This book introduces the concept of novel process windows, focusing on cost improvements, safety, energy and eco-efficiency throughout each step of the process.
The first part presents the new reactor and process-related technologies, introducing the potential and benefit analysis. The core of the book details scenarios for unusual parameter sets and the new holistic and systemic approach to processing, while the final part analyses the implications for green and cost-efficient processing.
With its practical approach, this is invaluable reading for those working in the pharmaceutical, fine chemicals, fuels and oils industries.
Содержание
Motivation –Who should read the book!? XVII
Acknowledgments XIX
Abbreviations XXI
Nomenclature XXIII
1 From Green Chemistry to Green Engineering – Fostered by Novel Process Windows 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 Process Windows 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 Temperature Windows 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 and Thermal 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 Os O4 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-Scope Widening by Virtue of Pressurizing Existing High-T Reactions 116
6.4.1 Nucleophilic Aromatic Substitution of 2-Halopyridines 116
6.4.2 Intramolecular Thermal 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 of Three 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 sc CO2 Droplets or Jets in Liquid Water 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 Enantioselective Thermal 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 Silia Cat 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-sc CO2 Enzymatic Biodiesel Synthesis 157
8.3.6 Supercritical Water, Non-Catalytic Beckmann Rearrangement 158
8.3.7 Supercritical Water, Non-Catalytic Pinacol Rearrangement 159
8.3.8 Supercritical Water 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 of Waste 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 Process Windows 283
13.1 Multifaceted Novel Process Windows: 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 Process Windows 287
13.3.2 EU Funding 289
References 291
14 Scientific Dissemination of Novel Process Windows 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
Об авторе
Volker Hessel, born 1964, is the Director of R&D and Head of the Chemical Process Technology Department at the Institute for Microtechnology Mainz Gmb H (IMM), Germany. His department focuses on mixing, fine chemistry, and energy generation by fuel processing using microstructured reactors. He was awarded his Ph.D. from the University of Mainz in organic chemistry in 1993, investigating structure-property relations of supramolecular structures. After having been appointed Group Leader for Microreaction Technology at the IMM in 1996, he became head of the newly founded Department of Microreaction Technology in 1999. He is author of more than 150 peer-reviewed publications in the fields of organic chemistry and chemical micro process engineering, 200 papers in total, five books and 15 patents. In July 2005, Prof. Dr. Hessel was appointed as part-time professor for the chair of Micro Process Engineering at Eindhoven University of Technology, TU/e. This professorship is under the umbrella of the Chemical Reactor Engineering group of Prof. Dr.ir. Jaap Schouten in the Department of Chemical Engineering and Chemistry. In September, 2009, he was appointed an honorary professorship at the Technical Chemistry Department at Technical University of Darmstadt.
Dr.-Ing. habil. Norbert Kockmann, born 1966, studied mechanical engineering at Technical University of Munich and received his diploma in 1991. Dr. Kockmann was awarded his doctorate thesis in 1996 on fouling in falling film evaporators and its mitigation from The University of Bremen. In 1997, Dr. Kockmann worked as a project engineer at Messer Griesheim, Germany and was project manager for air separation units and a syngas plant. After 5 years industrial experience, he formed a research group for micro process engineering at the IMTEK Albert-Ludwig University of Freiburg, and was awarded his habilitation in 2007 on transport phenomena in micro process engineering. Since October 2007, Dr. Kockmann is senior researcher at Lonza Ltd, Visp, Switzerland and responsible for microreactor development and continuous-flow reactor technology. His fields of research comprise micro process engineering for mixing, heat transfer, fine chemistry and pharmaceutics, and micro reactor development and fabrication. Dr. Kockmann is author or co-author of more than 30 journal publications and 65 conference contributions, five book chapters, and two books. In 2009, Dr. Kockmann received the ASME award ICNMM09 Outstanding Researcher in Transport Phenomena in Microchannels.
Dana Kralisch, born in 1973, studied environmental chemistry at the Friedrich-Schiller-University (FSU), Jena, Germany. After two years consulting in environmental analytics at the Agency for Agriculture of the Federal State of Thuringia, she started to work as a research assistant at the Institute of Technical and Environmental Chemistry (FSU) in 2002. In her work she concentrated on the integration of sustainability criteria into chemical process development with a focus on micro reaction technology and ionic liquids. In 2006, she was awarded her Ph D from the School of Chemical and Earth Sciences (FSU).Since 2007, she is leading the Green Process Engineering and Evaluation Research Group at the Institute of Technical and Environmental Chemistry. She is currently working on the coupling of life cycle assessment and green chemical process design in the framework of the German Novel Process Windows cluster and in the context of nanocellulose research. Dr. Kralisch is author or co-author of 13 per-reviewed publications, 4 book chapters, 27 conference contributions and two patents.
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