Basics of Flow Microreactor Synthesis (eBook)

Preface 6
Contents 7
1 Departure from Flask Chemistry 10
Abstract 10
1.1 Introduction 10
1.2 Flow Reactors and Batch Reactors 11
1.3 Fluid Dynamics 11
1.4 Residence Time 12
1.5 Relationship Between Residence Time and Reaction Time 13
1.6 How Reaction Proceeds in Batch Reactor 13
1.7 How Reaction Proceeds in Flow Reactor 14
1.8 How to Set Residence Time 15
1.9 Looking Forward 17
Reference 17
2 Controlling Residence Time 18
Abstract 18
2.1 Introduction 18
2.2 Monitoring the Progress of a Reaction in a Flow Reactor: Inline Analysis 19
2.3 Monitoring the Progress of a Reaction in a Flow Reactor: Quench-Flow Method [2, 3] 20
2.4 Generation and Reactions of Oxiranyllthiums: An Example of Quench-Flow Method [4, 5] 20
2.5 General Consideration on Controlling Reactions Involving Unstable Intermediates [13] 24
2.6 Temperature--Residence Time Mapping 27
2.7 Looking Forward 28
References 28
3 Fast Micromixing for High-Resolution Reaction Time Control 29
Abstract 29
3.1 Introduction 29
3.2 What Is Mixing? 30
3.3 Mixing by Stirring [1, 2] 31
3.4 Mixing Using Micromixer [1, 2] 33
3.5 Measuring Mixing Efficiency or Speed 37
3.6 Looking Forward 37
References 38
4 Use of Short-Lived Reactive Species Achieved by High-Resolution Reaction Time Control 39
Abstract 39
4.1 Introduction 39
4.2 Generation of Organometallic Species Containing Alkoxycarbonyl Groups 39
4.3 Decreasing the Reactivity of Organometallic Reagents to Increase Compatibility 40
4.4 Br--Li Exchange Reactions of Alkyl o-Bromobenzoates in a Batch Reactor [7, 8] 42
4.5 Br--Li Exchange Reactions of Alkyl o-Bromobenzoates in a Flow Microreactor [7, 8] 42
4.6 Br--Li Exchange Reactions of Alkyl p-Bromobenzoates in a Flow Microreactor [7, 8] 45
4.7 I--Li Exchange Reactions of Alkyl p-Iodobenzoates in a Flow Microreactor [5] 47
4.8 Looking Forward 49
References 49
5 Protecting-Group-Free Synthesis Achieved by High-Resolution Reaction Time Control 50
Abstract 50
5.1 Introduction 50
5.2 Protecting Group 50
5.3 Reactions of Organometallic Reagents with Carbonyl Groups [6] 51
5.4 Generation and Reaction of Aryllithium Species Bearing Ketone Carbonyl Groups 53
References 57
6 Controlling Isomerization by High-Resolution Reaction Time Control 58
Abstract 58
6.1 Introduction 58
6.2 Controlling Positional Isomers [1] 59
6.3 Controlling Diastereomers [2, 3] 59
6.4 Controlling Stereoisomers (Enantiomers) [4] 63
References 65
7 Controlling Competitive Consecutive Reactions Using Micromixing 66
Abstract 66
7.1 Introduction 66
7.2 Factors Determining Selectivity in Chemical Reactions 67
7.3 Competitive Consecutive Reactions 67
7.4 Disguised Chemical Selectivity [1, 2] 68
7.5 Controlling Selectivity of Friedel--Crafts-Type Reactions Using Micromixing [3, 4] 69
7.6 CFD Simulations 73
7.7 Controlling Other Reactions Using Micromixing 75
References 77
8 Flash Chemistry 79
Abstract 79
8.1 Introduction 79
8.2 What Is Flash Chemistry? 79
8.3 Some Examples of Flash Chemistry 80
8.4 Scientific Merits 81
8.5 High Productivity and Impact on Industry 82
References 82
9 Space Integration of Reactions 84
Abstract 84
9.1 Introduction 84
9.2 Integrating Reactions 84
9.3 Synthesizing o-Disubstituted Benzenes by Space Integration of Two Organolithium Reactions [3, 4] 86
9.4 Synthesizing TAC-101 by Integration of Three Organolithium Reactions [6] 88
9.5 Space Integration of Halogen--Lithium Exchange Reaction and Cross-Coupling Reaction [7] 88
References 91
10 Polymerization Using Flow Microreactor System 92
Abstract 92
10.1 Introduction 92
10.2 Controlling Competitive Consecutive Reactions and Chain-Growth Polymerization 92
10.3 Chemistry of Cationic Polymerization 94
10.4 Flash Cationic Polymerization 96
10.5 Flash Anionic Polymerization 100
10.6 Other Polymerizations Using Flow Microreactor System 103
References 104
11 Outlook 105
Appendix 106
Books on Flow Microreactor Synthesis 106
Review Articles on Flow Microreactor Synthesis 107