scheme 11).
An environmentally benign synthesis of 4-aminodiphenylamine was
developed by Monsanto. 5 In this process, nitrobenzene and aniline are heated
in presence oftetramethyl ammonium hydroxide to give condensation products
as tetramethyl ammonium salts, which on catalytic hydrogenation give
4-aminodiphenylamine while regenerating tetramethyl ammonium hydroxide
(Scheme 12).
246 GREEN CHEMISTRY
<}N~•
6 ¢
Cl Cl
0Benzene
Cl 2
•
Chlorobenzene
HN0 3
•
N02
Catalyst
p-N itrochlorobenzene
o
Q
Catalyst
NH2
4-Nitrodiphenyl amine 4-Aminodiphenyl amine
Scheme 11. Conventional synthesis of 4-Aminodiphenyl amine
66
Nitrobenzene
+
Aniline
+ (CH 3)4NOH
+ ~
-H 2O
~
Q Q Q
Q ¢
N N
+ +
.- H2/Cat.
.-
¢
NH + (CH3)4NOH-
-H2O
o_..... N, 0- O-..... N
NH2
(CH3)~+ (CH3)4N+
4-Aminodiphenyl
amine
Scheme 12. Convenient synthesis of 4-Aminodiphenyl amine

The new process avoids the use of halogenated intermediates and also the
use of nitric acid and is atom economical.
15.7 Selective Alkylation of Active Methylene Group

The conventional alkylation of active methylene group employs the reaction of
alkyl halides using a base like sodium ethoxide. At times, this method results in
multiple alkylations (Scheme 13).
~
_Na_O---,C2,-H,-s.. R ~CH-CN
~_I
CH3
Scheme 13. Conventional alkylation of active methylene group
A convenient method developed by Tudo involves the use of dimethyl

carbonate in presence of potassium carbonate6 (Scheme 14).
180-220°C
Scheme 14
15.8 Free Radical Bromination

The usual free radical bromination of toluene with N-bromosuccinimide gives
benzyl bromide. This bromination is carried out in a solvent, e.g., CCl4 • It has
been found 7 that free radical bromination of toluene with NBS in supercritical
carbon dioxide gave 100% yield of benzyl bromide (Scheme 15).
hv, 40°C, NBS

CO 2(SC) / 139 bar
AIBN, 4 hr
Toluene Benzyl bromide
(100%)
Scheme 15
248 GREEN CHEMISTRY
However, bromination oftoluene with bromine in supercritical CO 2 gave

70% benzyl bromide and minor amount of p-bromotoluene (Scheme 16).
6 Toluene
hv, 40 °C, Br2
CO2(SC) 1 250 bar
K2C0 3, 5 min
.. 6 Q
Benzyl bromide
(> 70%)
lli
+
Br
p-Bromo toluene
(minor)
Scheme 16
15.9 Acetaldehyde
It was obtained commercially by catalytic oxidation of ethyl alcohol or by the
hydration of acetxlene (Scheme 17).
AgiAir/250°C
orCu 1300 °C
..
Scheme 17
It is most conveniently obtained by the Wacker-chemie's oxidation process.

In this process ethylene is oxidised with oxygen in presence of the catalyst
solution8 (Scheme 18).
CH 2=CH 2 +0 2
Pd(II)/Cu(II)
..
Scheme 18
The acetaldehyde formed is removed by distillation and the aqueous solution

containing the catalyst is reused for the next run.
For internal oletins, the Wacker oxidation is regioselective. Thus, oxidation
of p,y-unsaturated esters in aqueous dioxane or THF under appropriate
condition gives y-ketoester (Scheme 19).9
aq. dioxane 61 %
C0 2Me
o
Scheme 19
15.10 Furfural from Biomass

Furfural is an industrial chemical and is used for the manufacture of furfural-
phenol plastics. It is also used as solvent in refining of petroleum oils and in
the preparation of pyromucic acid.
Furfural is prepared industrially from pentosans which are contained in
cereal strains and brans. It is obtained in the laboratory from corncobs. 10
In fact, cellulosic biomass has been converted into useful products. II
The furfural formation is via a dehydration process. The mechanism from
D-xylose is given (Scheme 20).
CHO
I
~:
CH20H
D-xylose +-H 0
2
o
QCHO
Furfural
Scheme 20
15.11 Synthesis of(S)-metolachlor, an Optically Active Herbicide

In the field of pharmaceuticals and pesticides, the desired big activity of the
molecule is in a pure enantiomer (chiral molecule). This has been made possible
by using either enzymes or chiral metal complexes (asymmetric catalysts).12
These chiral metal complexes, though expensive, are important for industrial
application (i.e., have a high turnover frequency). A typical example is the
synthesis of (S)-me~olachlor, a herbicide. It is prepared by asymmetric
250 GREEN CHEMISTRY
hydrogenation of the prochiral imine catalysed by an iridium (I) complex of a

chiral ferrocenyldiphosphine1 3 (Scheme 21).
Meo
l "'~ M'~ ?,
~N H,(80 bar) NH CICH,COCI. ' L Q.... C""CI
JN
Ir (~yliphos) • ~
HOAC, 50°C, 4 hr IQJ
'LQJ
(8) (S)-metolachlor
80%ee
Xyliphos
~P1Q),
-~ ,
Scheme 21
15.12 Synthesis oflbuprofen

Ibuprofen is one of the products used in large quantities for making
pharmaceutical drugs, in particular various kinds of analgesics (pain killers).
The traditional commercial synthesis of ibuprofen was developed by the
Boots Company of England in 1960s (U.S. Patent 3,385,886). This synthesis
is given (Scheme 22).
CICH 2CO,C,H, •
NaOEt
Ibuprofen
Scheme 22
The given synthesis (Scheme 22) is a six step process and results in large
quantities of unwanted waste chemical byproducts that must be disposed of.
There is 40% atom economy in this synthesis.
The BHC company developed a new greener commercial synthesis of
ibuprofen that consists of only three steps14 (Scheme 23).
o
HF ~ ~H3
I ~ CH3 _R_an_e_y_N_ilH....,~.2
CHr C-O-C-CH3 .Q
0
" 0
II 3 HC
Scheme 23
The above synthesis results in only small amount of unwanted products

and has very good atom economy (77%).
15.13 Synthesis of Parae etamol

Paracetamol is used in broad spectrum of arthritic and rheumatic conditions
linked with musculoskeletal pain, headaches, neuralgias and dysmenorrhea. It
is generally prepared from p-nitrophenol by reduction (Sn + HCI) followed by
reaction with acetic anhydride-acetic acid mixture. Alternatively it is obtained
by the Beckmann rearrangement of oxime of p-hydroxyacetophenone.
In the green synthesis ofparacetamoPSp-hydroxyacetophenone is reacted
with ammonia and hydrogen peroxide in presence of titanium(IV)-silicate
(TS-I) catalyst 16 to give the oxime of p-hydroxyacetophenone. In fact, in the
above reaction, ammoximation proceeds via in situ formation of hydroxylamine
by titanium-catalysed oxidation of ammonia with HP2 in the micropores of
the catalyst. Final reaction of hydroxylamine with the ketone occurs in the
bulk solution. This methodology can be applied to any ketone or aldehyde for
the formation of oximes. Typical is in preparation of cyc1ohexanone oxime,
which is used in the manufacture of caprolactam via the Beckmann
rearrangement of the oxime.
The oxime of p-hydroxyacetophenone (obtained above) on Beckmann
rearrangement gives paracetamol (Scheme 24).
252 GREEN CHEMISTRY
~CHl TS-J
HoM
p-Hydroxy
acetophenone
HoM
if:Hl w~
HO
Nr
0
NHCOCH3
Oxime of Paracetamol
p-hydroxy acetophenone
Scheme 24
15.14 Green Synthesis of3-phenyl Catechol

The 3-substituted catechols are important building blocks for the chemical
and pharmaceutical industries. Their chemical synthesis is cumbersome,
requiring organometallic reagents, HBr etc. An industrial green synthesis of
3-phenyl catechol consist in the transformation of 2-phenyl phenol (a man
made compound that has been widely used as a food protecting agent and as
a germicide) into 3-phenylcatechol by a 2-hydroxybiphenyI3-monooxygenase '7
(Scheme 25).
2-hyd,.,ybiph"yl
-:---------.~
3-monooxygenase
HO~o~H C 6 HS
2-Phenylphenol 3-PhenyIcatechol
Scheme 25
This enzyme has the potential for the synthesis of3-substituted catechols.
However, this strain could not be used for the synthesis of catechol.
15.15 Synthesis of Epoxystyrene

Styrene epoxide is a valuable building block and is used in the production of
the antihelmintic drug Levamisole. 18 The styrene epoxide for the synthesis of
drugs must be enantiopure. There are some chemical asymmetric synthetic
routes l9 but the yields are only in the range 45-50%.
A very convenient green synthesis of epoxystyrene has been developed.
It consist of the reaction of styrene with xylene mono oxygenase, which
introduces an epoxide in the vinyl double bond of styrene 20 (Scheme 26).
E. coli recombinants carrying only

xylene monooxygenase system
Styrene Styrene oxide

S 96%
R 4%
Scheme 26
15.16 Synthesis of CitraI

Citral is a valuable intermediate for the production of fragrances (like u- and
~-ionones) and also for building units for carotenoids and vitamin A. The
conventional industrial method using ~-pinene as the starting material requires
chlorine as oxidatant and involves five steps and the yields are low.
In the new BASF route, the cheap starting materials isobutene and
formaldehyde are made to react to form isoprenol (3-methyl-but-3-en-l-ol).
A part of this is isomerized and the other part is oxidised to the corresponding
aldehyde 21 (Scheme 27).
.------"-[O.-:...~- . ~CHO
3-methyl-3-butanal
>=CH2 + H2C O - ~ (isoprenal)
Isobutene Formaldehyde ~ OH
(isoprenol) isomerisation I
3-methyl-but-3-en-l-ol ~OH
3-methyl-but-2-en-l-ol
Scheme 27
The 3-methyl-3-butanal and 3-methyl-but-2-en-l-ol thus formed, react to

form citral in 95% overall yield (Scheme 28).
254 GREEN CHEMISTRY
citral
Scheme 28
15.17 Synthesis of Nicotinic Acid

Nicotinic acid is an important intermediate for pharmaceuticals and serves as
a provitamin in food additives for animal feeding. It is produced by the Lonza
process (involving oxidation of 2-methyl-5-ethyl pyridine using nitric acid)22
or by the Degussa process. 23 The latter process involved hydrolysis of P-
cyanopyridine, which in turn was produced by amminoxidation of P-picoline. 24
A third process involving selective vapour phase oxidation of P-picoline
catalysed by vanadium titanium oxide catalyst has also been described. 25
A convenient process involving direct oxidation of p-picoline has been
developed for the synthesis of nicotinic acid. 26
15.18 Use of Molting Accelerators to Replace More Toxic and

Harmful Insecticides
A number of insecticides have been used to control crop-destroying insects.
Some of the common class of insecticides in use are organochlorines,
organophosphates and carbamates. The well known DDT, which was in use
for the maximum period of time, is now known to be toxic to humans and
other non-target organisms. 27 The organophosphates and carbamates are less
persistent in the environment and are not readily incorporated into the food
chain as organochlorine insecticides (like aldrin, dieldrin and DDT). The
organophosphate and carbamates are not bioaccumulated (like DDT etc.), but
they readily decompose in the environment and tend to be more toxic to humans
and other non-target organisms. However, these are readily decomposed to
nontoxic products by reaction with water.
Both, the organophosphates and carbamates, work by inhibiting the
acetylcholinesterase enzyme in insects and thus cause failure of the nervous
system. These can also inhibit acetylcholinesterase enzyme in mammals (just
as they do in insects). Hence, organophosphates and carbamates are toxic to
humans and other mammals, as they also kill non-target insects, which are
beneficial.
A new class of insecticides, viz. diacetylhydrazines have been developed
by Room and Haas. This company uses tebufenozide as the active ingredient,
which control caterpillars. Two other members in this series, halofenozide

and methoxyfenozide have also been developed (Scheme 29).
0+
~J5
N 0
I NH
~ ~
I~
Tebufenozide Halofenozide
Scheme 29
For more details refer to real-world cases in green chemistry.28
15.19 An Environmentally Safe Marine Antifoulant

The antifouling agents are used on boat hulls to reduce the build up of marine
organisms (such as barnacles, algae, plants and diatoms). A build up of these
organism causes additional costs involved in increased fuel consumption and
cleaning time. Tributyltin (TBT) compounds were earlier used as antifoulant
agents. One of the main drawbacks was their persistence in the environment
and bioaccumulation in various nontargent marine organisms. 29
Rohm and Haas has developed the use of 4,5-dichloro-2-n-octyl-4-
isothiazolin-3-one (DCOI) as an antifouling agent. 28
Unlike tributyltinoxide (TBTO), the DCOI is far less persistent in marine

environments. Also in the case of DCOI, the product of the metabolism
256 GREEN CHEMISTRY
(Scheme 30) are non-toxic. 28
Cl):;S\
1
_ H17Cs':;NH0
- - - - l.... H17 C{
NH~O
I ..
N, HO CH3
Cl (CH 2hCH 3
o 0
DC 01
- - - - i..... H17C{
NH
Y 0
OH
Scheme 30. Metabolic products of DCOI
References
1. M. Karen Draths, W. John Frost, Environmentally Compatible Synthesis of Adipic

Acid from D-Glucose, J. Arn. Chern. Soc., 1994,116,399-400.
2. T. Paul Anastas, C. Tracy Williamson, Eds., Green Chemistry: Frontiers in Benign
Chemical Synthesis and Processes, Oxford University Press, New York, 1998.
3. A. Roger Sheldon, Catalyst and Pollution Prevention, Chern. Ind., 1997, 12-15.
4. W.D. McGhee and D.P. Riley, Organometallics II, 1993,900-907; W.D. McGhee,
D.P. Riley, M.E. Chrost and K.M. Christ, Organornetallics, 1993, 12, 1429-1433;
D.P. Riley, Y. Pan and D.D. Riley, J. Chern. Soc. Chern. Cornrnun., 1994,699-700;
T.E. Waldman, D.P. RileY,J. Chern. Soc. Chern. Cornrnun., 1994,957-958.
5. M.K. Stem, F.D. Hileman and lK. Bashkin, J. Arn. Chern. Soc., 1992,114,9237-8;
M.K. Stem and B.K. Cheng,.!. Org. Chern., 1993,58,6883-8; M.K. Stem, B.K. Cheny,
F.D. Mileman and lM. Allman,.!. Org. Chern., 1994, 59, 5627-32.
6. P. Tundo, F. Trotta and G. Moraglio,.!. Org. Chern., 1987,52, 1300; P. Tundo, F. Trotta,
G. Moraglio and F. Ligorati, Ind. Eng. Chern. Res., 1998, 27, 1565; P. Tundo, F. Trotta
and G. Moraglio,.!. Chern. Soc. Perkin Trans. 1, 1989, 1070; P. Tundo and M. Selven,
Cherntech.,1995,31-35.
7. lM. Tanko, R.H. Mas and N.K. Suleman, J. Arn. Chern. Soc., 1990, 112, 5557;
lM. Tanko, N.K. Suleman, G.A. Hulvey, A. Park and lE. Powers, J. Arn. Chern. Soc.,
1993, 115, 4520-26; lM. Tanko and N.K. Suleman,.!. Arn. Chern. Soc., 1994, 116,
5112-6; lM. Tanko and IF. Blackert, Science, 1994,263,203-5.
8. l Smidt, W. Hafner, R. Jira, R. Sieber, l Sedlmeer and A. Sabel, Angew. Chern. Int. Ed.
Engl., 1962, 1,80.
9. lK. Stille and R Divakaruni,.!. Arn. Chern. Soc., 1978, 100, 1303.
10. R Adams and V. Voorhees, Org. Syn. Call., 1941,1,280.
11. For a review, see O. Theander and D. Nelson, Adv. Carbohydr. Chern. Biochern., 1988,
46,273; F. Hoppe-Seyler, Ber., 1871,4, 15; M.S. Feather, Tetrahedron Lett., 1970,
4143; H.S. Ibell,J. Res. Natt. Bur. Stand., 1994,32,45.
12. RA. Sheldon, Chriotechnology: The industrial synthesis of optically active compounds,
Marcel Dekker, New York, 1993.
Synthesis Invoiving Basic Principles of Green Chemistry 257
13. H.U. Blaser and F. Spindler, Topics in Catalysis, 1998,5,275.

14. U.S. Patents, 4,981,995 and 5,068,448; 1991.
15.1. Le Bars, 1. Dakkaand R.A. Sheldon, Appl. Cata!' A. General, 1966,136,69.
16. B. Notari, Stud. Surt. Sci. Catal., 1988,37,413.
17. W.A. Suske, M. Held, A. Schmid, T. Fluschmann, M.G. Wubbolts and H.P.E. Kohler,
J. Bioi. Chern., 1997,227,24257; A. Schmid, H.P.E. Kohler and K.H. Engesser,J. Mol.
Catalysis, 1998, 5, 311.
18. 1. Hasegawa and T. Ohashi, Chemistry Today, 1996, 44.
19. M. Tokunaga, 1.F. Larrow, F. Kakuichi and E.N. Jacobsen, Science, 1997,277,936;
M.G. Wubbolts, J. Hoven, B. Melgert and B. Witholt, Enzyme and Microbial Technology,
1994,16,887.
20. M.G. Wubbolts, P. Reuvekamp and B. Witholt, Enzyme Microbial Technology, 1994,16,
608.
21. W.F. Hoelderich, Stud. Surf Sci. Cata!., 1993,75,127; W. Aquita, H. Fuchs, O. Worz,
W. Ruppel and K. Halbritter, u.s. 6013 843, 2000.
22. A. Stocker, O. Marti, T. Pfammatter, G. Schreiner and S. Brander, DE 2046566, 1970.
23. H. Beschke, H. Friedrich, K.P. Muller and G. Schreyer, DE 2517 054, 1975.
24. T. Lussling, H. Schaefer and W. Weigert, DE 1948 715, 1969.
25. S. Jaras and S.T. Lundin,J. Appl. Chern. Biotechnol., 1977,27,499; R. Yokoyama and
S. Sawada, u.s. 3803156,1969; M. Gasier, J. Haber and T. Macheg,Appl. Catal., 1987,
33,1.
26. W.F. Foelderich and F. Kollmer, Pure Appl. Chern., 2000, 72, 1273 and the references
cited therein.
27. Colin Baird, Environmental Chemistry, 2nd edn., w.H. Freeman, New York, 1999.
28. For more details refer to real world cases in Green Chemistry, Michael C. Cann and More
E. Cannelly, American Chemical Society, 2000 (ISBN 0-8412-37336).
29. A. Rouhi, Chern. Eng. News, 1998,41-42.
Suggested Readings
1. Green Chemistry, Theory and Practice, Paul T. Anastas and John C. Warner,
Oxford University Press, 1998, New York, USA.
2. Real-World Cases in Green Chemistry, Michael C. Cann, Mare E. Connelly,
American Chemical Society, 2000.
3. Green Chemical Synthesis and Processes, Paul T. Anastas, Luren G. Heine and
Tracy C. Williamson (Editors), ACS Publication 2000.
4. Green Chemistry in India, M. Kidwai, Pure and Applied Chmistry, Vol. 73, No.8,
1261-1263,2001.
5. Pure and Applied Chemistry, Special Topic Issued on Green Chemistry, IUPAC,
Vol. 72, No.7, July 2000.
6. Organic Synthesis: Speical Techniques, V. K. Ahluwalia and Renu Aggarwal,
Narosa Publishing House, 2001, New Delhi.
7. Green Chemistry: An Introductory Text, Mike Lancaster, Green Chemistry
Network, University of York, RSC, 2002.
8. Green Chemistry in Indian Context: Challenges Mandates and Chances of
Success, Upasana Bora, Mihir K. Chaudhri and Sanjay K. Dehury, Current Science,
Vol. 82,1427,2002.
9. Organic Synthesis in Water, Paul A. Grieco (Editor), Blackie Academic and
Professional, London, UK.
10. Organic Reactions in Aqueous Media, CHAU-JUN Li and TAK-Hang Chan,
John Wiley & Sons Inc., New York.
Index
Acetaldehyde 248 Aspergillus ochraceus 94

Acetylenes 119 Aspergillus tamarii 94
Acid catalysts 27 Asymmetric Michael addition 120
Acidic ionic liquids 233 Aziridines 46,210,214
Active methylene compounds 68 Azoles 219
Active methylene group 247 Azomethines 209
N-Acylamino acids 103
Baeyer's test 136
Addition reactions 7,76
Baeyer-Villigeroxidation 94,141
S-Adenosylhomocysteine 104
Baeyer-Villiger reaction 96
Adipic acid 241
Baker's yeast 100
Adiponitrile 170
Basic Catalysts 30
Alcohols 62
Beckmann rearrangement 201
Aldehydes 46,140
Benzalacetophenone 127
Aldol condensation 120, 195
Benzamide 61
Aliquat 336 40
Benzil-Benzilic acid rearrangement 201
Alkenes 139
Benzoin condensation 126
3-Alkyl coumarins 49
Benzyl chloride 61
Alkyl fluorides 42
Benzyl tributyl ammonium chloride 40
Alkylation(s) 56, 68, 77
Benzyl triethyl ammonium chloride 40
C-Alkylation(s) 45, 77
Benzyl trimethyl ammonium chloride 40
N-Alkylation 46, 77, 236
Benzyl triphenyl phosphonium iodide 40
O-Alkylation 77,236
Biocatalysis 31, 88
S-Alkylation 47
Biocatalytic conversions 88
Alkynes 140
Biochemical (microbial) oxidations 90
Allylrethrone 119
Biodegradable 12,159
Amines 143,200
Biomass 249
Analytical techniques 14
Bouveault reaction 83
Anhydride(s) 52, 69
Bromoorganics 35
Anti dihydroxylation 138
t-butyl hydroperoxide 134
Antifouling agent 255
By-products 5
L-Arginine 104
Aromatic amines 245 Cannizaro reaction 84
3-Aryl-2H-l, 4-Benzoxazines 50 Capsacin 166
Ascorbic acid 11 9 Carbene 54
Aspartic acid 104 Carbonyl compounds 152
Aspergillus niger 100 Carbonylation 173
260 Index
(-)-Carvone 149 syn-Dihydroxylation 136

Carvotanacetone 149 Dimethylcarbonate 21
Catalyst(s) 2,11,27 Disodium iminodiacetate (DSIDA) 131
Catechol 241 Displacement reaction 54
Cetyl trimethyl ammonium chloride 40 Disulphides 211
Chalcones 65 Dry cleaning 15
Chalkones 136
Electrochemical reactions 171
Chapmann rearrangement 202
Electrochemical synthesis 169
Chemoselective oxidation 141
Elimination reaction(s) 8,44,54
Chlorofluorocarbons 3, 18
Emulsion polymerisation 160
I-Chlorooctane 40
Enantioselective hydrogenation 153
m-Chloroperbenzoic acid 142
Enantioselective Michael addition 192
Cholesterol 94
Energy requirements 9
Chromenes 86
Environment pollution 19
Cigarette beetle 100
Enzymatic reductions 99
Cinnamaldehyde 127
Enzymes 88
Citral 253
Epoxidation 133
L-Citraline 104
Epoxystyrene 253
Claisen rearrangement 113, 189
Esterification 51,64,74
Claisen-Schmidt condensation 127
Ethers 212
Clayzic 28
Exhaust emissions 20
Coumarins 222
Coupling reaction(s) 81,126,203 Fenestrene aldehyde 114
18-Crown-6 51 Ferricyanide 147
Crown ethers 31, 51 Flavones 49
3-Cyanocoumarins 124 Free radical bromination 247
l-Cyanooctane 40 Friedel-Crafts reaction(s) 28, 82
1,2-Cyclooctane diol 138 Fries rearrangement 64
Cyclooctene 138 [60] Fullerene 205
Cyclopropane derivatives 209 Fumaric acid 104
Furan 217
Dakin reaction 141
Furfural 249
Darzen's reaction 47
Deacetylation 67 Geotrichum candidum 100
Decanoic acid 150 Gibberellafujikuroi 94
Decarboxylation 66 Green catalysts 27
Dehydration 194 Green solvents 232
3-Dehydroshikimic acid 241 Greenhouse gas 19
Deprotection 67 Grignard reaction 196
Designing a green synthesis 2
Dieckmann condensation 196 Halofenozide 255
Dielectric constant 60 Halogenation 189
Diels-Alderreaction 65,82,109,113,235 Hazardous products 8
Dihalocarbenes 42 Heck reaction 129,236
(+)-Dihydro carvone 149 Hetero-Diels-Alder reaction 112
Index 261
Hofmann elimination 61 (S)-Metolachlor 249

Homoallylic alcohols 209 Meyer-Schuster rearrangement 202
Homologation 177 Michael addition 191
Horse liver dehydrogenase 96 Michael reaction 117
Horseradish peroxidase 97 Microencapsulated Lewis acids 27
Hydroboration 80 Microwave-assisted reactions 61
Hydroformylation 176 Microwaves 59
Hydrogen peroxide 50, 137 Monomers 158
Hydrogenations 235 Montmorillonite KIO clay 70
Hydrogenolysis 157 Montreal Protocol 18
Hydrohalogenation 191 Mukaiyama reaction 121, 128
Hydrolases 89 Mushroom polyphenol oxidase 97
Hydrolysis 61, 74
lla-Hydroxyprogesterone 94 Neutral ionic liquids 235
Hypochlorite 147 Nicotinic acid 254
Nitration 199
Ibuprofen 250 Nitriles 41,45,68,119,144
Imidazoles 218 o-Nitrochalcones 179
Indoles 179 Nitro compounds 143, 144
Intramolecular aza-Diels-Alder 3,8-Nonadienoic acid 150
reaction 112 3-Nonenoic acid 150
Ionic liquids 232 Nuclear bromination 198
Isomerases 90
Isomerisation of alkenes 172 Oesterone 94
Isooctane 36 Orthoester claisen rearrangement 65
Osmium tetroxide 137
Ketones 46
Oxadiazines 225
Knoevenagel reaction 123
Oxazolidines 208
p-Lactams 46,215 Oxidation(s) 78, 132
Ligases 90 Oxidation catalysts 29
Lung cancer 17 Oxidative coupling 205
Lyases 89 Oxidoreductases 88
Oxirazies 210
Malic acid 104
Mandelic acids 43 Paracetamol 251
Manicone 128 Patemo-Buchi reaction 162
Mannich type reactions 178 Payne's reaction 136
Mannitol 171 Penacylase 88
Manufacturing plants 13 Penicillium chrysogenum 94
Mesotastaric acids 104 Peracids 141
7-Methoxyfenozide 255 Performic acid 140
Methyl methacrylate 243 Phase transfer catalysis 31, 40
Methylbenzoate 63 Phenylacetate 142
Methylene Insertion 237 3-Phenyl catechol 252
17-Methyltestosterone 94 L-Phenylalanine 104
262 Index
5-Phospho-D-ribosyl-I-pyropho- Pyrrole 217

sphate 105
Photo fries rearrangements 163 Quinoline(s) 179,223
Photocatalysis 31
Photocatalyst 34 Reagents 2
Photochemical oxidative dimerisation 166 Rearrangement reactions 6
Photochemical reactions 162 Recycling of polymers 158
Photo irradiation 164 Reduction(s) 70,78, 148
Pinacol coupling 125,204 Reductive dehalogenation 156
Pinacol-Pinacolone rearrangement 200 Reforrnatsky reaction 84, 197
a-Pinene 53 Regioselective epoxidation 134
Pinonic acid 53 Rhizopus nigrioans 94
Polycarbonates 159 Rose-Bengal 33
Polymer supported catalysts 31
Saccharomyces cerevisiae 100
Polymer supported chromic acid 22
Safer chemicals 9
Polymer supported peptide
Samarium iodide 153
coupling agent 26
Saponification 51,63,68,74
Polymer supported peracids 22
Sebacic acid 171
Polymer supported phase
Sepedonium ampullosporium 94
transfer catalysts 33
Sharpless dihydroxylation 138
Polymer supported photo sensitizers 33
[3,3]-Sigmatropic rearrangement 113
Polymer supported reagents 22
Simmons-Smith reaction 82
Polymeric organotin dihydride reagent 24
Sodium borohydride 70, 152
Polymeric phenylthiomethyl
Sodium percarbonate 141
lithium reagent 25
Solid phase organic synthesis 189
Polymeric super acid catalysts 32
Solid state reactions 66
Polymeric thioanisolyl resin 22
Solid support reagents 34
Polymerisation reactions 158
Solid supported organic
Polymers 158
synthesis 189,213
Poly-N-bromosuccinimide (PNBS) 22
Solvent(s) 3,9
Polystyrene anhydride 24
Sonochemistry 73
Polystyrene carbodiimide 24
Sorbitol 171
Polystyrene Wittig reagent 25
Starting materials 2, 10
Polystyrene-aluminium chloride 32
Stereoselective aldol condensation 121
Polystyrene-metalloporphyrins 32
Strecker synthesis 84, 131
Potassium hydroxide 51
Styrene 240
Potassium perrnanganate 52
Substitution reaction(s) 7,53,75
9p-10a-Pregna-4,6-diene-3,20-dione 94
(S)-(+)-SuIcatol 100
Prelog'srule 99,100
Sulfonazide polymer 24
Progesterone 94
Sulphides 145
Protecting groups 10
Sulphur ylides 48
Pyrazoles 217
Pyridines 222 Supercritical CO 2 fluid 3
Pyridinium fluorochromate (PFC) 35 Superoxide 55
Pyrimidines 224 Synthesis in solid state 189
Index 263
Tebufenozide 255 Versatile bleaching agent 15

Testololactone 94 Vic-dibromoalkanes 44
Tetra-n-butyl ammonium chloride 40 Vinylidene carbenes 44
Thermoanaerobium brockii 100
Weiss-Cook reaction 178
Thiadiazepines 227
Wieland-Miescher ketone 118
Thiocarbonylimidazolide derivatives 212
Williamson ether synthesis 48
Toluene 62
Wittig reaction 48, 197
Transferases 89
Wittig-Horner reaction 116
Truxillic acid 167
Wurtz reaction 132
l3-truxinic acid 167
Ytterbium triflate [yb(OTf)31 118
Ullmann's coupling 81
Ultrasound 73 Zeolites 28
Urethane 245 Zn-Cu couple 125

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Organic chemistry has played a vital role in the development of diverse

PROF. JAVED IQBAL, PhD, FNA

Organic chemistry dealS' with the synthesis of molecules having diverse

2. Designing a Green Synthesis 2

3. Basic Principles of Green Chemistry 5

4. Green Chemistry in Day-to-Day Life 15

8. Phase Transfer Catalysis in Green Synthesis 39

9. Microwave Induced Green Synthesis 59

9.2.3 Microwave Solvent Free Reactions (Solid State Reactions) 66

10. Ultrasound Assisted Green Synthesis 73

11. Biocatalysts in Organic Synthesis 88

12. Aqueous Phase Reactions 108

12.18 Electrochemical Synthesis 169

13. Organic Synthesis in Solid State 189

Synthesis of Thiocarbonylimidazolide Derivatives 212

14. Versatile Ionic Liquids as Green Solvents 232

15. Synthesis Involving Basic Principles of

15.10 Furfural from Biomass 249

Suggested Readings 259

2.1 Choice of Starting Materials

2.2 Choice of Reagents

2.3 Choice of Catalysts

out the required chemical transformation should be explored. Certain

2.4 Choice of Solvents

A versatile solvent, ionic-liquid for carrying out reactions is discussed in

Green chemistry is defined as environmentally benign chemical synthesis.

3.1 Prevention ofWaste/By-Products

3.2 Maximum Incorporation ofthe Reactants (Starting Materials

3.2.1 Rearrangement Reactions

HC~ /CH ~CH

3.2.2 Addition Reactions

3.2.3 Substitution Reactions

Ethyl propionate Methyl amine Propionamide Ethyl alcohol

Reactants Utilised Unutilised

Total C 6 H 1S N0 2 133.189 C 4 H 9 NO 87.106 C 2HpH 46.069

The elimination reaction is not very atom-economical. The percentage

This dehydrohalogenation (an elimination reaction) is also not very atom-

3.3 Prevention or Minimization of Hazardous Products

controls, respirator etc. This, however, adds to the cost of production. It is

3.4 Designing Safer Chemicals

3.5 Energy Requirements for Synthesis

3.6 Selection of Appropriate Solvent

carried out on the use of immobilised solvents. The immobilised solvent

3.7 Selection of Starting Materials

3.8 Use of Protecting Groups

Reactions of this type are common in the synthesis of fine chemicals,

3.9 Use of Catalyst

(i) Better yields. Hydrogenation or reduction of ole fins in presence of nickel

(iii) Selectivity enhancement

H3C-C=CH + H2 Pd-BaSO. .. H3 C- CH=CH2

Selectivity in C-methylation versus O-methylation

In addition to the above mentioned beneficial use of catalysts, there is significant

3.10 Products Designed Should be Biodegradable