Motivation –Who should read the book!? XVII

Acknowledgments XIX

Abbreviations XXI

Nomenclature XXIII

1 FromGreen Chemistry to Green Engineering – Fostered by Novel ProcessWindows Explored in Micro-Process Engineering/Flow Chemistry 1

1.1 Prelude – Potential for Green Chemistry and Engineering 1

1.2 Green Chemistry 2

1.2.1 12 Principles in Green Chemistry 2

1.3 Green Engineering 3

1.3.1 10 Key Research Areas in Green Engineering 3

1.3.2 12 Principles in Chemical Product Design 4

1.4 Micro- and Milli-Process Technologies 6

1.4.1 Microreactors 6

1.4.2 Microstructured Reactors 6

1.5 Flow Chemistry 9

1.5.1 10 Key Research Areas in Flow Chemistry 9

1.6 Two Missing Links – Cross-Related 9

References 12

2 Novel ProcessWindows 15

2.1 Transport Intensification –The Potential of Reaction Engineering 15

2.2 Chemical Reactivity in Match or Mismatch to Intensified Engineering 17

2.3 Chemical Intensification through Harsh Conditions – Novel Process Windows 18

2.4 Flash Chemistry 19

2.5 Process-Design Intensification 21

References 23

3 Chemical Intensification – Fundamentals 25

3.1 Length Scale 25

3.2 Time Scale 26

3.3 Length and Time Scale of Chemical Reactions 28

3.3.1 Solution of Kinetic Equations 29

3.3.2 Reaction Time and Reaction Classification 31

3.3.3 Example for Reaction Time and Residence Time 32

3.4 Temperature Intensification 33

3.4.1 Harsh Process Conditions 33

3.4.2 New TemperatureWindows 33

3.4.3 Reaction Rate – Arrhenius Equation 35

3.5 Pressure Intensification 36

3.5.1 Reaction Rate – Activation Volumes 36

3.5.2 Equilibrium 37

3.5.3 Electron Kinetic Energy 38

3.5.4 Material Properties 38

3.5.5 Mixture Properties 40

3.5.6 Illustration of Pressure Effect on Selected Chemical Reactions 41

References 42

4 Making Use of the “Forbidden” – Ex-Regime/High Safety Processing 45

4.1 Hazardous Reactants and Intermediates 45

4.1.1 Tetrazole Formation 45

4.1.2 Strecker Synthesis 47

4.1.3 Phosgene Chemistry 47

4.1.4 Diazomethane Synthesis 48

4.1.5 Ozonolysis 50

4.1.6 Organic Peroxide Formation 51

4.2 Ex-Regime andThermal Runaway Processing 52

4.2.1 Oxidation 52

4.2.2 Hydrogen Peroxide Synthesis 52

4.2.3 Direct Fluorination 53

4.2.4 Ionic Liquid Synthesis 53

4.2.5 Moffatt–Swern Oxidation 54

4.2.6 Reaction Between Cyclohexanecarboxylic Acid and Oleum 55

4.2.7 Nitration of Toluene 55

4.2.8 Aromatic Amidoxime Formation 56

4.2.9 Decarboxylative Trichloromethylation of Aromatic Aldehydes 56

4.2.10 Dihydroxylation Reactions with Nanobrush-Immobilized OsO4 58

References 58

5 Exploring New Paths – New Chemical Transformations 61

5.1 Direct Syntheses via One Step 61

5.1.1 Fluorination with Elemental Fluorine 61

5.1.2 Hydrogen Peroxide Synthesis out of the Elements 62

5.1.3 Direct Aryllithiums Route 62

5.1.4 C–O Bond Formation by a Direct α-C–H Bond Activation 63

5.1.5 Direct Adipic Acid Route from Cyclohexene 65

5.1.6 New Biocatalytic Pathways without Protecting Groups – Inter-Glycosidic Condensation 68

5.2 Direct Syntheses via Multicomponent Reactions 69

5.2.1 “Odor-Sealed” Isocyanide Formation 69

5.3 Multistep One-Flow Syntheses 70

5.4 Multistep Syntheses in One Microreactor/Chip 73

5.4.1 Multistep Synthesis of [18F]-Radiolabeled Molecular Imaging Probe 73

5.4.2 Combining Asymmetric Organocatalysis and Analysis on a Single Microchip 75

5.4.3 Two-Step Strecker Reaction 75

5.5 Multistep Syntheses in Coupled Microreactors/Chips 76

5.5.1 Chlorohydrination of Allyl Chloride 76

5.5.2 Lithiation/Borylation/Suzuki–Miyaura Cross-Coupling 77

5.5.3 Suzuki–Miyaura Cross-Coupling-Phenols-Aryl Triflates-Biaryls 77

5.5.4 Ring-Closing Metathesis and Heck Reaction 77

5.5.5 Imidazo[1,2-a]pyridine-2-carboxylic Acids in Two Steps 78

5.5.6 Suzuki–Miyaura Cross-Coupling/Hydrogenation 78

5.5.7 Sodium Nitrotetrazolate – Diazonium Ion Formation/Sandmeyer Reaction 79

5.5.8 Murahashi Coupling/Br–Li Exchange 79

5.5.9 5′-Deoxyribonucleoside Glycosylation 80

5.5.10 Two-Carbon Homologation of Esters to α,β-Unsaturated Esters 81

5.5.11 Low-Pressure Carbonylations with Acids as CO Precursors 81

5.5.12 Coupled Microreactor-Purification-Analytics for δ-Opioid Receptor Agonist 82

5.5.13 Synthesis of TAC-101 Analogs 82

5.5.14 Multistep Enzymatic Synthesis to 2-Amino-1,3,4-Butanetriol 83

5.5.15 Multistep Enzymatic Synthesis to δ-D-Gluconolactone 83

5.5.16 Diarylethene Synthesis in Two Steps 87

References 87

6 Activate – High-T Processing 91

6.1 Tailored High-T Microreactor Design and Fabrication 93

6.1.1 Glass Capillary Coil in Ceramic Housing 93

6.1.2 Modularly Packaged Silicon Microreactor 93

6.1.3 Modular Thermal Platform for High-Temperature Flow Reactions 93

6.2 Cryogenic to Ambient – Allowing Fast Reactions to be Fast 94

6.2.1 Synthesis of Triflates for the Heck Alkenylation 94

6.2.2 Enantioselective 1,4-Addition of Enones 96

6.2.3 Swern–Moffatt Oxidation of Benzyl Alcohol 97

6.2.4 Tf2NH-Catalyzed [2+2] Cycloaddition 98

6.3 From Reflux to Superheated – Speeding-Up Reactions 99

6.3.1 Kolbe–Schmitt Reaction 99

6.3.2 C–F Bond Formation 99

6.3.3 NMP Radical Polymerization of Styrene 100

6.3.4 Noncatalytic Claisen Rearrangement 100

6.3.5 Nucleophilic Substitution of Difluoro-benzenes 100

6.3.6 Aminolysis of Epoxides 101

6.3.7 Synthesis of 2,4,5-Trisubstituted Imidazoles 102

6.3.8 2-Methylbenzimidazole Formation, 3,5-Dimethyl-1-Phenylpyrazole Formation, and Diels–Alder Cycloaddition – Benchmarking High-p,t Flow to Microwave 102

6.3.9 Fischer Indole Synthesis of Tetrahydrocarbazole 103

6.3.10 Thermal Hydrolysis of Triglycerides 103

6.3.11 Chlorodehydroxylation to n-Alkyl Chlorides 104

6.3.12 1,3,4-Oxadiazoles via N-Acylation of 5-Substituted Tetrazoles 105

6.3.13 Cobalt-Catalyzed Borohydride Reduction of Tetralone 106

6.3.14 Dimethylcarbonate Methylation 107

6.3.15 Selective Aerobic Oxidation of Benzyl Alcohol Using Iron Oxide Nano-/TEMPO Catalyst 108

6.3.16 Rufinamide Synthesis 110

6.3.17 Several High-T, High-p Processes 111

6.3.18 Click Chemistry 111

6.3.19 4-(Pyrazol-1-yl) Carboxanilide Multistep Synthesis 112

6.3.20 4-Hydroxy-2-cyclopentenone Synthesis 113

6.3.21 Hydrothermal Treatment of Glucose 114

6.3.22 Tetrahydroisoquinoline Synthesis 114

6.4 Solvent-ScopeWidening by Virtue of Pressurizing Existing High-T Reactions 116

6.4.1 Nucleophilic Aromatic Substitution of 2-Halopyridines 116

6.4.2 IntramolecularThermal Cyclization and Benzannulation 116

6.4.3 Catalyst-Free Transesterification and Esterification of Aliphatic and Aromatic Acids 117

6.4.4 Aminolysis of Epoxides 117

6.5 New Temperature Field for Product and Material Control 118

6.5.1 Palladium-Catalyzed Aminocarbonylation 118

6.5.2 Aminolysis of Epoxides 119

6.5.3 Flash Flow Pyrolysis 119

6.5.4 Indium Phosphide Nanocrystal 120

6.5.5 Quantum Dot Synthesis 121

6.5.6 High-T Flow Cycloaddition to Fullerene Derivatives 123

6.6 Energy Activation Other than Temperature – Photo, Electrochemical, Plasma 125

6.6.1 Photo-Oxygenation of Dimethylsulfide 125

6.6.2 Microwave Flow Reactor for Stable High-p,T Operation 125

References 125

7 Press – High-p Processing 129

7.1 Tailored High-p Microreactor Design and Fabrication 129

7.1.1 Solder-Based Silicon Microsystem 129

7.1.2 In-Plane Fiber-Based Interfaced Microreactor 129

7.2 High Pressure to Intensify Interfacial Transport in Gas–Liquid Reactions 130

7.2.1 Hydrogenation of Cyclohexane 130

7.2.2 Carbamic Acid Formation 130

7.2.3 Intramolecular Aldol Condensation to 1-Methyl-1-cyclopenten-3-one 131

7.2.4 Catalytic Hydrogenation of Acetone 131

7.2.5 Propylene Oxide Synthesis 132

7.2.6 Asymmetric Amino-2-indanol Hydrogenation 132

7.2.7 Hydrogen Gas Liquefication in Guaiacol Conversion (hydroprocessing) 132

7.3 Pressure as Direct Means – Activation Volume Effects and More 133

7.3.1 Claisen Rearrangement 133

7.3.2 Nucleophilic Aromatic Substitution ofThree p-Halonitrobenzenes 133

7.3.3 Diels–Alder Reaction with Furylmethanols and Cyclopentadiene 134

7.3.4 Aza Diels–Alder Reaction 136

7.3.5 Esterification of Phthalic Anhydride 136

7.4 Pressure for Advanced Fluidic Studies – to be Used for Shaping Materials and More 137

7.4.1 scCO2 Droplets or Jets in LiquidWater 138

References 138

8 Collide and Slide – High-c and Tailored-Solvent Processing 141

8.1 Batch Process-Based Inspirations for High-c Flow Processes 141

8.1.1 Polypropylene and Polycarbonate Polymerizations 141

8.1.2 EnantioselectiveThermal and Photochemical Solid-State Reaction 142

8.2 Solvent-Free or Solvent-Less Operation – “Highest-c” 142

8.2.1 Bromination of 3-Bromo-imidazo[1,2-a]Pyridine 142

8.2.2 Thiophene Bromination 142

8.2.3 Claisen Rearrangement of Substituted Phenyl Phenols 142

8.2.4 Michael Addition 143

8.2.5 Peroxidation of Methyl Ethyl Ketone 144

8.2.6 Beckmann Rearrangement (High-c) 144

8.2.7 [2+2] Photocycloaddition of a Chiral Cyclohexenone (High-c) 145

8.2.8 Bromination of Toluene (Solvent-Free) 148

8.2.9 Sulfonation of Nitrobenzene (Solvent-Free) 148

8.2.10 Synthesis of Nitro Herbicides (High-c, Solvent-Free) 148

8.2.11 Suzuki–Miyaura Reaction over Sol–Gel Entrapped Catalyst SiliaCat DPP-Pd 150

8.2.12 Enzyme and Coenzyme (High-c in Bioprocessing) 150

8.2.13 Enzyme and Coenzyme (High-c in Bioprocessing) 151

8.3 Supercritical Fluids to Combine the Former Separated – Mass Transfer Boost 152

8.3.1 Supercritical Hydrogenation of Cyclohexene 155

8.3.2 Supercritical Hydrogenations of Double and Triple Bounds 155

8.3.3 Ascaridole Synthesis under Photo-Supercritical Conditions 157

8.3.4 Citronellol Oxidation under Photo-Supercritical Conditions 157

8.3.5 Near-scCO2 Enzymatic Biodiesel Synthesis 157

8.3.6 SupercriticalWater, Non-Catalytic Beckmann Rearrangement 158

8.3.7 SupercriticalWater, Non-Catalytic Pinacol Rearrangement 159

8.3.8 SupercriticalWater Oxidation 159

8.3.9 Supercritical-Acetonitrile, Nitriles from Carboxylic Acids 162

8.3.10 Self-Optimizing Continuous Reactions under Supercritical Conditions 162

References 163

9 Doing More by Combining – Process Integration 165

9.1 Integration of Reaction and Cooling/Heating, Separation, or Other 165

9.1.1 Integrated Micro-Steam Reformer-Catalytic Combustor for Methane Fuel Processing 165

9.1.2 Integrated Microburner/Thermoelectric Device for System Start-Up 166

9.1.3 Integrated Micro Reactor–Evaporative Cooler 167

9.1.4 Integrated Microwave–Microreactor 167

9.1.5 Integrated Enzyme Microreactor–Extractor 167

9.1.6 Integrated Membrane Microreactor for Knoevenagel Reaction 168

9.1.7 Continuous Multiple Liquid–Liquid Separation: Diazotization of Amino Acids 169

9.1.8 Coupling of the Hydroxylation of Progesterone Using Rhizopus Nigricans with Flow Extraction 169

9.1.9 Coupling of the Esterification to Isoamyl Acetate Using Lipase B with Flow Extraction 170

9.2 Integration of Process Control and Sensing 171

9.2.1 Integrated Process Control for Methanol Steam Reforming 171

9.2.2 Integrated Sensing, Catalyst, and Heating for Ammonia Oxidation 171

9.2.3 Integration of the Esterification to Ethyl Oleate Using Lipase B with Photoionization Mass Spectrometry 172

9.2.4 Integration of the Intramolecular Friedel–Crafts Addition with Ultra-High-Pressure Liquid Chromatography 173

9.2.5 Integration of Pyrane Flow Reaction and Synchrotron-Based IR and X-Ray Beam Analysis 174

9.2.6 Integration of Multistep Organic Transformations Catalyzed by Au Nanoclusters 176

9.3 Thermal Integration on a Process Level 177

9.3.1 Thermal Integration of a Methanol Micro-fuel Processor/Fuel Cell 177

9.4 Integration of Units on Racks, Backbones, Frames, Interfaces, or Similar Level 178

9.4.1 Integrated Circuit Socket for Fluidic-Electric Interface 178

9.4.2 Chassis-Type Unit Racking and System Automation 178

9.4.3 Modularization of (Flow) Plant Equipment 179

9.4.4 Modular Gas–Liquid Microreactor 179

9.5 Fully Intensified/Flow Process Development 179

9.5.1 Adipic Acid Large-Scale Manufacture 179

References 183

10 Doing the Same with Less – Process Simplification 185

10.1 Omitting the Use of a Catalyst 185

10.1.1 Air Oxidation of Cyclohexane 185

10.1.2 Bromination of Toluene 185

10.1.3 Tetrazole Click Chemistry 186

10.2 Simplifying Separation 186

10.2.1 Phenyl Boronic Acid Synthesis 187

10.2.2 Simplifying Operation 188

10.2.3 Trans-1,2-Cyclohexanediol – Exothermic Steps Done “All-in-Once” 188

10.2.4 Olefin Autoxidation 189

References 190

11 Implications of NPW to Green and Cost Efficient Processing 191

11.1 Introduction 191

11.2 Knowledge-Based Design of Future Chemistry – Coupling the Implementation of NPWwith Evaluation and Decision Support Tools 192

11.3 Evaluation Methods 192

11.3.1 Single Metrics 193

11.3.2 Holistic Approaches 194

11.3.3 Life Cycle Costing 201

11.3.3.1 Cradle-to-Gate Approach in LCC 202

11.3.3.2 Calculation of Costs 204

11.3.3.3 Separation of Costs in Variable and Fixed Costs 206

11.3.4 Summary of Life Cycle-Based Evaluation Methods 206

11.4 Evaluation of the NPWConcept Impact on Sustainability 206

11.4.1 Evaluation of New Chemical Transformations 207

11.4.1.1 One-Pot Multistep Synthesis of Fine Chemicals 207

11.4.1.2 Avoidance ofWaste Products 207

11.4.2 Evaluation of High-Temperature, High-Pressure Operation 208

11.4.2.1 p-Xylene Partial Oxidation under Harsh Conditions 208

11.4.2.2 Process Intensification of Biodiesel Generation 209

11.4.2.3 Generation of Carbon Nanotubes at High Temperatures 211

11.4.2.4 Activation of Carbon Dioxide 213

11.4.2.5 Impact of Harsh Process Conditions of Catalyst Deactivation 215

11.4.2.6 Methane Decomposition at High Reaction Temperatures 216

11.4.2.7 Synthesis of Fullerenes by Pyrolysis versus Plasma 217

11.4.2.8 Epoxidation Reaction at Accelerated Temperature 219

11.4.2.9 Trade-Off Designs for a Hydrocarbon Biorefinery 220

11.4.3 Reduction and Replacement of Solvents 222

11.4.3.1 Sildenafil Citrate Process 222

11.4.3.2 Suzuki–Miyaura Cross-Coupling 224

11.4.3.3 Synthesis and Application of Ionic Liquids 225

11.4.4 Evaluation of Process Integration 226

11.4.4.1 Acceleration of Multiphase Reactions via Ultrasound 226

11.4.4.2 Process Optimization of a Pharmaceutical Synthesis 229

11.4.4.3 Process Simplification of Adipidic Acid Synthesis 231

11.4.4.4 Process Enhancement via Phase Transfer Catalysis 232

11.4.4.5 Separate Step versus Coproduction for Methanol Production 234

11.4.4.6 Process Integration in Terms of Costs 234

11.4.4.7 The Effects of Modular Plants 235

11.5 Future Environmental and Economic Sustainability Evaluation in the Context of Flow-Chemistry under NPWConditions 236

References 238

12 From Milligrams to Kilograms – Scale-Up in Modular Flow Reactors 241

12.1 Reactor Types 241

12.2 Scale-Up Parameters 243

12.2.1 Geometry 244

12.3 Numbering-Up 246

12.3.1 Internal Numbering-Up 246

12.3.2 External Numbering-Up 246

12.4 Single-Channel Operation 247

12.4.1 Fluid Dynamics in a Rectangular Channel 247

12.4.2 Mean Residence Time and Its Distribution 248

12.4.3 Pressure Loss and Mixing 252

12.4.4 Heat Transfer in Channel Reactors 254

12.4.5 Parametric Sensitivity and Reactor Thermal Stability 256

12.5 Methodology for Continuous-Flow Process Development 258

12.5.1 General Chemical Plants and Modular Setup 261

12.5.2 Platform Concept and Scalability 264

12.5.3 Modular Process Development 267

12.5.3.1 Module A: Feasibility Study – Milestone Decision 268

12.5.3.2 Module B: Process Synthesis and Optimization – Milestone Decision 270

12.5.3.3 Module C: Process Robustness and Economy – Milestone Decision 273

12.5.3.4 Module D: Pilot Production and Commercial Manufacturing 274

12.6 Conclusions 278

References 280

13 Evolution of Novel ProcessWindows 283

13.1 Multifaceted Novel ProcessWindows: Evolution 283

13.1.1 Novel Chemistry – Liberation of Chemical Potential (2005) 283

13.1.2 NPW-Route Classification and Experimental Demonstration (2009) 283

13.1.3 NPW-Reaction Compilation Out of One Source – 1 (2010) 284

13.1.4 NPW-Reaction Compilation Out of One Source – 2 (2010) 284

13.1.5 Flow Chemistry High-T Overview – Superheated Processing (2010) 284

13.1.6 Flow Chemistry High-T Overview – from-Cryo-to-Ambient Processing 285

13.1.7 NPW-Methodology and Intensification Considerations for High-T Flow Reactions (2011) 285

13.2 High-p,T Commercial Flow Chemistry Equipment 286

13.3 Funding Agency Initiatives 286

13.3.1 DBU Cluster Novel ProcessWindows 287

13.3.2 EU Funding 289

References 291

14 Scientific Dissemination of Novel ProcessWindows 293

14.1 Literature Share for Chemical Intensification 293

14.1.1 Search Methodology and Limitations 293

14.1.2 High-Temperature, High-Pressure, High-Concentration in Chemistry and Chemical Engineering Literature 294

14.1.3 High-T, -p, -c in Microreactor Literature 295

14.1.4 High-(T, p, c) and NPWImportance in Current Microreactor and Overall Literature 298

14.2 Literature Share for Process-Design Intensification 298

References 300

15 Outlook 301

15.1 Process Automation 301

15.1.1 Computer-Controlled Flow Processing 301

15.1.2 Process-Automated Application Example 301

15.2 Means of Activation Other than High-Temperature, High-Pressure, High-Concentration, and High-Solvent 303

15.2.1 Photoactivation 303

15.2.2 Activation by Instable Catalyst Precursors 305

References 307

Index 309

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