Flash chemistry: fast chemical synthesis by using microreactors.

This concept article provides a brief outline of the concept of flash chemistry for carrying out extremely fast reactions in organic synthesis by using microreactors. Generation of highly reactive species is one of the key elements of flash chemistry. Another important element of flash chemistry is the control of extremely fast reactions to obtain the desired products selectively. Fast reactions are usually highly exothermic, and heat removal is an important factor in controlling such reactions. Heat transfer occurs very rapidly in microreactors by virtue of a large surface area per unit volume, making precise temperature control possible. Fast reactions often involve highly unstable intermediates, which decompose very quickly, making reaction control difficult. The residence time can be greatly reduced in microreactors, and this feature is quite effective in controlling such reactions. For extremely fast reactions, kinetics often cannot be used because of the lack of homogeneity of the reaction environment when they are conducted in conventional reactors such as flasks. Fast mixing using micromixers solves such problems. The concept of flash chemistry has been successfully applied to various organic reactions including a) highly exothermic reactions that are difficult to control in conventional reactors, b) reactions in which a reactive intermediate easily decomposes in conventional reactors, c) reactions in which undesired byproducts are produced in the subsequent reactions in conventional reactors, and d) reactions whose products easily decompose in conventional reactors. The concept of flash chemistry can be also applied to polymer synthesis. Cationic polymerization can be conducted with an excellent level of molecular-weight control and molecular-weight distribution control.

[1]  J. Yoshida Flash chemistry using electrochemical method and microsystems. , 2005, Chemical communications.

[2]  Selim Senkan,et al.  Combinatorial Heterogeneous Catalysis-A New Path in an Old Field. , 2001, Angewandte Chemie.

[3]  R. Chambers,et al.  Elemental fluorine. Part 13. Gas-liquid thin film microreactors for selective direct fluorination. , 2001, Lab on a chip.

[4]  Mar Michael Meier,et al.  Combinatorial Methods, Automated Synthesis and High-Throughput Screening in Polymer Research: Past and Present , 2003 .

[5]  Jandeleit,et al.  Combinatorial Materials Science and Catalysis. , 1999, Angewandte Chemie.

[6]  Peter H Seeberger,et al.  Oligosaccharide synthesis in microreactors. , 2007, Organic letters.

[7]  Jan Passchier,et al.  Rapid multiphase carbonylation reactions by using a microtube reactor: applications in positron emission tomography 11C-radiolabeling. , 2007, Angewandte Chemie.

[8]  M. Sawamoto Modern cationic vinyl polymerization , 1991 .

[9]  Holger Löwe,et al.  Addition of Secondary Amines to α,β-Unsaturated Carbonyl Compounds and Nitriles by Using Microstructured Reactors , 2006 .

[10]  V. Hessel,et al.  Numerical simulation of polymerization in interdigital multilamination micromixers. , 2005, Lab on a chip.

[11]  Combinatorial Materials Research in the Polymer Industry: Speed versus Flexibility , 2003 .

[12]  H. Löwe,et al.  Chemistry in microstructured reactors. , 2004, Angewandte Chemie.

[13]  Yoichi M. A. Yamada,et al.  Instantaneous Carbon−Carbon Bond Formation Using a Microchannel Reactor with a Catalytic Membrane , 2006 .

[14]  David Linke,et al.  Application of microstructured reactor technology for the photochemical chlorination of alkylaromatics , 2002 .

[15]  Paul Watts,et al.  The application of micro reactors for organic synthesis. , 2005, Chemical Society reviews.

[16]  Ying Mei,et al.  Block Copolymer PEO‐b‐PHPMA Synthesis Using Controlled Radical Polymerization on a Chip , 2005 .

[17]  T. Wirth,et al.  Advanced organic synthesis using microreactor technology. , 2007, Organic & biomolecular chemistry.

[18]  F. Weinhold Geometric representation of equilibrium thermodynamics , 1976 .

[19]  Holger Löwe,et al.  Polymerisationen in mikrostrukturierten Reaktoren: Ein Überblick , 2005 .

[20]  R. Chambers,et al.  Elemental fluorine. Part 16. Versatile thin-film gas-liquid multi-channel microreactors for effective scale-out. , 2005, Lab on a chip.

[21]  Jun-ichi Yoshida,et al.  Generation and reactions of o-bromophenyllithium without benzyne formation using a microreactor. , 2007, Journal of the American Chemical Society.

[22]  Markus Kinzl,et al.  Development of an automated microreaction system with integrated sensorics for process screening and production , 2004 .

[23]  K. Mae,et al.  Room-temperature Swern oxidations by using a microscale flow system. , 2005, Angewandte Chemie.

[24]  Albert van den Berg,et al.  On-microchip multiphase chemistry - a review of microreactor design principles and reagent contacting modes , 2005 .

[25]  Christopher W. Jones,et al.  Continuous Living Polymerization in Miniemulsion Using Reversible Addition Fragmentation Chain Transfer (RAFT) in a Tubular Reactor , 2005 .

[26]  Peter H. Seeberger,et al.  Microreactor Synthesis of β‐Peptides , 2006 .

[27]  J. Kobayashi,et al.  Multiphase organic synthesis in microchannel reactors. , 2006, Chemistry, an Asian journal.

[28]  R. Chambers,et al.  Elemental fluorine. Part 18. Selective direct fluorination of 1,3-ketoesters and 1,3-diketones using gas/liquid microreactor technology. , 2005, Lab on a chip.

[29]  K. Beers,et al.  Microchannel confined surface-initiated polymerization , 2005 .

[30]  J. Yoshida,et al.  Grignard Exchange Reaction Using a Microflow System: From Bench to Pilot Plant , 2005 .

[31]  M. Sawamoto,et al.  Living Polymerization and Selective Dimerization: Two Extremes of the Polymer Synthesis by Cationic Polymerization , 1984 .

[32]  M. Cunningham,et al.  Nitroxide-Mediated Polymerization of Styrene in a Continuous Tubular Reactor , 2005 .

[33]  Christopher W. Jones,et al.  Continuous Reversible Addition-Fragmentation Chain Transfer Polymerization in Miniemulsion Utilizing a Multi-Tube Reaction System , 2004 .

[34]  Adeniyi Lawal,et al.  Nitration of toluene in a microreactor , 2007 .

[35]  Jun-ichi Yoshida,et al.  Cation pool-initiated controlled/living polymerization using microsystems. , 2004, Journal of the American Chemical Society.

[36]  G. Hadziioannou,et al.  High-temperature nitroxide-mediated radical polymerization in a continuous microtube reactor: Towards a better control of the polymerization reaction , 2007 .

[37]  K. Jensen,et al.  Multistep continuous-flow microchemical synthesis involving multiple reactions and separations. , 2007, Angewandte Chemie.

[38]  Takashi Okazoe,et al.  Versatile Gas/Liquid Microreactors for Industry , 2005 .

[39]  J. Yoshida,et al.  Cycloaddition of "N-Acyliminium ion pools" with carbon-carbon multiple bonds , 2005 .

[40]  J. Yoshida,et al.  Free Radical Polymerization in Microreactors. Significant Improvement in Molecular Weight Distribution Control , 2005 .

[41]  Jun-ichi Yoshida,et al.  Microsystem controlled cationic polymerization of vinyl ethers initiated by CF3SO3H. , 2007, Chemical communications.

[42]  Takahide Fukuyama,et al.  Spurring radical reactions of organic halides with tin hydride and TTMSS using microreactors. , 2008, Organic letters.

[43]  Laurent Ducry,et al.  Controlled autocatalytic nitration of phenol in a microreactor. , 2005, Angewandte Chemie.

[44]  J. Yoshida,et al.  Synthesis of photochromic diarylethenes using a microflow system. , 2007, Chemical communications.

[45]  Masaaki Sato,et al.  Low pressure Pd-catalyzed carbonylation in an ionic liquid using a multiphase microflow system. , 2006, Chemical communications.

[46]  J. Yoshida,et al.  Three-component coupling based on the "cation pool" method. , 2004, Journal of the American Chemical Society.

[47]  J. Yoshida,et al.  "N-acyliminium ion pool" as a heterodiene in [4 + 2] cycloaddition reaction. , 2003, Organic letters.

[48]  Naoya Kawano,et al.  Radical polymerization using microflow system: Numbering-up of microreactors and continuous operation , 2006 .

[49]  M. T. Reetz,et al.  Kombinatorische und evolutionsgesteuerte Methoden zur Bildung enantioselektiver Katalysatoren , 2001 .

[50]  M. Sawamoto,et al.  Metal-catalyzed living radical polymerization. , 2001, Chemical reviews.

[51]  Dale L Boger,et al.  Solution-phase combinatorial libraries: modulating cellular signaling by targeting protein-protein or protein-DNA interactions. , 2003, Angewandte Chemie.

[52]  K. Mae,et al.  Control of extremely fast competitive consecutive reactions using micromixing. Selective Friedel-Crafts aminoalkylation. , 2005, Journal of the American Chemical Society.

[53]  G M Greenway,et al.  Electric field-induced mobilisation of multiphase solution systems based on the nitration of benzene in a micro reactor. , 2001, The Analyst.

[54]  Masahiro Sato,et al.  Rapid and highly selective copper-free sonogashira coupling in high-pressure, high-temperature water in a microfluidic system. , 2007, Angewandte Chemie.

[55]  Jun-ichi Yoshida,et al.  Integrated micro flow synthesis based on sequential Br-Li exchange reactions of p-, m-, and o-dibromobenzenes. , 2007, Chemistry, an Asian journal.

[56]  J. Yoshida,et al.  Highly selective Friedel-Crafts monoalkylation using micromixing. , 2003, Chemical communications.

[57]  Andrés E. Goeta,et al.  Elemental fluorine: Part 20. Direct fluorination of deactivated aromatic systems using microreactor techniques , 2007 .

[58]  J. Yoshida,et al.  Reactions of a N-acyliminium ion pool with benzylsilanes. Implication of a radical/cation/radical cation chain mechanism involving oxidative C-Si bond cleavage. , 2007, Journal of the American Chemical Society.

[59]  Paul Watts,et al.  Micro reactors: principles and applications in organic synthesis , 2002 .

[60]  Howard Turner,et al.  Kombinatorische Materialforschung und Katalyse , 1999 .

[61]  Thomas Schwalbe,et al.  Novel Innovation Systems for a Cellular Approach to Continuous Process Chemistry from Discovery to Market , 2004 .

[62]  J. Yoshida,et al.  "Cation pool" method based on C-C bond dissociation. Effective generation of monocations and dications. , 2005, Journal of the American Chemical Society.

[63]  Y. Kato,et al.  Pharmaceutical Industrial Experiments on Continuous Cryogenic Reactions Using Mini-Sized Multi-Stage Reactors , 2006 .

[64]  Holger Löwe,et al.  Fluorinations, Chlorinations and Brominations of Organic Compounds in Micro Reactors , 2004 .

[65]  Selim Senkan Kombinatorische heterogene Katalyse – ein neuer Weg in einem alten Gebiet , 2001 .

[66]  Paul Rys The Selectivity of Chemical Reactions Disguised by Diffusion. Part I: Chemical Selectivity Disguised by Mixing , 1977 .

[67]  M. Sawamoto,et al.  Living polymerization of isobutyl vinyl ether with hydrogen iodide/iodine initiating system , 1984 .

[68]  H. Winterbauer,et al.  A Modular Micro Reactor for Mixed Acid Nitration , 2005 .

[69]  Holger Löwe,et al.  Chemie in Mikrostrukturreaktoren , 2004 .

[70]  A. deMello Control and detection of chemical reactions in microfluidic systems , 2006, Nature.

[71]  R. Chambers,et al.  Microreactors for oxidations using fluorine , 2003 .

[72]  R. Chambers,et al.  Microreactors for elemental fluorine , 1999 .

[73]  P. Rys Diffusionsmaskierte Selektivität chemischer Reaktionen. Teil I: Mischungsmaskierte chemische Selektivität , 1977 .

[74]  Klavs F. Jensen,et al.  Microfabricated Multiphase Reactors for the Selective Direct Fluorination of Aromatics , 2003 .

[75]  P. D. Cook,et al.  Methodologies for Generating Solution-Phase Combinatorial Libraries. , 2000, Chemical reviews.

[76]  Dale L. Boger,et al.  Kombinatorische Flüssigphasensynthese von Bibliotheken: auf der Suche nach Modulatoren für Protein‐Protein‐ und Protein‐DNA‐Wechselwirkungen in der zellulären Signaltransduktion , 2003 .

[77]  Peter H Seeberger,et al.  Microreactors as tools for synthetic chemists-the chemists' round-bottomed flask of the 21st century? , 2006, Chemistry.

[78]  A new synthetic method for controlled polymerization using a microfluidic system. , 2004, Journal of the American Chemical Society.

[79]  M. Reetz Combinatorial and Evolution-Based Methods in the Creation of Enantioselective Catalysts. , 2001, Angewandte Chemie.

[80]  Holger Löwe,et al.  Selectivity Gains and Energy Savings for the Industrial Phenyl Boronic Acid Process Using Micromixer/Tubular Reactors , 2004 .

[81]  Wolfgang Ehrfeld,et al.  Direct fluorination of toluene using elemental fluorine in gas/liquid microreactors , 2000 .

[82]  J. Yoshida,et al.  Indirect cation pool method. Rapid generation of alkoxycarbenium ion pools from thioacetals. , 2006, Journal of the American Chemical Society.

[83]  J. Yoshida,et al.  Basic concepts of "cation pool" and "cation flow" methods and their applications in conventional and combinatorial organic synthesis. , 2002, Chemistry.

[84]  E. Harth,et al.  New polymer synthesis by nitroxide mediated living radical polymerizations. , 2001, Chemical reviews.

[85]  M. Keane,et al.  Advantages of synthesizing trans-1,2-cyclohexanediol in a continuous flow microreactor over a standard glass apparatus. , 2007, The Journal of organic chemistry.

[86]  J. Yoshida,et al.  Radical addition to "cation pool". Reverse process of radical cation fragmentation. , 2005, Journal of the American Chemical Society.

[87]  Klavs F Jensen,et al.  Accelerating reactions with microreactors at elevated temperatures and pressures: profiling aminocarbonylation reactions. , 2007, Angewandte Chemie.

[88]  Shin-ichi Tanaka,et al.  Large-scale synthesis of immunoactivating natural product, pristane, by continuous microfluidic dehydration as the key step. , 2007, Organic letters.

[89]  Jun-ichi Yoshida,et al.  Selective monoiodination of aromatic compounds with electrochemically generated I+ using micromixing. , 2006, Chemical communications.

[90]  K. Ding,et al.  Combinatorial chemistry approach to chiral catalyst engineering and screening: rational design and serendipity. , 2004, Chemistry.

[91]  D. Seebach,et al.  Synthese von β‐Peptiden im Mikroreaktor , 2006 .