Handbook of Green Chemistry. Green Processes. Volume 7: Green Synthesis

Contents
About the Editors XIII
List of Contributors XV
Preface XIX
1 Atom Economy: a Challenge for Enhanced Synthetic Efficiency 1
1.1 Vinylidenes 2
1.1.1 Cycloisomerization of Hydroxyalkynes 2
1.1.2 Reconstitutive Condensation 6
1.2 Redox Isomerization 7
1.2.1 Allyl Alcohols 7
1.3 Ruthenacyclopentadiene Intermediates 9
1.4 Ruthenacyclopentene Intermediates 13
1.4.1 Intermolecular Alkene-Alkyne Coupling 13
1.4.2 Butenolide Formation and Related Reactions 16
1.4.3 Pyran Formation 17
1.4.4 Intramolecular Alkene–Alkyne Coupling 19
1.4.5 [5 þ 2] Cycloaddition 19
1.4.6 Vinyl Ketones as Alkyne Partners 21
1.5 Allylic C– H Insertion 22
1.6 Reactions of Alkenes 24
1.6.1 Allene–Alkene Coupling 24
1.6.2 Heterocycles via Allene–Alkene Coupling 27
1.7 Conclusion 28
References 29
2 Evaluating the Greenness of Synthesis 35
2.1 General Considerations About Green Chemistry and Green Engineering Metrics 35
2.2 Selected Metrics Used in the Past 37
2.2.1 Yield 37
2.2.1.1 Effective Mass Yield 37
2.2.2 E-Factor 38
2.2.3 Atom Economy 39
2.2.3.1 Key Assumptions About Atom Economy 40
2.2.3.2 How Atom Economy Is calculated 41
2.3 Reaction Mass Efficiency 42
2.4 Mass Intensity and Mass Productivity (Mass Efficiency) 43
2.5 Cost Implications and Green Chemistry Metrics 47
2.6 Life-Cycle Assessment Metrics 49
2.7 Process Metrics 50
2.7.1 Materials 52
2.7.1.1 Physical Form and Properties 52
2.7.1.2 Mass 52
2.7.1.3 Inherent Hazard 53
2.7.1.4 Cost 54
2.7.1.5 Renewability 54
2.7.1.6 Recyclability 55
2.7.2 Equipment and Operability Intertwined 55
2.7.2.1 Type and Number of Unit Operations 56
2.7.2.2 Size of Unit Operations 56
2.7.2.3 Scalability 56
2.7.2.4 Controllability 57
2.7.2.5 Robustness 58
2.7.2.6 Throughput/Cycle Time 58
2.7.2.7 Energy 59
2.7.2.8 Cleaning and Maintenance 60
2.7.3 EHS Hazards and Risk 61
2.7.3.1 Occupational Exposure Hazards and Risk 62
2.7.3.2 Process Safety Hazards Risk 63
2.7.3.3 Environmental Hazards and Risk 63
2.7.4 Quality 64
2.7.4.1 Purity 64
2.8 Conclusions 65
References 65
3 Alternative Feedstocks for Synthesis 69
3.1 Introduction 69
3.1.1 Renewable Resources as Natural Feedstock 69
3.1.2 Challenges of Using Renewable Resources 70
3.2 Carbohydrates 71
3.2.1 Polysaccharides 71
3.2.1.1 Cellulose 71
3.2.1.2 Starch 72
3.2.2 Disaccharides 73
3.2.2.1 Sucrose 74
3.2.2.2 Lactose 74
3.2.3 Monosaccharides 74
3.2.3.1 D-Glucose 75
3.2.3.2 D-Fructose 75
3.3 Lignin 76
3.4 Fats and Oils 77
3.4.1 Catalytic Derivatization of Unsaturated Fatty Compounds 78
3.4.1.1 Selective Catalytic Hydrogenation 79
3.4.1.2 Selective CC Linkage Reactions 80
3.4.1.3 CN Linkage Reactions 80
3.4.1.4 CO Linkage Reactions 81
3.4.2 Glycerol 82
3.4.2.1 Glycerol Esters 83
3.4.2.2 Etherification 83
3.4.2.3 Glycerol Oxidation and Dehydration 84
3.5 Terpenes 85
3.6 Carbon Dioxide 87
3.6.1 Reactions with Alkanes, Alkenes, and Dienes 88
3.6.2 Conversion to Formic Acid and Dimethylformamide 89
3.6.3 Plasma Activation of Carbon Dioxide 89
References 90
4 Synthesis in Green Solvents 93
4.1 The Role of Solvents in Synthesis 93
4.2 Types of Solvent 94
4.2.1 Atomic Liquids 94
4.2.2 Molecular Liquids 94
4.2.3 Ionic Liquids 95
4.2.4 Solvent Polarity 95
4.2.5 Protic Solvents 96
4.3 Problems with Solvents 96
4.4 Application of Green Solvents 96
4.4.1 Water 96
4.4.2 Fluorous Solvents 102
4.4.3 Supercritical Carbon Dioxide 107
4.4.4 Ionic Liquids 112
4.5 Conclusion 117
References 117
5 Development and Application of Isocyanide-based Multicomponent Reactions 121
5.1 Introduction 121
5.2 Basic Principle of MCRs 124
5.3 Discovering Novel MCRs 125
5.3.1 Union Concept 127
5.3.2 Rational Substrate Design 127
5.3.3 Mechanism-Based Design 137
5.3.3.1 ‘‘ Split-Ugi’’ Reaction 137
5.3.3.2 Ugi–Smiles 4CR 139
5.3.3.3 Activation of Imines by Other Electrophiles 140
5.3.4 Serendipity 142
5.4 MCRs Imitated by Addition of Isocyanides to Alkynes 144
5.5 Metal-Catalyzed IMCRs 146
5.6 Enantioselective P-3CR 149
5.7 Application in Medicinal Chemistry and in Natural Product Synthesis 151
5.8 Conclusion 152
References 152
6 Flow Syntheses 159
6.1 Introduction 159
6.1.1 Continuous Flow Reactors: What Are They and How are They Used? 159
6.2 Examples of Their Use as Tools for the Research Chemist 160
6.2.1 Liquid Phase 160
6.2.1.1 Solvent Free 160
6.2.1.2 Liquid– Liquid Phase 163
6.2.1.3 Elevated Reaction Temperatures 164
6.2.1.4 Reduced Reaction Temperatures 174
6.2.2 Solid– Liquid Phase 176
6.2.2.1 Solid-Supported Catalysts 177
6.2.2.2 Solid-Supported Reagents 185
6.2.2.3 Solid-Supported Scavengers 190
6.2.3 Gas– Liquid Phase 190
6.2.4 Gas– Liquid–Solid Phase 191
6.2.5 Biocatalysis 194
6.2.5.1 Liquid Phase 194
6.2.5.2 Immobilized Biocatalytic Flow Reactors 197
6.2.6 Photochemistry 199
6.2.6.1 Homogeneous Photochemical Reactions 199
6.2.6.2 Heterogeneous Photochemical Reactions 202
6.3 Process Intensifi cation Achieved Through the Use of Flow Reactors 204
6.3.1 Synthesis of Azo Dyes 205
6.3.2 Synthesis of Ionic Liquids Under Continuous Flow 206
6.3.3 DSM Nitration 207
6.3.4 Synthesis of Rimonabant 208
6.3.5 Biocatalytic Synthesis of Vitamin A 209
6.4 Conclusions and Outlook 210
References 210
7 Synthesis Without Protecting Groups 215
7.1 The Present Use of Protecting Groups 215
7.2 Protecting Group-Free Synthesis? 218
7.3 Use of In Situ Protections in Lieu of Short-Term Protecting Groups 220
7.4 Follow Nature\'s Biogenetic Routes to Avoid Protecting Groups 221
7.5 Apply Functional Group-Tolerant Construction Reactions to Avoid Protecting Groups 224
7.6 Aim for Higher Chemoselectivity to Avoid Protecting Groups 224
7.7 Change the Order of Synthesis Steps to Avoid Protecting Groups 227
7.8 Enlist Latent Functionality to Avoid Explicit Protecting Group Steps 229
7.9 Summary 231
References 233
8 Biological Synthesis of Pharmaceuticals 237
8.1 Introduction 237
8.2 New Enzymes for Chemical Synthesis 237
8.2.1 Enzymatic Halogenation 238
8.2.2 Macrocyclization 239
8.2.3 Glycosylation 241
8.2.4 Heterocyclization 242
8.2.5 Methylation 243
8.2.6 Oxygenation 244
8.3 Synthesis of Pharmaceuticals via Isolated Enzymes 244
8.3.1 Penicillins and Cephalosporins 244
8.3.2 Pregabalin 246
8.3.3 Atorvastatin 247
8.3.4 Levetiracetam 248
8.4 Synthesis of Pharmaceuticals via Whole Cells 249
8.4.1 Paclitaxel 249
8.4.2 Epothilones 251
8.4.3 Oseltamivir 251
8.4.4 Avermectins 252
8.5 Conclusion 254
References 255
9 Syntheses via C–H Bond Functionalizations 259
9.1 Introduction 259
9.2 Direct Arylations of Arenes 261
9.2.1 ‘‘ Green’’ Aspects of Direct Arylation of Aryl C– H Bonds 264
9.2.2 Chelation-Assisted Direct Arylations of Arenes 265
9.2.3 Non-Directed Direct Arylations of Arenes 275
9.2.4 Direct Arylations of Heteroarenes 279
9.2.4.1 Direct Arylations of Electron-Defi cient Heteroarenes 279
9.2.4.2 Direct Arylations of Electron-Rich Heteroarenes 280
9.3 Catalytic Oxidative Arylations of (Hetero)arenes 293
9.3.1 Introduction 293
9.3.2 Oxidative Homocouplings 295
9.3.3 Cross-Dehydrogenative Arylations 296
9.4 Conclusion 298
References 298
10 Synthesis Without Metals 307
10.1 Introduction 307
10.2 Organic Reactions Promoted by Non-Metallic Catalysts 308
10.3 Asymmetric Organocatalysts 311
10.3.1 Introduction 311
10.3.2 Classification by Reaction Types 312
10.3.2.1 Covalent Organocatalysis 312
10.3.2.2 Non-Covalent Organocatalysis 312
10.3.3 Organocatalysts 312
10.3.3.1 Cinchona Alkaloids and Derivatives 312
10.3.3.2 Proline Derivatives and MacMillan’s Catalyst 313
10.3.3.3 Peptide Catalysts 318
10.3.3.4 Ketone Catalysts 319
10.3.3.5 Phase-Transfer Catalysts 319
10.3.3.6 Amine Catalysts 320
10.3.3.7 Guanidinium Salts 321
10.3.3.8 Hydrogen Bond Catalysts 321
10.3.3.9 Stronger Brønsted Acid Catalysts 324
10.3.3.10 Counteranion Catalysis 329
10.4 Conclusion 330
References 331
11 Chemistry Beyond Functional Group Transformation 335
11.1 Introduction 335
11.2 C– H Bond Activation 336
11.2.1 sp3 C–H Bond Activation 337
11.2.1.1 C–C Bond Formation 337
11.2.1.2 C–N Bond formation 343
11.2.1.3 C–O Bond Formation 347
11.2.2 sp2 C–H Bond Activation 349
11.2.2.1 C–C Bond Formation 349
11.2.2.2 C–N Bond Formation 353
11.2.2.3 C–O Bond Formation 353
11.3 C–C Bond Activation 353
11.3.1 Utilization of Strained Molecules 354
11.3.2 Utilization of Chelating Substrates 355
11.3.3 Utilization of Activating Functional Groups 357
11.4 C–O Bond Activation 357
11.5 C–F Bond Activation 357
11.6 C–N Bond Activation 359
11.7 Small Molecule Activation 359
11.7.1 H2 359
11.7.2 O2 360
11.7.3 CH4 361
11.8 Conclusions and Outlook 362
References 363
12 Synthesis Assisted by Electricity 369
12.1 Electroorganic Synthesis in Green Reaction Media (Homogeneous System) 369
12.1.1 Electroorganic Synthesis in Aqueous Solutions 369
12.1.2 Electroorganic Synthesis in Supercritical Carbon Dioxide 370
12.1.3 Electroorganic Synthesis in Ionic Liquids 370
12.2 Electroorganic Synthesis in Liquid–Liquid Biphasic Systems 372
12.3 Electroorganic Synthesis in Thermomorphic Liquid–Liquid Biphasic Systems 373
12.4 Electroorganic Synthesis in Solid–Liquid Biphasic Systems 374
12.4.1 Solid-Supported Mediators 375
12.4.2 Solid–Liquid Biphasic System for Electrolysis Without Intentionally Added Supporting Electrolyte 376
12.4.2.1 SPE Technology 376
12.4.2.2 Electrolysis Using Solid-Supported Bases 377
12.5 Electroorganic Synthesis in Microflow Systems 378
12.5.1 Electrochemical Microflow Cells 379
12.5.2 Paired Electrolysis in Microflow Systems 380
12.5.3 Electroorganic Synthesis in a Microflow System Without Using Intentionally Added Supporting  Electrolyte 381
12.6 Future Outlook 383
References 383
13 Parameterization and Tracking of Optimization of Synthesis Strategy Using Computer Spreadsheet Algorithms 387
13.1 Introduction 387
13.2 Synthesis Strategy Parameterization 390
13.3 Case Study: Lysergic Acid 393
References 413
Index 415