Preface |
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xiii | |
Acknowledgments |
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xv | |
Authors |
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xvii | |
Abbreviations |
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xix | |
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Chapter 1 Introduction to Micro Reaction Technology |
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1 | (36) |
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1.1 What Is Micro Reaction Technology? |
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1 | (1) |
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1.2 Fabrication/Construction of Micro Reactors |
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2 | (2) |
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2 | (1) |
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3 | (1) |
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3 | (1) |
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3 | (1) |
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4 | (1) |
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1.2.6 Reactor to World Interface |
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4 | (1) |
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1.3 Manipulation of Reactants and Products within Flow Reactors |
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4 | (3) |
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1.3.1 Mixing within Micro Reactors |
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5 | (1) |
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1.3.2 Flow Types within Biphasic Systems |
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6 | (1) |
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1.4 Advantages of Micro Reaction Technology |
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7 | (4) |
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7 | (1) |
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1.4.2 Novel Reaction Conditions |
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8 | (1) |
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1.4.3 Reduced Waste Generation |
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9 | (2) |
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1.4.4 On-Site Chemical Processing |
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11 | (1) |
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1.5 Disadvantages of Micro Reactors |
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11 | (2) |
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1.5.1 Handling of Insoluble Materials |
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12 | (1) |
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1.6 Process Intensification |
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13 | (1) |
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1.7 In Situ Reaction Monitoring |
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14 | (10) |
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14 | (2) |
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1.7.2 In Situ Analysis by FTIR Spectroscopy |
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16 | (5) |
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1.7.3 Nuclear Magnetic Resonance Detection |
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21 | (1) |
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1.7.4 Chromatographic Techniques |
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22 | (1) |
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1.7.5 Development of Sensors for Process Monitoring |
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23 | (1) |
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1.8 Commercial Availability of Continuous Flow Reactor Technology |
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24 | (7) |
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31 | (1) |
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31 | (6) |
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Chapter 2 Micro Reactions Employing a Gaseous Component |
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37 | (40) |
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2.1 Gas-Phase Micro Reactions |
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37 | (7) |
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2.1.1 Gas-Phase Oxidations |
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38 | (3) |
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2.1.2 Hydrogenation Reactions within Microstructured Reactors |
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41 | (1) |
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2.1.3 Dehydration and Dehydrogenation Reactions |
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42 | (1) |
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2.1.4 Fischer-Tropsch Synthesis |
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43 | (1) |
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2.1.5 Synthesis of Methylisocyanate in a Micro Reactor |
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43 | (1) |
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2.2 Gas-Liquid-Phase Micro Reactions |
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44 | (16) |
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2.2.1 Continuous Flow Chlorination Reactions |
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44 | (1) |
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2.2.2 Continuous Flow Fluorination Reactions |
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45 | (1) |
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2.2.3 Ozonolysis within Micro Reactors |
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45 | (3) |
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2.2.4 Biphasic Carbonylations |
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48 | (7) |
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2.2.5 Transfer Hydrogenations under Continuous Flow Conditions |
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55 | (2) |
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2.2.6 Miscellaneous Biphasic Micro Reactions |
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57 | (3) |
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2.3 Gas-Liquid-Solid Micro Reactions |
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60 | (10) |
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2.3.1 Triphasic Oxidations under Flow Conditions |
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61 | (1) |
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2.3.2 Carbonylations Using Solid-Supported Catalysts |
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62 | (1) |
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2.3.3 Hydrogenations within Continuous Flow Reactors |
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63 | (3) |
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2.3.4 Slurry-Based Micro Reactions |
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66 | (3) |
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2.3.5 Miscellaneous Triphasic Micro Reactions |
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69 | (1) |
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70 | (7) |
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Chapter 3 Liquid-Phase Micro Reactions |
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77 | (144) |
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3.1 Nucleophilic Substitution |
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77 | (36) |
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3.1.1 C-C Bond Formation: Acylation Reactions |
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77 | (1) |
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3.1.2 C-C Bond Formation: Alkylation Reactions |
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78 | (5) |
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3.1.3 Enantioselective C-C Bond-Forming Reactions |
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83 | (2) |
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3.1.4 C-O Bond Formation: Esterification Reactions |
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85 | (4) |
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3.1.5 C-O Bond Formation: Etherification Reactions |
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89 | (1) |
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3.1.6 C-O Bond Formation: Epoxide Hydrolysis |
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90 | (1) |
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3.1.7 C-N Bond Formation: Alkylation Reactions |
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90 | (3) |
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3.1.8 C-N Bond Formation: Acylation Reactions |
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93 | (5) |
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3.1.9 C-N Bond Formation: Arylation Reactions |
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98 | (1) |
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3.1.10 C-N Bond Formation: Azidation Reactions |
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99 | (3) |
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3.1.11 C-N Bond Formation: Synthesis of Hydroxamic Acids |
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102 | (1) |
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3.1.12 C-N Bond Formation: Aminolysis of Epoxides |
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103 | (6) |
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3.1.13 C-F Bond Formation |
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109 | (4) |
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3.2 Electrophilic Substitution |
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113 | (23) |
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113 | (13) |
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3.2.2 C-N Bond-Forming Reactions: Nitration Reactions |
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126 | (4) |
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3.2.3 C-Hetero Bond-Forming Reactions: Halogenations under Flow |
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130 | (3) |
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3.2.4 C-Hetero Bond-Forming Reactions: Diazotizations under Flow |
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133 | (3) |
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3.2.5 C-Hetero Bond-Forming Reactions: Sulfonations under Flow |
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136 | (1) |
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3.3 Nucleophilic Addition |
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136 | (22) |
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3.3.1 C-C Bond Formation: Aldol Reaction/Condensation |
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136 | (3) |
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3.3.2 C-C Bond Formation: Knoevenagel Condensation |
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139 | (3) |
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3.3.3 C-C Bond Formation: Michael Addition |
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142 | (2) |
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3.3.4 C-C Bond Formation: Diels-Alder Reaction |
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144 | (2) |
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3.3.5 C-C Bond Formation: Horner-Wadsworth-Emmons |
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146 | (2) |
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3.3.6 C-C Bond Formation: Enantioselective Examples |
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148 | (1) |
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3.3.7 C-Hetero Bond Formation: Aza-Michael Addition |
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149 | (2) |
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3.3.8 C-Hetero Bond Formation: Alkylation of Amines |
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151 | (1) |
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3.3.9 C-Hetero Bond Formation: Synthesis of Triazoles |
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152 | (5) |
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3.3.10 C-Hetero Bond Formation: Addition of Hydrazine to Carbonyl Compounds |
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157 | (1) |
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3.4 Elimination Reactions |
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158 | (5) |
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3.4.1 Dehydration Reactions |
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158 | (2) |
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3.4.2 Dehalogenations: Tris(Trimethylsilyl)Silane-Mediated Reductions |
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160 | (3) |
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163 | (10) |
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3.5.1 Oxidations: Inorganic Oxidants |
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163 | (1) |
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3.5.2 Oxidations: Swern-Moffat Oxidation |
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164 | (3) |
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3.5.3 Oxidations: TEMPO-Mediated Oxidations |
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167 | (1) |
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3.5.4 Oxidations Using Oxone |
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168 | (1) |
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3.5.5 Oxidations: Epoxidations under Flow Conditions |
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168 | (4) |
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3.5.6 Oxidation: Deprotection of Amines |
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172 | (1) |
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173 | (2) |
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3.6.1 Transition Metal Free Reductions |
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173 | (1) |
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173 | (2) |
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3.7 Metal-Catalyzed Cross-Coupling Reactions |
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175 | (12) |
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3.7.1 Suzuki-Miyaura Reaction |
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175 | (2) |
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177 | (6) |
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3.7.3 Sonogashira Reaction |
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183 | (2) |
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3.7.4 Other Metal-Catalyzed Coupling Reactions |
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185 | (2) |
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187 | (11) |
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3.8.1 Claisen Rearrangement |
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187 | (4) |
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3.8.2 Newman-Kwart Rearrangement |
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191 | (2) |
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3.8.3 Hofmann Rearrangement |
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193 | (2) |
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3.8.4 Fisher Indolization |
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195 | (1) |
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3.8.5 Curtius Rearrangement |
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196 | (1) |
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3.8.6 Dimroth Rearrangement |
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197 | (1) |
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3.9 Multistep/Multicomponent Liquid-Phase Reactions |
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198 | (13) |
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3.9.1 Multicomponent Synthesis of Heterocycles |
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198 | (1) |
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3.9.2 Multistep Synthesis of 1,2,4-Oxadiazoles |
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199 | (2) |
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3.9.3 Continuous Flow Synthesis of Ibuprofen |
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201 | (2) |
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3.9.4 Cation-Mediated Sialylation Reactions |
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203 | (2) |
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3.9.5 Oligosaccharide Synthesis |
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205 | (1) |
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3.9.6 Synthesis of Indole Alkaloids Using Metal-Coated Capillary Reactors |
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206 | (1) |
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3.9.7 Iododeamination under Flow |
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206 | (3) |
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3.9.8 Radical Additions under Flow |
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209 | (2) |
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211 | (1) |
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211 | (10) |
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Chapter 4 Multi-Phase Micro Reactions |
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221 | (68) |
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4.1 Nucleophilic Substitution |
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221 | (4) |
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4.1.1 C-O Bond-Forming Reactions: Esterifications |
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221 | (3) |
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4.1.2 C-N Bond-Forming Reactions: Azidations |
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224 | (1) |
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4.2 Electrophilic Substitution |
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225 | (2) |
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225 | (1) |
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226 | (1) |
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4.3 Nucleophilic Addition |
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227 | (14) |
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4.3.1 C-C Bond-Forming Reactions: Knoevenagel Condensation |
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227 | (2) |
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4.3.2 C-C Bond-Forming Reactions: Michael Additions |
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229 | (1) |
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4.3.3 C-C Bond-Forming Reactions: Henry Reaction |
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230 | (2) |
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4.3.4 C-C Bond-Forming Reactions: Diels-Alder |
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232 | (1) |
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4.3.5 C-C Bond-Forming Reactions: Benzoin Condensation |
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232 | (2) |
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4.3.6 C-C Bond-Forming Reactions: Trifluoromethylation under Continuous Flow |
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234 | (1) |
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4.3.7 C-C Bond Formation: Aldol Reaction |
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234 | (3) |
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4.3.8 C-N Bond Formation: Cycloaddition Reactions |
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237 | (3) |
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4.3.9 C-O Bond-Forming Reactions: Acetalizations |
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240 | (1) |
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4.3.10 C-S Bond-Forming Reactions: Thioacetalizations |
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241 | (1) |
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4.4 Elimination Reactions |
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241 | (1) |
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4.4.1 Dehydration Reactions |
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241 | (1) |
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4.4.2 Dehydration Reactions |
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242 | (1) |
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242 | (8) |
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4.5.1 Catalytic Oxidations |
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243 | (4) |
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247 | (3) |
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4.6 Metal-Catalyzed Cross-Coupling Reactions |
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250 | (11) |
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4.6.1 Suzuki-Miyaura Reaction |
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250 | (2) |
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4.6.2 Heck Coupling Reactions |
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252 | (3) |
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4.6.3 Other Metal-Catalyzed Coupling Reactions |
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255 | (6) |
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261 | (1) |
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4.8 Enantioselective Reactions |
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262 | (10) |
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4.8.1 Chemically Promoted Reactions |
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262 | (4) |
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4.8.2 Enzymatic Enantioselective Micro Reactions |
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266 | (6) |
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4.9 Multistep/Multicomponent Reactions |
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272 | (9) |
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4.9.1 Independent Multistep Flow Reactions |
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272 | (1) |
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4.9.2 Integrated Multistep Sequences |
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272 | (2) |
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4.9.3 Reagents and Scavengers in Series |
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274 | (1) |
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4.9.4 Combined Chemical and Biochemical Catalysis |
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274 | (3) |
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4.9.5 "Catch and Release" Strategies under Continuous Flow |
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277 | (3) |
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4.9.6 Casein Kinase I Inhibitor Synthesis |
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280 | (1) |
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281 | (2) |
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283 | (6) |
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Chapter 5 Electrochemical and Photochemical Applications of Micro Reaction Technology |
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289 | (36) |
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5.1 Electrochemical Synthesis under Continuous Flow |
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289 | (13) |
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5.1.1 Electrochemical Oxidations |
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290 | (6) |
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5.1.2 Electrolyte-Free Electroorganic Synthesis |
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296 | (2) |
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5.1.3 Electrochemical Reductions |
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298 | (1) |
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5.1.4 Electrolyte-Free Reductions under Flow |
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299 | (2) |
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301 | (1) |
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5.2 Photochemical Synthesis under Continuous Flow |
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302 | (10) |
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5.2.1 Photocycloadditions under Continuous Flow |
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303 | (4) |
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5.2.2 Photodecarboxylative Addition |
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307 | (1) |
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307 | (1) |
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5.2.4 Photochemical Halogenations |
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308 | (1) |
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5.2.5 Nitrite Photolysis under Flow Conditions |
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309 | (2) |
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5.2.6 Photochemical Dimerization |
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311 | (1) |
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5.2.7 Photosensitized Diastereo Differentiation |
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312 | (1) |
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5.3 Multiphase Photochemical Reactions |
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312 | (9) |
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5.3.1 Photocatalytic Reductions |
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313 | (1) |
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5.3.2 Photocatalytic Oxidation Reactions |
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314 | (1) |
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5.3.3 Photocatalytic Alkylation Reactions |
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315 | (1) |
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5.3.4 Photocatalytic Cyclizations |
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316 | (1) |
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5.3.5 Gas-Liquid Transformations |
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317 | (4) |
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5.3.6 Gas-Liquid-Solid Reactions |
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321 | (1) |
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321 | (1) |
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321 | (4) |
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Chapter 6 The Use of Microfluidic Devices for the Preparation and Manipulation of Droplets and Inorganic/Organic Particles |
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325 | (22) |
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6.1 Droplet Formation Using Continuous Flow Methodology |
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325 | (5) |
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6.1.1 Polymerization of Droplets under Flow |
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328 | (2) |
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6.2 Preparation of Inorganic Nanoparticles under Continuous Processing Conditions |
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330 | (2) |
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6.3 Formation of Organic Particles within Continuous Flow Devices |
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332 | (4) |
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6.4 The Use of Micro Reactors for the Postsynthetic Manipulation of Organic Compounds |
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336 | (2) |
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6.5 Mixed Particle Formation |
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338 | (3) |
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6.5.1 Microencapsulation of Active Pharmaceuticals |
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338 | (3) |
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341 | (2) |
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343 | (4) |
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Chapter 7 Industrial Interest in Micro Reaction Technology |
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347 | (40) |
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7.1 MRT in Production Environments |
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347 | (2) |
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7.2 Synthesis of Fine Chemicals Using Micro Reactors |
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349 | (14) |
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7.2.1 Synthesis of Carbamates under Continuous Flow Conditions |
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350 | (1) |
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7.2.2 Production-Scale Synthesis of Ionic Liquids |
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351 | (2) |
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7.2.3 Scalable Technique for the Synthesis of Diarylethenes |
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353 | (1) |
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7.2.4 Continuous Flow Synthesis of Light-Emitting Materials |
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354 | (2) |
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7.2.5 2-(2,5-Dimethyl-1H-Pyrrol-1-yl)Ethanol Synthesis |
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356 | (1) |
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7.2.6 Synthesis of Pigments under Flow Conditions |
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357 | (1) |
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7.2.7 Production of Thermally Labile Compounds under Flow Conditions |
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358 | (2) |
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7.2.8 Peracetic Acid Production Using an On-Site Microprocess |
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360 | (2) |
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7.2.9 The In Situ Synthesis and Use of Diazomethane |
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362 | (1) |
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7.3 Synthesis of Pharmaceuticals and Natural Products Using Continuous Flow Methodology |
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363 | (19) |
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7.3.1 Ciprofloxacin and Its Analogs |
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363 | (1) |
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7.3.2 Synthesis of Pristane |
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363 | (3) |
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7.3.3 Synthesis of Imatinib under Flow Conditions |
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366 | (2) |
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7.3.4 Synthesis of Aspirin and Vanisal Sodium |
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368 | (1) |
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7.3.5 Synthesis of Suberoylanilide Hydroxamic Acid |
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369 | (1) |
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7.3.6 Synthesis of Rimonabant and Efaproxiral Using AlMe3 |
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370 | (2) |
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7.3.7 Continuous Flow Synthesis of Sildenafil |
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372 | (1) |
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7.3.8 Synthesis of 6-Hydroxybuspirone |
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372 | (1) |
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7.3.9 A Key Step in the Synthesis of (rac)-Tramadol |
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373 | (1) |
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7.3.10 Claisen Rearrangement to Afford 2,2-Dimethyl-2H-1-Benzopyrans |
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373 | (2) |
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7.3.11 Synthesis of a 5HT1B Antagonist |
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375 | (3) |
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7.3.12 Serial Approach to a Novel Anticancer Agent Using Flow Reactors |
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378 | (1) |
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7.3.13 Synthesis of Grossamide under Flow Conditions |
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378 | (1) |
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7.3.14 Synthesis of the Natural Product (±)-Oxomaritidine |
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378 | (3) |
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7.3.15 Synthesis of Furofuran Ligans |
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381 | (1) |
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7.4 Synthesis of Small Doses of Radiopharmaceuticals |
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382 | (2) |
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384 | (1) |
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384 | (3) |
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Chapter 8 Microscale Continuous Separations and Purifications |
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387 | (40) |
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387 | (1) |
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8.2 Liquid-Liquid Extractions |
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387 | (16) |
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8.2.1 Side-by-Side (Stratified) Contacting |
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388 | (4) |
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8.2.2 Three-Phase Microextractions |
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392 | (3) |
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395 | (3) |
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8.2.4 Fluorous Phase Extractions |
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398 | (3) |
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8.2.5 Comparison of Liquid-Liquid Extraction Efficiencies |
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401 | (2) |
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8.3 Gas-Liquid Separation |
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403 | (4) |
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8.3.1 Membrane Separators |
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403 | (1) |
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8.3.2 Microfluidic Distillations |
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403 | (4) |
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8.4 Solvent Exchange and Solvent Removal |
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407 | (3) |
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8.5 The Use of Scavenger Resins for Product Purification under Flow |
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410 | (3) |
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8.5.1 Trace Metal Removal |
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410 | (1) |
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8.5.2 Removal of Unreacted Starting Materials |
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411 | (2) |
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8.6 Continuous Flow Resolutions |
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413 | (5) |
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8.6.1 Biocatalytic Resolutions |
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415 | (1) |
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8.6.2 Chemical Racemization |
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416 | (2) |
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418 | (3) |
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8.7.1 Antisolvent Precipitation |
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418 | (2) |
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8.7.2 Lysozyme Crystallization |
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420 | (1) |
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8.7.3 Solution Crystallization |
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420 | (1) |
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421 | (1) |
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421 | (6) |
Index |
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427 | |