Edited by

Antonio de la Hoz and Andre Loupy

Microwaves in Organic Synthesis

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Edited by Antonio de la Hoz and Andre Loupy

Microwaves in Organic Synthesis

Third, Completely Revised and Enlarged Edition

Volume 1

The Editors

Prof. Antonio de la HozUniversidad de Castilla-la ManchaFacultad de QuımicaDepartamento de Quımica Organica13071 Ciudad RealSpain

Dr. Andre LoupyUniversite Paris-SudLaboratoire des Reactions Selectives surSupportsBatiment 41091405 Orsay CedexFrance

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V

Contents to Volume 1

Preface XIXList of Contributors XXI

Part I Fundamental Aspects of Microwave Irradiation in OrganicChemistry 1

1 Microwave–Materials Interactions and Dielectric Properties: fromMolecules and Macromolecules to Solids and Colloidal Suspensions 3Didier Stuerga

1.1 Fundamentals of Microwave–Matter Interactions 31.1.1 Introduction 41.1.1.1 History 41.1.1.2 The Electromagnetic Spectrum 71.1.1.3 What About Chemistry: Energetic Comments 81.1.2 The Complex Dielectric Permittivity 111.1.2.1 Effect of Real Part: Polarization and Storage of Electromagnetic

Energy 141.1.2.2 Effect of Imaginary Part: Dielectric Losses 181.1.2.3 Thermal Dependence of the Dielectric Permittivity 261.1.2.4 Conduction Losses 281.1.2.5 Magnetic Losses 301.2 Dielectric Properties and Molecular Behavior 301.2.1 Dielectric Properties Within a Complex Plane 301.2.1.1 Argand Diagram 301.2.1.2 Cole–Cole Model 311.2.1.3 Davidson–Cole Model 321.2.1.4 Glarum’s Generalization 331.2.1.5 Molecules with Two or More Polar Groups 331.2.2 Dielectric Properties of Condensed Phases 331.2.2.1 Pure Liquids: Water and Alcohols 341.2.2.2 Effects of Electrolytes 351.2.2.3 Intermolecular Interactions and Complexes 371.2.2.4 Intermolecular Interactions and Hydrogen Bonding 38

VI Contents

1.2.2.5 What Is New About Bound Water? 381.2.3 Dielectric Properties of Macromolecules and Polymers 401.2.3.1 Macromolecules and Polymers 401.2.3.2 Highly Functional Inorganic–Polymer Composites 411.2.4 Dielectric Properties of Solids and Adsorbed Phases 431.2.4.1 Solids and Dipole Relaxation of Defects in Crystals Lattices 431.2.4.2 Solids and Adsorbed Phases 441.2.5 Dielectric Properties of Interfaces and Colloidal Suspensions 451.2.5.1 Interfacial Relaxation and the Maxwell–Wagner Effect 451.2.5.2 Colloids 461.3 Conclusion 50

References 51

2 Development and Design of Reactors in Microwave-AssistedChemistry 57Bernd Ondruschka, Werner Bonrath, and Didier Stuerga

2.1 Introduction 572.2 Basic Concepts for Reactions and Reactors in Organic Synthesis 582.3 Methods for Enhancing the Rates of Organic Reactions 592.4 Microwave-Assisted Organic Syntheses 612.4.1 Microwave Ovens and Reactors – Background 632.4.1.1 Applicators, Waveguides, and Cavities 632.4.1.2 Single-Mode or Multi-Mode? 642.4.1.3 Limits of Domestic Ovens 652.4.1.4 Temperature Measurement Limits 652.4.1.5 Design Principles of Microwave Applicators 652.4.2 Scale-Up of Microwave Cavities 662.4.3 Efficiency of Energy and Power 672.4.4 Field Homogeneity and Penetration Depth 682.4.5 Continuous Tube Reactors 692.4.6 MAOS – an Interdisciplinary Field 692.5 Commercial Microwave Reactors 702.5.1 Market Overview 702.5.2 Enterprises’ Products 712.5.3 SAIREM’s Products 742.5.3.1 The LABOTRON Series 742.5.3.2 The LABOTRON HTE and i-WASP 762.5.3.3 The MiniLABOTRON 772.5.3.4 The Miniflow 782.6 Selected Equipment and Applications 792.6.1 Heterogeneous Catalysis 822.6.2 Hyphenated Techniques in Combination with Microwaves 832.6.2.1 Microwave Oven Cascade 832.6.2.2 Photoconversions by Use of Microwave–UV Methods 842.6.2.3 Microwaves–Ultrasound 85

Contents VII

2.6.3 Combination of Microwave Irradiation with a Pressure Setup 852.6.3.1 The RAMO System 882.6.3.2 The Naxagoras Technology Pilot Plant 892.6.3.3 Supercritical Microwave Reactor 902.6.3.4 The Coconut Reactor 912.6.4 Synthesis of Laurydone 922.6.5 Industrial Equipment: Batch or Continuous Flow? 932.6.5.1 The Turbosphere System 932.6.5.2 The Pulsar System 932.6.5.3 The Thermostar System 952.7 Qualification and Validation of Reactors and Results 962.8 Conclusion and the Future 97

References 98

3 Key Ingredients for Mastery of Chemical Microwave Processes 105Didier Stuerga and Pierre Pribetich

3.1 The Systemic Approach 1053.2 Thermal Dependence of Dielectric Loss 1083.2.1 Thermal Dependence of Dielectric Properties 1093.2.2 Microwave Bistability 1103.3 Electric Field Effects 1113.3.1 Penetration and Skin Depths 1113.3.2 Dimensional Resonances 1133.4 Loop Modes or Strange Solutions of Maxwell’s Equations 1143.5 Hydrodynamic Aspects 1163.6 Thermodynamic and Other Effects of Electric Fields 1173.7 Athermal and Specific Effects of Electric Field 1183.8 The Thermal Path Effect: Anisothermal Conditions 1203.9 Hot Spots and Heterogeneous Kinetics 1223.10 Conclusion 123

References 124

4 Nonthermal Effects of Microwaves in Organic Synthesis 127Laurence Perreux, Andre Loupy, and Alain Petit

4.1 Introduction 1274.2 Origin of Microwave Effects 1284.3 Specific Nonthermal Microwave Effects 1304.4 Effects of the Medium 1344.4.1 Polar Solvents 1344.4.2 Nonpolar Solvents 1364.4.3 Solvent-Free Reactions 1384.5 Effects Depending on Reaction Mechanisms 1404.5.1 Isopolar Transition-State Reactions 1414.5.2 Bimolecular Reactions Between Neutral Reactants Leading to Charged

Products 144

VIII Contents

4.5.3 Anionic Bimolecular Reactions Involving Neutral Electrophiles 1454.5.4 Unimolecular Reactions 1464.6 Effects Depending on the Position of the Transition State Along the

Reaction coordinate 1464.7 Effects on Selectivity 1474.8 Some Illustrative Examples 1504.8.1 Bimolecular Reactions Between Neutral Reactants 1514.8.1.1 Nucleophilic Additions to Carbonyl Compounds 1514.8.1.2 Michael Additions 1644.8.1.3 SN2 Reactions 1664.8.1.4 Aromatic and Vinylic Nucleophilic Substitutions 1724.8.1.5 Solvent-Free Synthesis of New Oxoazetidines 1744.8.2 Bimolecular Reactions with One Charged Reactant 1754.8.2.1 Anionic SN2 Reactions Involving Charge-Localized Anions 1754.8.2.2 Anionic SN2 Reactions Involving Charge-Delocalized Anions 1804.8.2.3 Nucleophilic Additions to Carbonyl Compounds 1824.8.2.4 Reactions Involving Positively Charged Reactants 1854.8.3 Unimolecular Reactions 1884.8.3.1 Imidization Reaction of a Polyamic Acid 1884.8.3.2 Cyclization Reactions 1894.8.3.3 Intramolecular Nucleophilic Aromatic Substitution 1904.8.3.4 Intramolecular Michael Additions 1914.8.3.5 Deprotection of Allyl Esters 1924.8.3.6 Synthesis of Pyrido-Fused Ring Systems 1934.8.3.7 Ring-Closing Alkene Metathesis 1934.8.4 Some Illustrative Examples of the Effects on Selectivity 1944.8.4.1 Benzylation of 2-Pyridone 1944.8.4.2 Addition of Vinylpyrazoles to Imine Systems 1944.8.4.3 Stereo Control of β-Lactam Formation 1954.8.4.4 Cycloaddition to C70 Fullerene 1954.8.4.5 Selective Alkylation of 1,2,4-Triazole 1964.8.4.6 Rearrangement of Ammonium Ylides 1974.9 Concerning the Absence of Microwave Effects 1984.10 Conclusion: Suitable Conditions for Observation of Specific MW

Effects 199References 200

5 Selectivity Modifications Under Microwave Irradiation 209Angel Dıaz-Ortiz, Antonio de la Hoz, Jose Ramon Carrillo, and MarıaAntonia Herrero

5.1 Introduction 2095.2 Selective Heating 2105.2.1 Solvents 2105.2.2 Catalysts 2115.2.3 Reagents; Molecular Radiators 214

Contents IX

5.2.4 Susceptors 2155.3 Modification of Chemoselectivity and Regioselectivity 2185.3.1 Protection and Deprotection of Alcohols 2185.3.1.1 Electrophilic Aromatic Substitution 2195.3.2 Synthesis and Reactivity of Heterocyclic Compounds 2215.3.2.1 Cycloaddition Reactions 2255.3.2.2 Polymerization 2285.3.2.3 Miscellaneous 2305.4 Modification of Stereo- and Enantioselectivity 2345.5 Conclusion 240

Acknowledgments 240References 240

6 Elucidation of Microwave Effects: Methods, Theories, and PredictiveModels 245Antonio de la Hoz, Angel Dıaz-Ortiz, Marıa Victoria Gomez,Pilar Prieto, and Ana Sanchez Migallon

6.1 Introduction 2456.2 Thermal Effects 2466.2.1 Elimination of Wall Effects Caused by Inverted Temperature

Gradients 2466.2.2 Overheating 2476.2.3 ‘‘Hot Spots’’: Inhomogeneities 2496.3 Non-Thermal Effects 2566.3.1 Reactions and Theories 2576.3.1.1 Photochemistry. Triplet State 2576.3.1.2 Radical Reactions 2586.3.1.3 Polymerization Reactions 2586.3.1.4 Enzymes and Natural Products 2646.3.1.5 Heterogeneous Reactions. Diffusion 2666.3.2 Methods to Elucidate the Occurrence of Non-Thermal Microwave

Effects 2716.3.2.1 Microwave Irradiation with Simultaneous Cooling 2716.3.2.2 Development of Mixed Reactors 2746.3.2.3 Use of Silicon Carbide Vessels 2776.3.2.4 Reactions at 1 GHz 2796.3.2.5 Raman Spectroscopy 2796.3.2.6 Conductivity Measurements 2806.3.2.7 Computational Calculations 2816.4 Conclusion 291

Acknowledgments 291References 291

X Contents

7 Microwave Susceptors 297Thierry Besson and C. Oliver Kappe

7.1 Introduction 2977.2 Graphite as a Sensitizer 2997.2.1 Diels–Alder Reactions 2997.2.2 Ene Reactions 3047.2.3 Oxidation of Propan-2-ol 3057.2.4 Thermolysis of Esters 3067.2.5 Thermal Reactions in Heterocyclic Syntheses 3077.2.5.1 Synthesis of Quinazolines and Derivatives 3087.2.5.2 Benzothiazoles and Derivatives 3107.2.5.3 Synthesis of 2H-Benzopyrans (Coumarins) 3127.2.6 Decomplexation of Metal Complexes 3137.2.7 Redistribution Reactions Between Tetraalkyl- or Tetraarylgermanes

and Germanium Tetrahalides 3147.2.8 Pyrolysis of Urea 3157.2.9 Esterification of Stearic Acid by n-Butanol 3167.3 Graphite as Sensitizer and Catalyst 3167.3.1 Analysis of Two Synthetic Commercial Graphites 3177.3.2 Acylation of Aromatic Compounds 3187.3.3 Acylative Cleavage of Ethers 3227.3.4 Ketodecarboxylation of Carboxylic Diacids 3237.4 The Use of Silicon Carbide Susceptors in Microwave Chemistry 3267.4.1 Silicon Carbide as Passive Heating Element 3267.4.2 Silicon Carbide Reaction Vessels 3327.4.3 Microtiter Plates Made from Silicon Carbide 337

Acknowledgments 340References 340

8 Tools for Monitoring Reactions Performed Using MicrowaveHeating 347Nicholas E. Leadbeater, Jason R. Schmink, and Trevor A. Hamlin

8.1 Introduction 3478.2 Watching Microwave-Heated Reactions in Real Time 3488.2.1 Use of a Digital Camera Interfaced with a Scientific Microwave

Unit 3488.2.2 Use of Thermal Imaging Equipment 3508.3 Monitoring Microwave-Heated Reactions Using InSitu Spectroscopic

Tools 3538.3.1 Introduction 3538.3.2 Raman Spectroscopy 3548.3.2.1 Introduction 3548.3.2.2 Qualitative Reaction Monitoring 3568.3.2.3 Quantitative Reaction Monitoring 3598.3.2.4 Probing Non-Thermal Microwave Effects 363

Contents XI

8.3.3 Infrared Spectroscopy 3678.3.4 UV–Visible Spectroscopy 3708.3.5 Neutron and X-Ray Scattering 3728.4 Conclusion 374

References 374

9 Microwave Frequency Effects in Organic Synthesis 377Satoshi Horikoshi and Nick Serpone

9.1 Introduction 3779.2 Historical Review of Microwave Frequency Effects in Chemical

Reactions 3809.3 Microwave Chemical Reaction Apparatus Operating at Various

Frequencies 3819.3.1 Basic Configuration of Single-Mode Resonance Microwave Irradiation

Apparatus 3819.3.2 Types of Microwave Generator 3829.3.3 Commercial Microwave Organic Synthesis Apparatus Operating

at Various Frequencies 3849.3.3.1 5.8 GHz Microwave Devices with Large-Sized Reactors 3849.4 Frequency Effects and Heating Efficiency in Various Solutions 3869.4.1 Microwave Frequency Effect in Water as a Green Solvent 3869.4.2 Features of Microwave Frequency Effects of Various Aqueous

Electrolyte Solutions 3909.4.3 Frequency Effect in the Heating of Some Common Solvents 3949.4.4 Rates of Temperature Increase for Common Organic Solvents and for

Water 3959.4.5 Dielectric Parameters of Common Organic Solvents and Water at

Different Frequencies 3999.4.6 Rate of Temperature Increase of Common Solvents with a

Single-Mode Resonance Microwave Applicator 4029.5 Examples of Chemical Reactions Impacted by Microwave Frequency

Effects 4049.5.1 Microwave Frequency Effect in a Diels–Alder Reaction Taken as a

Model Organic Synthesis 4049.5.2 Microwave Frequency Effect in the Synthesis of the Ionic Liquid

[BMIM]BF4 4069.5.2.1 Synthesis of [BMIM]BF4 4079.5.2.2 Factors Impinging on the High Yields of [BMIM]BF4 by 5.8 GHz

Microwave Heating 4089.5.2.3 Temperature Distribution in the Microwave-Driven Synthesis of

[BMIM]BF4 4109.5.2.4 Advantage of Frequency Effects in the Synthesis of an Ionic

Liquid 4129.5.3 Microwave Frequency Effect in Catalyzed Reactions 412

XII Contents

9.5.3.1 The Suzuki–Miyaura Coupling Reaction in a Polar Solvent(Homogeneous Catalysis) 412

9.5.3.2 The Suzuki–Miyaura Coupling Reaction in a Nonpolar Solvent(Heterogeneous Catalysis) 414

9.5.3.3 Control of Hot Spots by the Frequency Effect 4169.5.4 Synthesis of Gemini Surfactants under 915 MHz Microwave

Irradiation 4209.6 Conclusion 421

Acknowledgments 421References 422

Part II Applications of Microwave Irradiation 425

10 Organic Synthesis Using Microwaves and Supported Reagents 427Rajender S. Varma and R.B. Nasir Baig

10.1 Introduction 42710.2 Microwave-Accelerated Solvent-Free Organic Reactions 42810.3 Protection–Deprotection Reactions 42910.3.1 Formation of Acetals and Dioxolanes 42910.3.2 N-Alkylation Reactions 43010.3.3 Deacylation Reactions 43110.3.4 Cleavage of Aldehyde Diacetates 43110.3.5 Cleavage of Carboxylic Esters on a Solid Support 43210.3.6 Selective Cleavage of the N-tert-Butoxycarbonyl Group 43310.3.7 Desilylation Reactions 43310.3.8 Dethioacetalization Reaction 43410.3.9 Deoximation Reactions 43510.3.10 Cleavage of Semicarbazones and Phenylhydrazones 43610.3.11 Dethiocarbonylation 43710.3.12 Cleavage of Methoxyphenyl Methyl and Tetrahydropyranyl

Ethers 43710.4 Condensation Reactions 43810.4.1 Wittig Olefination Reactions 43810.4.2 Knoevenagel Condensation Reactions – Synthesis of Coumarins 43910.4.3 Synthesis of Imines, Enamines, Nitroalkenes, and

N-Sulfonylimines 43910.4.4 MW-Assisted Michael Addition Reactions 44310.4.5 MW-Assisted Solid Mineral-Promoted Miscellaneous Condensation

Reaction 44410.5 Isomerization and Rearrangement Reactions 44510.5.1 Eugenol–Isoeugenol Isomerization 44610.5.2 Pinacol–Pinacolone Rearrangement 44610.5.3 Beckmann Rearrangement 44710.5.4 Claisen Rearrangement 44710.6 Diels–Alder Cycloaddition of a Triazole Ring 448

Contents XIII

10.7 Addition Reactions 44810.8 Oxidation Reactions – Oxidation of Alcohols and Sulfides 44810.8.1 Activated Manganese Dioxide–Silica 44910.8.2 Chromium Trioxide–Wet Alumina 44910.8.3 Selective Solvent-Free Oxidation with Clayfen 45010.8.4 Oxidations with Claycop–Hydrogen Peroxide 45110.8.5 Other Metallic Oxidants: Copper Sulfate–or Oxone–Alumina 45110.8.6 Nonmetallic Oxidants: Iodobenzene Diacetate Impregnated on

Alumina 45210.8.7 Oxidation of Thiols to Disulfides 45210.8.8 Oxidation of Sulfides to Sulfoxides and Sulfones: Sodium

Periodate–Silica 45310.8.9 Oxidation of Sulfides to Sulfoxides: Iodobenzene

Diacetate–Alumina 45310.8.10 Oxidation of Arenes and Enamines: Potassium

Permanganate–Alumina 45410.8.11 Oxidation Using [Hydroxyl(tosyloxy)iodo]benzene 45410.8.12 Other Oxidation Reactions 45510.9 Reduction Reactions 45510.9.1 Reduction of Carbonyl Compounds with Aluminum Alkoxides 45510.9.2 Reduction of Carbonyl Compounds to Alcohols: Sodium

Borohydride–Alumina 45610.9.3 Reductive Amination of Carbonyl Compounds 45710.9.4 Solid-State Cannizzaro Reaction 45810.9.5 Reduction of Aromatic Nitro Compounds to Amines with

Alumina-Supported Hydrazine 45810.10 Synthesis of Heterocyclic Compounds 45910.10.1 Flavones 45910.10.1.1 2-Amino Substituted Isoflav-3-enes 46010.10.2 Synthesis of Isobenzofuran-1(3H)-ones 46010.10.3 Substituted Thiazoles, Benzothiazepines, and Thiiranes 46110.10.4 Synthesis of 1,3,4-Thiadiazoles 46210.10.5 Synthesis of 2-Aroylbenzofurans 46310.10.6 Synthesis of Quinolones and Other Nitrogen Heterocycles 46310.10.7 Synthesis of 1,3,4-Oxadiazoles 46610.10.8 Solvent-Free Assembly of Pyrido-Fused Ring Systems 46610.10.9 Synthesis of Uracils 46710.10.10 MW-Assisted Synthesis of Benzoxazinones 46710.10.11 Multicomponent Reactions 46810.11 Miscellaneous Reactions 47110.11.1 Conversion of Arylaldehydes to Nitriles 47110.11.2 Nitration of Styrenes – Preparation of β-Nitrostyrenes 47110.11.3 Bromination of Alkanones Using Microwaves 47210.11.4 MW-Assisted Elimination Reactions 47210.11.5 Synthesis of N-Arylsulfonylimines 473

XIV Contents

10.11.6 Synthesis of β-Amino Alcohols 47310.11.7 N-Formylation of Amines 47310.11.8 Organometallic Reactions (Carbon–Carbon Bond-Forming

Reactions) 47410.11.9 Synthesis of Radiolabeled Compounds – Exchange Reactions 47510.11.10 Enzyme-Catalyzed Reactions 47610.11.11 Solvent-Free Synthesis of Ionic Liquids 47610.12 Conclusion 478

References 479

11 Gaseous Reactants in Microwave-Assisted Synthesis 487Achim Stolle, Peter Scholz, and Bernd Ondruschka

11.1 Introduction 48711.2 Liquid-Phase Synthesis 48811.2.1 Application of Hydrogen as a Reducing Agent 48911.2.1.1 Hydrogenation of C=C Double Bonds 48911.2.1.2 Hydrogenation of C–C Triple Bonds 49111.2.1.3 Hydrogenation of (Hetero)aromatic Double Bonds 49111.2.1.4 Miscellaneous Reductions 49211.2.2 Application of Oxygen for Synthesis 49311.2.3 Reactions with Carbon Monoxide 49411.2.4 Reactions Employing Carbon Dioxide 49811.2.5 Hydroformylation Reactions 50011.2.6 Reactions with Ethylene and Propyne 50311.2.7 Reactions with Ammonia and Hydrogen Sulfide 50511.3 Wet Air Oxidation 50811.4 Gas-Phase Synthesis 50811.4.1 Oxidative Coupling of Methane 50911.4.2 Reforming 51211.4.3 Oxidative Dehydrogenation of Hydrocarbons 51411.4.4 Other Reactions 51511.5 Waste Gas Treatment 51611.5.1 Combustion Engines 51611.5.2 Total Oxidation of Volatile Organic Compounds 51611.5.3 Catalytic NOx and SO2 Reductions 51711.5.4 Other Reactions 51911.6 Conclusion and Outlook 519

References 520

12 Microwaves and Electrochemistry 525Sara E.C. Dale, Richard G. Compton, and Frank Marken

12.1 Introduction to Microwave Assisted Electrode Processes 52512.2 Macroelectrode Processes in the Presence of Microwaves 52712.3 Microelectrode Processes in the Presence of Microwaves 53012.4 Junction-Electrode Processes in the Presence of Microwaves 533

Contents XV

12.5 Electrochemical Flow Reactor Processes in the Presence ofMicrowaves 533

12.6 Future Trends 536References 537

13 The Combined Use of Microwaves and Ultrasound: Methods andPractice 541Giancarlo Cravotto and Pedro Cintas

13.1 Introduction 54113.2 The Search for the Best Coupling 54213.2.1 Dielectric Heating and Sound: a Bird’s-Eye View 54213.2.2 First Insights and Technical Implementation 54413.3 Microwave- and Ultrasound-Enhanced Synthesis and Catalysis 54913.4 Formation of Advanced Materials 55813.5 Conclusion and Future Trends 560

References 560

14 Microwaves in Photochemistry and Photocatalysis 563Vladimır Cırkva

14.1 Introduction 56314.2 UV/Vis Discharges in Electrodeless Lamps 56414.2.1 Theory of Plasma-Chemical Microwave Discharges 56514.2.2 Construction of MW-Powered EDLs 56614.2.3 Preparation of the Thin Titania Films on EDLs 56814.2.4 Spectral Characteristics of the EDLs 57114.2.5 Performance of the EDLs 57214.2.5.1 Effect of Envelope Material 57214.2.5.2 Effect of Fill Material 57314.2.5.3 Effect of Nature and Pressure of Inert Fill Gas 57414.2.5.4 Effect of EDL Temperature 57614.2.5.5 Effect of Microwave Output Power 57714.2.5.6 Effect of Solvent Polarity 57814.3 Microwave Photochemical and Photocatalytic Reactors 57914.3.1 Performance in Batch Photoreactors 57914.3.1.1 Batch Photoreactors with External Classical UV Lamp (Type A1) 58014.3.1.2 Batch Photoreactors with Internal EDL (Type A2) 58014.3.1.3 Batch Photoreactors with EDL Inside Double Wall (Type A3) 58514.3.2 Performance in Flow-Through Photoreactors 58514.3.2.1 Flow-Through Photoreactors with Internal Classical UV Lamp

(Type B1) 58614.3.2.2 Annular Flow-Through Photoreactors with Internal EDL

(Type B2) 58614.3.2.3 Cylindrical Flow-Through Photoreactors Surrounded with EDL

(Type B3) 58614.3.2.4 Mixed Flow-Through Photoreactors with Internal EDL (Type B4) 587

XVI Contents

14.4 Interactions of UV/Vis and Microwave Radiation with Matter 58914.5 Microwave Photochemistry and Photocatalysis 59114.6 Applications 59114.6.1 Analytical Applications 59114.6.2 Environmental Applications 59114.6.3 Other Applications 59714.7 Future Trends 598

Acknowledgments 598References 598

Contents to Volume 2

Preface XVList of Contributors XVII

15 Microwave-Heated Transition Metal-Catalyzed CouplingReactions 607Francesco Russo, Luke R. Odell, Kristofer Olofsson,Peter Nilsson, and Mats Larhed

16 Microwaves in Heterocyclic Chemistry 673Jean Pierre Bazureau, Ludovic Paquin, Daniel Carrie, Jean MartialL’Helgoual’ch, Solene Guiheneuf, Karime Wacothon Coulibaly,Guillaume Burgy, Sarah Komaty, and Emmanuelle Limanton

17 Microwave-Assisted Cycloaddition Reactions 737Khalid Bougrin and Rachid Benhida

18 Microwave-Assisted Heterogeneously Catalyzed Processes 811Rafael Luque, Alina Mariana Balu, and Duncan J. Macquarrie

19 Microwaves in the Synthesis of Natural Products 843Erik V. Van der Eycken, Jitender B. Bariwal, and Jalpa J. Bariwal

20 Microwave-Enhanced Synthesis of Peptides, Proteins, andPeptidomimetics 897Jonathan M. Collins

21 A Journey into Recent Microwave-Assisted CarbohydrateChemistry 961Antonino Corsaro, Venerando Pistara, Maria Assunta Chiacchio, andGiovanni Romeo

Contents XVII

22 Polymer Chemistry Under Microwave Irradiation 1013Dariusz Bogdal and Urszula Pisarek

23 Application of Microwave Irradiation in Carbon Nanostructures 1059Fernando Langa and Pilar de la Cruz

24 Microwave-Assisted Multicomponent Reactions in the Synthesis ofHeterocycles 1099Art Kruithof, Eelco Ruijter, and Romano V.A. Orru

25 Microwave-Assisted Continuous Flow Organic Synthesis(MACOS) 1173Jesus Alcazar and Juan de M. Munoz

Index 1205

V

Contents

Preface XIXList of Contributors XXI

Part I Fundamental Aspects of Microwave Irradiation in OrganicChemistry 1

1 Microwave–Materials Interactions and Dielectric Properties: fromMolecules and Macromolecules to Solids and Colloidal Suspensions 3Didier Stuerga

2 Development and Design of Reactors in Microwave-AssistedChemistry 57Bernd Ondruschka, Werner Bonrath, and Didier Stuerga

3 Key Ingredients for Mastery of Chemical Microwave Processes 105Didier Stuerga and Pierre Pribetich

4 Nonthermal Effects of Microwaves in Organic Synthesis 127Laurence Perreux, Andre Loupy, and Alain Petit

5 Selectivity Modifications Under Microwave Irradiation 209Angel Dıaz-Ortiz, Antonio de la Hoz, Jose Ramon Carrillo, and MarıaAntonia Herrero

6 Elucidation of Microwave Effects: Methods, Theories, and PredictiveModels 245Antonio de la Hoz, Angel Dıaz-Ortiz, Marıa Victoria Gomez, Pilar Prieto,and Ana Sanchez Migallon

7 Microwave Susceptors 297Thierry Besson and C. Oliver Kappe

VI Contents

8 Tools for Monitoring Reactions Performed Using MicrowaveHeating 347Nicholas E. Leadbeater, Jason R. Schmink, and Trevor A. Hamlin

9 Microwave Frequency Effects in Organic Synthesis 377Satoshi Horikoshi and Nick Serpone

Part II Applications of Microwave Irradiation 425

10 Organic Synthesis Using Microwaves and Supported Reagents 427Rajender S. Varma and R.B. Nasir Baig

11 Gaseous Reactants in Microwave-Assisted Synthesis 487Achim Stolle, Peter Scholz, and Bernd Ondruschka

12 Microwaves and Electrochemistry 525Sara E.C. Dale, Richard G. Compton, and Frank Marken

13 The Combined Use of Microwaves and Ultrasound: Methods andPractice 541Giancarlo Cravotto and Pedro Cintas

14 Microwaves in Photochemistry and Photocatalysis 563Vladimır Cırkva

Contents to Volume 2

Preface XVList of Contributors XVII

15 Microwave-Heated Transition Metal-Catalyzed Coupling Reactions 607Francesco Russo, Luke R. Odell, Kristofer Olofsson,Peter Nilsson, and Mats Larhed

15.1 Introduction 607

15.2 Cross-Coupling Reactions 608

15.2.1 The Suzuki–Miyaura Reaction 608

15.2.2 The Stille Reaction 626

15.2.3 The Negishi Reaction 629

15.2.4 The Kumada Reaction 631

15.2.5 The Hiyama Reaction 632

15.3 Arylation of C, N, O, S, P and Halogen Nucleophiles 633

15.3.1 The Sonogashira Coupling Reaction 633

15.3.2 The Cyanation Reaction 637

Contents VII

15.3.3 Aryl–Nitrogen Couplings 64015.3.4 Aryl–Oxygen Bond Formation 64715.3.5 Aryl–Phosphorus Couplings 64915.3.6 Aryl–Sulfur Bond Formation 65015.3.7 Aryl Halide Exchange Reactions 65215.4 The Heck Reaction 65315.5 Carbonylative Coupling Reactions 66115.6 Conclusion 663

Acknowledgments 664References 664

16 Microwaves in Heterocyclic Chemistry 673Jean Pierre Bazureau, Ludovic Paquin, Daniel Carrie, Jean MartialL’Helgoual’ch, Solene Guiheneuf, Karime Wacothon Coulibaly,Guillaume Burgy, Sarah Komaty, and Emmanuelle Limanton

16.1 Introduction 67316.2 Microwave-Assisted Synthesis of Four- and Five-Membered Systems

with One and More Than Two Heteroatoms 67416.2.1 Synthesis of Azetidines 67416.2.2 Synthesis of Five- and Six-Membered Lactams 67416.2.3 Five-Membered Heterocycles with N and S Atoms: Synthesis of Pyrroles

and Thiophenes 67416.2.4 Synthesis of Imidazoles and Related Compounds 67616.2.5 Synthesis of Pyrazoles and Related Compounds 67716.2.6 Synthesis of Thiazoles, Isothiazoles, Thiazolines, and

Thiazolidinones 67916.2.7 Synthesis of Oxazolines, Thiazolines, and Isooxazoles 68016.2.8 Synthesis of Triazoles and Related Compounds 68216.3 Six-Membered Systems with One Heteroatom 68216.3.1 Synthesis of Pyridines 68216.3.2 Synthesis of Dihydropyridines and Pyridinones 68416.3.3 Synthesis of Condensed Naphthyridines 68516.3.4 Synthesis of Imidazo-, Thiazolo-, Pyrano-, and Isoxazolopyridines 68516.4 Six-Membered Systems with More Than One Heteroatom 68616.4.1 Synthesis of Pyrimidines and Related Compounds 68616.4.2 Synthesis of Triazines, Piperazines, and Related Compounds 68816.5 Bicyclic Systems (Six Atoms + Five Atoms) with One, Two, and More

Heteroatoms 69116.5.1 Synthesis of Benzofurans Under Microwave Irradiation 69116.5.2 Synthesis of Indoles and Derivatives 69216.5.3 Synthesis of Benzimidazoles, Benzoxazoles, and Benzothiazoles 69416.5.4 Synthesis of Tetrahydroindazolones and Pyridazine Derivatives 69716.5.5 Synthesis of Heterophosphole Sulfides 69716.6 Bicyclic Systems (Six Atoms + Six Atoms) with One, Two, and More

Heteroatoms 697

VIII Contents

16.6.1 Synthesis of Quinoline and Isoquinoline Derivatives Under MicrowaveIrradiation 697

16.6.2 Synthesis of Quinazolines and Related Compounds 70116.6.3 Synthesis of Quinoxalines, Phthalazines, and Related Compounds 70516.6.4 Synthesis of Coumarins, Flavones, and Chromones 70516.6.5 Synthesis of Benzothiazinones and Benzooxazinones 70816.7 Seven Membered Heterocycles with Two Heteroatoms:

Microwave-Assisted Synthesis of Benzodiazepines and RelatedCompounds 710

16.8 Microwave-Assisted Nucleophilic Aromatic Substitution (SNAr) 71416.9 Microwaves in Total Synthesis of Bioactive Heterocycles 71916.10 Conclusion 729

Acknowledgments 729References 730

17 Microwave-Assisted Cycloaddition Reactions 737Khalid Bougrin and Rachid Benhida

17.1 Introduction 73717.2 Microwave-Assisted [3 + 2]-Cycloaddition Reactions 73817.2.1 Cycloadditions of Azides 74017.2.2 Cycloadditions of Nitrile Oxides, Nitriles Sulfides, and Nitrones 75717.2.2.1 Nitrile Oxides 75717.2.2.2 Nitrones 76017.2.2.3 Nitrile Sulfides 76417.2.3 Azomethine Ylides 76617.2.4 Azomethine Imines and Nitrile Imines 77217.3 Microwave-Assisted [4 + 2]-Cycloaddition Reactions 77517.3.1 Intramolecular Diels–Alder Reactions 77517.3.2 Intramolecular Hetero-Diels–Alder Reactions 77817.3.3 Intermolecular Diels–Alder Reactions 78717.3.4 Intermolecular Hetero-Diels–Alder Reactions 79217.4 Microwave-Assisted [2 + 2]-Cycloaddition Reactions 79517.4.1 Intramolecular [2 + 2]-Cycloaddition Reactions 79617.4.2 Intermolecular [2 + 2]-Cycloaddition Reactions 79817.5 Other Microwave-Assisted Cycloaddition Reactions 79917.6 Conclusion 804

Acknowledgments 804References 805

18 Microwave-Assisted Heterogeneously Catalyzed Processes 811Rafael Luque, Alina Mariana Balu, and Duncan J. Macquarrie

18.1 Introduction 81118.2 Acid-Catalyzed Reactions 81218.3 Based-Catalyzed Reactions 82018.3.1 Michael Additions 820

Contents IX

18.3.2 Condensation Reactions 82118.4 Redox Reactions 82218.4.1 (Ep)oxidations 82218.4.2 Hydrogenation Reactions 82418.4.3 Asymmetric Reduction of Imines 82418.5 Coupling Reactions 82618.5.1 C−C Coupling Processes 82618.5.2 Oxidative Coupling of Amines 82718.6 Other Reactions 82918.6.1 Silylation and Reactions of Silylated Molecules 82918.6.2 Oxime Formation 83018.6.3 Heterocycle Formation 83118.6.4 Multistep Syntheses 83218.6.5 Esterification and Transesterification Reactions 83618.7 Conclusion and Outlook 838

Acknowledgments 839References 839

19 Microwaves in the Synthesis of Natural Products 843Erik V. Van der Eycken, Jitender B. Bariwal, and Jalpa J. Bariwal

19.1 Introduction 84319.2 Total Synthesis of Various Classes of Natural Products 84419.2.1 Synthesis of Frondosin C (97) 85719.2.2 Frondosin B (102) 85719.3 Total Synthesis of Various Classes of Alkaloids 85919.4 Synthesis of Analogs of Natural Products 87619.5 Synthesis of Building Blocks (Subunits) for Natural Product 88619.6 Conclusion and Overview 893

References 893

20 Microwave-Enhanced Synthesis of Peptides, Proteins, andPeptidomimetics 897Jonathan M. Collins

20.1 Introduction 89720.2 Synthesis Approaches 89920.2.1 Recombinant Synthesis 89920.2.2 Solution-Phase Peptide Synthesis 90020.2.3 Solid-Phase Peptide Synthesis 90020.3 Microwave Theory for Peptide Synthesis 90120.3.1 History of Microwave Application in Peptide Synthesis 90120.3.2 Energy Transfer Mechanisms in SPPS 90320.3.3 Comparison of Microwave and Conductive Heating 90420.4 Nα-Amino Protection Strategies 90620.4.1 Carboxybenzyl (Cbz) Protection 90720.4.1.1 Overview 907

X Contents

20.4.1.2 Microwave-Enhanced Carboxybenzyl (Cbz) Removal 90720.4.2 Boc Protection 90720.4.2.1 Overview 90720.4.2.2 Microwave-Enhanced Boc Removal 90820.4.3 Fmoc Chemistry 90920.4.3.1 Overview 90920.4.3.2 Microwave-Enhanced Fmoc Removal 91120.4.3.3 Base-Catalyzed Side Reactions 91220.4.4 Bsmoc Chemistry 91720.4.4.1 Overview 91720.4.4.2 Microwave-Enhanced Bsmoc Removal 91820.5 Amide Bond Formation 91920.5.1 Carbodiimide-Promoted Coupling 91920.5.1.1 Overview 91920.5.1.2 Microwave-Enhanced Carbodiimide-Promoted Coupling 92120.5.2 Onium Salt-Promoted Coupling 92120.5.2.1 Overview 92120.5.2.2 Microwave-Enhanced Onium Salt-Promoted Activation 92520.5.3 Side Reactions During Coupling 92720.5.3.1 Epimerization 92720.5.3.2 Enolization 92820.5.3.3 Oxazolone Formation 93220.5.3.4 Arginine Lactam Formation 93320.5.3.5 Guanidine Capping 93520.6 Modified Peptides 93520.6.1 Phosphopeptides 93520.6.2 Glycopeptides 93620.6.3 N-Methylated Peptides 93920.6.4 Cyclic Peptides 93920.6.4.1 Head-to-Tail Cyclization 93920.6.4.2 Disulfide Bonding 94020.6.4.3 Ring-Closing Metathesis 94120.7 Non-Natural Peptidomimetics 94120.7.1 Microwave-Enhanced Peptidomimetic Synthesis 94120.8 Resin Cleavage 94220.8.1 Overview 94220.8.2 Microwave-Enhanced Resin Cleavage 94320.9 Recommended Protocols 94420.10 Conclusion 94620.11 Abbreviations 948

Acknowledgment 950References 950

Contents XI

21 A Journey into Recent Microwave-Assisted CarbohydrateChemistry 961Antonino Corsaro, Venerando Pistara, Maria Assunta Chiacchio, andGiovanni Romeo

21.1 Introduction 96121.2 Acylation 96221.2.1 Acetylation, Benzoylation 96221.2.2 Peracetylation, Perbenzoylation, Permethacrylation 96421.2.3 Thioacylation 96421.3 Glycosylation 96521.3.1 O- and N-Glycosylation 96621.3.2 F- and C-Glycosylation 97121.3.3 Synthesis of 2′-Deoxy C-Aryl-α- and -β-Glycopyranosides 97321.3.4 S-Glycosylation 97321.4 Halogenation-Dehalogenation 97521.5 Sulfation 97621.6 Anomerization 97621.7 Synthesis of Sugar Derivatives 97721.8 Synthesis of Biologically and Pharmacological Active

Compounds 98421.9 Synthesis of Heterocycles 98721.9.1 Hetero-Diels–Alder and Diels–Alder Reactions 99321.9.2 1,3-Dipolar Cycloadditions of Nitrile Sulfides and

Nitrones 99421.9.3 Triazoles via ‘‘Click’’ Reactions (CuAAC) 99621.9.4 Synthesis of Imino Sugars 100221.10 Synthesis of Phosphorus Compounds 100421.11 Synthesis of Nanostructured Materials 100621.12 Conclusion 1007

Acknowledgment 1008References 1008

22 Polymer Chemistry Under Microwave Irradiation 1013Dariusz Bogdal and Urszula Pisarek

22.1 Introduction 101322.2 Synthesis of Polymers Under Microwave Irradiation 101322.2.1 Chain Polymerizations 101422.2.1.1 Free-Radical Polymerization Reactions 101422.2.1.2 Controlled ‘‘Living’’ Radical Polymerization 102122.2.1.3 Ring-Opening Polymerization 102722.2.1.4 Metathesis Polymerization 103222.2.2 Step-Growth Polymerization 103422.2.2.1 Epoxy Resins 103422.2.2.2 Polyethers and Polyesters 103822.2.2.3 Polyamides and Polyimides 1041

XII Contents

22.2.3 Miscellaneous Polymers 104822.3 Conclusion 1052

References 1053

23 Application of Microwave Irradiation in Carbon Nanostructures 1059Fernando Langa and Pilar de la Cruz

23.1 Fullerenes Under Microwave Irradiation 105923.1.1 Introduction 105923.1.2 Reactivity of Fullerenes Under Microwave Irradiation 106023.1.2.1 Diels–Alder Cycloaddition Reactions 106023.1.2.2 1,3-Dipolar Cycloaddition Reactions 106423.1.2.3 Azomethine Ylides 106523.1.2.4 Nitrile Oxides 107123.1.2.5 Nitrile Imines 107223.1.2.6 Other Reactions 107823.2 Microwave Irradiation in Carbon Nanotubes 108023.2.1 Synthesis and Purification 108023.2.2 Functionalization of Carbon Nanotubes 108223.3 Microwave Irradiation in Other Carbon Nanoforms 108823.4 Conclusion 1090

References 1091

24 Microwave-Assisted Multicomponent Reactions in the Synthesis ofHeterocycles 1099Art Kruithof, Eelco Ruijter, and Romano V.A. Orru

24.1 Introduction 109924.2 Nitrogen Heterocycles 110024.2.1 Azetes 110024.2.2 Pyrroles 110024.2.2.1 Pyrazoles 110424.2.3 Imidazoles 110624.2.4 Tetrazoles 110924.2.5 Pyridines 110924.2.5.1 Unfused Pyridines 111024.2.5.2 Fused Pyridines 111624.2.5.3 Spiro Di- and Tetrahydropyridines 112624.2.6 Pyrimidines 113124.2.6.1 Biginelli Reaction 113224.2.6.2 Fused and Spiro Dihydropyrimidines 113324.2.7 Pyrazines and Triazines 113724.2.8 (Di)azepines 113824.3 Oxygen-Containing Rings 114224.4 Sulfur-Containing Rings 114524.5 Oxygen- and Nitrogen-Containing Rings 114824.6 Carbacycles 1151

Contents XIII

24.7 Multiple Ring Systems 115324.8 Conclusion 116324.9 Abbreviations 1164

References 1164

25 Microwave-Assisted Continuous Flow Organic Synthesis(MACOS) 1173Jesus Alcazar and Juan de M. Munoz

25.1 Introduction 117325.2 Equipment 117425.3 MACOS in Homogeneous System 117725.3.1 Microfluidic Reactors 117725.3.2 Mesofluidic Reactors 118225.3.3 Large Reactors 118725.4 MACOS in Heterogeneous System 119025.4.1 Stop-Flow processing 119125.4.2 Solid-Supported 119125.4.3 Combination of MACOS with Ultrasound 120025.5 Conclusion and Outlook 1201

References 1202

Index 1205