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Microreactors as Tools in the Hands of Synthetic Chemists

  • P. H. Seeberger
  • K. Geyer
  • J. D. C. Codée
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/3)

Abstract

Recent developments in the construction of microstructured reaction devices and their wide-ranging applications in many different areas of chemistry suggest that microreactors may significantly impact the way chemists conduct experiments. Miniaturizing reactions offers many advantages for the synthetic organic chemist: high-throughput scanning of reaction conditions, precise control of reaction variables, the use of small quantities of reagents, increased safety parameters, and ready scale-up of synthetic procedures. A wide range of single and multiphase reactions has been performed in microfluidic-based devices. Certainly, microreactors cannot be applied to all chemistries yet and microfluidic systems also have disadvantages. Limited reaction time ranges, high sensitivity to precipitating products, and analytical challenges have to be overcome. An overview of microfluidic devices available for chemical synthesis is provided and some specific examples, mainly from our laboratory, are discussed to illustrate the potential of microreactors.

Keywords

Ethyl Acrylate Multistep Synthesis Multiphase Reaction Microfluidic Reactor Ethyl Cinnamate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Acke DRJ, Orru RVA, Stevens CV (2006) Continuous synthesis of tri- and tetrasubstituted imidazoles via a multicomponent reaction under microreactor conditions. QSAR Comb Sci 25:474–483Google Scholar
  2. Antes J, Tuercke T, Marioth E, Lechner F, Scholz M, Schnürer F, Krause HH, Löbbecke S (2001) In: Matlosz M, Ehrfeld W, Baselt JP (eds) IMRET 5: Proceedings of the Fifth International Conference on Microreaction Technology. Springer Berlin New York Heidelberg, pp 446–453Google Scholar
  3. Barrow D, Cefai J, Taylor S (1999) Shrinking to fit. Chem Ind 15:591–594Google Scholar
  4. Bradley D (1999) Chemical Reduction. Eur Chem 1:17–20Google Scholar
  5. Chambers RD, Spink RCH (1999) Microreactors for Elemental Flourine. Chem Comm 10:883–884CrossRefGoogle Scholar
  6. Chambers RD, Holling D, Spink RCH, Sandford G (2001) Elemental Fluorine – Part 13. Gas-Liquid Thin Film Microreactors for Selective Direct Fluorination. Lab Chip 1:132–137CrossRefGoogle Scholar
  7. Chambers RD, Fox MA, Sandford G (2005) Elemental fluorine – Part 18. Selective Direct Fluorination of 1,3-Ketoesters and 1,3-Diketones using Gas/Liquid Microreactor Technology. Lab Chip 5:1132–1139CrossRefGoogle Scholar
  8. Cheng RP, Gellman SH, DeGrado WF (2001) Beta-Peptides: From Structure to Function. Chem Rev 101:3219–3232CrossRefGoogle Scholar
  9. Cooper J, Disley D, Cass T (2001) Microsystems Special – Lab-On-A-Chip and Microarrays. Chem Ind 20:653–655Google Scholar
  10. Cowen S (1999) Chip service. Chem Ind 15:584–586Google Scholar
  11. CPC (2007) Cytos Lab System. http://www.cpc-net.com/cytosls.shtml. Cited 5 February 2007Google Scholar
  12. Curran DP (2002) Fluorous Reverse Phase Silica Gel. A New Tool For Preparative Separations in Synthetic Organic and Organofluorine Chemistry. Synlett 1488–1496Google Scholar
  13. Curran DP, Luo ZY (1999) Fluorous Synthesis with Fewer Fluorines (Light Fluorous Synthesis): Separation of Tagged from Untagged Products by Solid-Phase Extraction with Fluorous Reverse-Phase Silica Gel. J Am Chem Soc 121:9069–9072CrossRefGoogle Scholar
  14. De Mas N, Jackman RJ, Schmidt MA, Jensen KF (2002) In: Matkisz M, Ehrfeld W, Baselt JP (eds) IMRET 5: Proceedings of the Fifth International Conference on Microreaction Technology. Springer Berlin, New York, Heidelberg, pp 60–67Google Scholar
  15. De Mas N, Günther A, Schmidt MA, Jensen KF (2003) Microfabricated Multiphase Reactors for the Selective Direct Fluorination of Aromatics. Ind Eng Chem Res 42:698–710CrossRefGoogle Scholar
  16. De Visser PC, van Helden M, Filippov DV, van der Marel GA, Drijfhout JW, van Boom JH, Noort D, Overkleeft HS (2003) A novel, Base-Labile Fluorous Amine Protecting Group: Synthesis and Use as a Tag in the Purification of Synthetic Peptides. Tetrahedron Lett 44:9013–9016Google Scholar
  17. DeWitt SH (1999) Microreactors for Chemical Synthesis. Curr Opin Chem Biol 3:350–356CrossRefGoogle Scholar
  18. Doku GN, Haswell SJ, McCreedy T, Greenway GM (2001) Electric Field-Induced Mobilisation of Multiphase Solution Systems Based on the Nitration of Benzene in a Microreactor. Analyst 126:14–20CrossRefGoogle Scholar
  19. Duan J, Sun L, Liang Z, Zhang J, Wang H, Zhang L, Zhang W, Zhang Y (2006) Rapid Protein Digestion and Identification using Monolithic Enzymatic Microreactor Coupled with Nano-Liquid Chromatography-Electrospray Ionization Mass Spectrometry. J Chromatogr A 1–2:165–174CrossRefGoogle Scholar
  20. Ehrfeld Mikrotechnik BTS (2007) http://www.ehrfeld-shop.biz/shop/catalog/index.php. Cited 5 February 2007Google Scholar
  21. Ehrfeld W, Hessel V, Löwe H (2000) Microreactors: new technology for modern chemistry. Wiley-VCH, WeinheimGoogle Scholar
  22. Ehrich H, Linke C, Morgenschweis K, Baerns M, Jahnisch K (2002) Application of Microstructured Reactor Technology for the Photochemical Chlorination of Alkylaromatics. Chimia 56:647–653CrossRefGoogle Scholar
  23. Filippov DV, van Zoelen DJ, Oldfield SP, van der Marel GA, Overkleeft HS, Drijfhout JW, van Boom JH (2002) Use of Benzyloxycarbonyl (Z)-Based Fluorophilic Tagging Reagents in the Purification of Synthetic Peptides. Tetrahedron Lett 43:7809–7812CrossRefGoogle Scholar
  24. Erdélyi M, Gogoll A (2002) Rapid Microwave-Assisted Solid Phase Peptide Synthesis. Synthesis 1592–1596Google Scholar
  25. Fletcher PDI, Haswell SJ (1999) Downsizing Synthesis. Chem Ber 35:38–41Google Scholar
  26. Fletcher PDI, Haswell SJ, Paunov VN (1999) Theoretical Considerations of Chemical Reactions in Microreactors Operating under Electroosmotic and Electrophoretic Control. Analyst 124:1273–1282CrossRefGoogle Scholar
  27. Fletcher PDI, Haswell SJ, Pombo-Villar E, Warrington BH, Watts P, Wong SYF, Zhang XL (2002) Microreactors: Principles and Applications in Organic Synthesis. Tetrahedron 58:4735–4757CrossRefGoogle Scholar
  28. Flögel O, Codée JDC, Seebach D, Seeberger PH (2006) Microreactor Synthesis of Beta-Peptides. Angew Chem Int Ed 45:7000–7003CrossRefGoogle Scholar
  29. Geyer K, Codee JDC, Seeberger PH (2006) Microreactors as Tools for Synthetic Chemists – The Chemists' Round-Bottomed Flask of the 21st Century? Chem Eur J 12:8434–8442CrossRefGoogle Scholar
  30. Geyer K, Seeberger PH (2007) Optimization of Glycosylation Reactions in a Microreactor. Helv Chim Acta 90:395–403Google Scholar
  31. Greenway GM, Haswell SJ, Morgan DO, Skelton V, Styring P (2000) The Use of a Novel Microreactor for High Throughput Continuous Flow Organic Synthesis. Sens Actuator B Chem 63:153–158CrossRefGoogle Scholar
  32. Hansen CL, Classen S, Berger JM, Quake SR (2006) A Microfluidic Device for Kinetic Optimization of Protein Crystallization and In Situ Structure Determination. J Am Chem Soc 128:3142–3143Google Scholar
  33. Haswell SJ, Middleton RJ, O'Sullivan B, Skelton V, Watts P, Styring P (2001a) The Application of Microreactors to Synthetic Chemistry. Chem Commun 5:391–398CrossRefGoogle Scholar
  34. Haswell SJ, O'Sullivan B, Styring P (2001b) Kumada-Corriu Reactions in a Pressure-Driven Microflow Reactor. Lab Chip 1:164–166CrossRefGoogle Scholar
  35. Hessel V, Ehrfeld W, Golbig K, Haverkamp V, Löwe H, Storz M, Wille C, Guber A, Jahnisch K, Baerns M (2000) In: Ehrfeld W (ed) IMRET 3: Proceeding of the Third International Conference on Microreaction Technology. Springer Berlin, New York, Heidelberg, pp 526–540Google Scholar
  36. Hessel V, Kolb G, de Bellefon C (2005a) Catalytic Microstructured Reactors – Preface. Catal Today 110:1–1CrossRefGoogle Scholar
  37. Hessel V, Löwe H, Müller A, Kolb G (2005b) Chemical micro process engineering 1 + 2. Fundamentals modelling and reactions/processes and plants. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  38. Jähnisch K, Baerns M, Hessel V, Ehrfeld W, Haverkamp V, Löwe H, Wille C, Guber A (2000) Direct Fluorination of Toluene Using Elemental Fluorine in Gas/Liquid Microreactors. J Fluor Chem 105:117–128CrossRefGoogle Scholar
  39. Jähnisch K, Hessel V, Löwe H, Baerns M (2004) Chemistry in Microstructured Reactors. Angew Chem Int Ed 43:406–446CrossRefGoogle Scholar
  40. Jensen KF (2001) Microreaction Engineering – is Small Better? Chem Eng Sci 56:293–303CrossRefGoogle Scholar
  41. Kawaguchi T, Miyata H, Ataka K, Mae K, Yoshida J (2005) Room-Temperature Swern Oxidations by Using a Microscale Flow System. Angew Chem Int Ed 44:2413–2416CrossRefGoogle Scholar
  42. Kiwi-Minsker L, Renken A (2005) Microstructured reactors for catalytic reactions. Catal Today 110:2–14CrossRefGoogle Scholar
  43. Kockmann N, Brand O, Fedder GK (2006) Micro process engineering. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  44. Kolb G, Hessel V (2004) Micro-Structured Reactors for Gas Phase Reactions. Chem Eng J 98:1–38CrossRefGoogle Scholar
  45. Lee CC, Sui GD, Elizarov A, Shu CYJ, Shin YS, Dooley AN, Huang J, Daridon A, Wyatt P, Stout D, Kolb HC, Witte ON, Satyamurthy N, Heath JR, Phelps ME, Quake SR, Tseng HR (2005) Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics. Science 310:1793–1796CrossRefGoogle Scholar
  46. Lelais G, Seebach D, Jaun B, Mathad RI, Flögel O, Rossi F, Campo M, Wortmann A (2006) Beta-Peptidic Secondary Structures fortified and enforced by Zn2+ Complexation – On the Way to Beta-Peptidic Zinc Fingers? Helv Chim Acta 89:361–403Google Scholar
  47. Lu H, Schmidt MA, Jensen KF (2001) Photochemical Reactions and On-Line UV Detection in Microfabricated Reactors. Lab Chip 1:22–28CrossRefGoogle Scholar
  48. Manz A, Harrison DJ, Verpoorte EMJ, Fettinger JC, Ludi H, Widmer HM (1991) Miniaturization of Chemical-Analysis Systems – A Look into next Century Technology or just a Fashionable Craze. Chimia 45:103–105Google Scholar
  49. McCreedy T (1999) Reducing the Risks of Synthesis. Chem Ind 15:588–590Google Scholar
  50. McCreedy T (2000) Fabrication Techniques and Materials Commonly Used for the Production of Microreactors and Micro Total Analytical Systems. Trac Trends Anal Chem 19:396–401CrossRefGoogle Scholar
  51. McCreedy T (2001) Rapid Prototyping of Glass and PDMS Microstructures for Micro Total Analytical Systems and Micro Chemical Reactors by Microfabrication in the General Laboratory. Anal Chim Acta 427:39–43CrossRefGoogle Scholar
  52. Murray JK, Gellman SH (2005) Application of Microwave Irradiation to the Synthesis of 14-Helical Beta-Peptides. Org Lett 7:1517–1520CrossRefGoogle Scholar
  53. Nikbin N, Watts P (2004) Solid-Supported Continuous Flow Synthesis in Microreactors Using Electroosmotic Flow. Org Process Res Dev 8:942–944CrossRefGoogle Scholar
  54. Panke G, Schwalbe T, Stirner W, Taghavi-Moghadam S, Wille S (2003) A Practical Approach of Continuous Processing to High Energetic Nitration Reactions in Microreactors. Synthesis 18:2827–2830Google Scholar
  55. Pennemann H, Watts P, Haswell SJ, Hessel V, Löwe H (2004) Benchmarking of Microreactor Applications. Org Process Res Dev 8:422–439CrossRefGoogle Scholar
  56. Ratner DM, Murphy ER, Jhunjhunwala M, Snyder DF, Jensen KF, Seeberger PH (2005) Microreactor-Based Reaction Optimization in Organic Chemistry – Glycosylation as a Challenge. Chem Comm 5:578–580Google Scholar
  57. Rouhi AM (2004) Microreactors Eyed for Industrial Use. Chem Eng News 82:18–19Google Scholar
  58. Saaby S, Knudsen KR, Ladlow M, Ley SV (2005) The Use of a Continuous Flow-Reactor Employing a Mixed Hydrogen-Liquid Flow Stream for the Efficient Reduction of Imines to Amines. Chem Commun 23:2909–2911CrossRefGoogle Scholar
  59. Seebach D, Overhand M, Kühnle FNM, Martinoni D, Oberer L, Hommel U, Widmer H (1996) Beta-Peptides: Synthesis by Arndt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-ray Crystallography. Helical Secondary Structure of a Beta-Hexapeptide in Solution and its Stability Towards Pepsin. Helv Chim Acta 79:913–941CrossRefGoogle Scholar
  60. Seebach D, Schreiber JV, Arvidsson PI, Frackenpohl J (2001) The Miraculous CD Spectra (and Secondary Structures?) of Beta-Peptides as they Grow Longer – Preliminary Communication. Helv Chim Acta 84:271–279CrossRefGoogle Scholar
  61. Seebach D, Beck AK, Bierbaum DJ (2004) The World of Beta- and Gamma-Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components. Chem Biodiv 1:1111–1239CrossRefGoogle Scholar
  62. Skelton V, Greenway GM Haswell SJ, Styring P, Morgan DO, Warrington B, Wong SYF (2001a) The preparation of a Series of Nitrostilbene Ester Compounds Using Microreactor Technology. Analyst 126:7–10CrossRefGoogle Scholar
  63. Skelton V, Greenway GM, Haswell SJ, Styring P, Morgan DO, Warrington BH, Wong SYF (2001b) The Generation of Concentration Gradients Using Electroosmotic Flow in Microreactors Allowing Stereoselective Chemical Synthesis. Analyst 126:11–13CrossRefGoogle Scholar
  64. Snyder DA, Noti C, Seeberger PH, Schael F, Bieber T, Rimmel G, Ehrfeld W (2005) Modular Microreaction Systems for Homogeneously and Heterogeneously Catalyzed Chemical Synthesis. Helv Chim Acta 88:1–9CrossRefGoogle Scholar
  65. Syrris (2007) http://www.syrris.com. Royston, UK. Cited 5 February 2007Google Scholar
  66. Taghavi-Moghadam S, Kleemann A, Overbeck S (2000) VDE World Microtechnologies Congress MICROtech 2000, Vol. 2, VDE, Berlin, p 489Google Scholar
  67. Thales Nano (2006) http://thalesnano.com/. Cited 5 February 2007Google Scholar
  68. Thayer AM (2005) Harnessing Microreactions. Chem Eng News 83:43–52Google Scholar
  69. Wang B, Zhao Q, Wang F, Gao C (2006) Biologically Driven Assembly of Polyelectrolyte Microcapsule Patterns To Fabricate Microreactor Arrays. Angew Chem Int Ed 45:1560–1563CrossRefGoogle Scholar
  70. Watts P, Haswell SJ (2005) The Application of Microreactors for Organic Synthesis. Chem Soc Rev 34:235–246CrossRefGoogle Scholar
  71. Watts P, Wiles C, Haswell SJ, Pombo-Villar E, Styring P (2001) The Synthesis of Peptides Using Microreactors. Chem Comm 11:990–991CrossRefGoogle Scholar
  72. Watts P, Wiles C, Haswell S, Pombo-Villar E (2002a) Investigation of Racemisation in Peptide Synthesis within a Microreactor. Lab Chip 2:141–144CrossRefGoogle Scholar
  73. Watts P, Wiles C, Haswell S, Pombo-Villar E (2002b) Solution Phase Synthesis of Beta-Peptides Using Microreactors. Tetrahedron 58:5427–5439CrossRefGoogle Scholar
  74. Wehle D, Dejmek M, Rosenthal J, Ernst H, Kampmann D, Trautschold S, Pechatschek R (2000) DE10036603 AGoogle Scholar
  75. Wiles C, Watts P, Wiles C, Haswell S, Pombo-Villar E (2001) The Aldol Reaction of Silyl Enol Ethers within a Microreactor. Lab Chip 1:100–101CrossRefGoogle Scholar
  76. Zhang W (2004) Fluorous Synthesis of Heterocyclic Systems. Chem Rev 104:2531–2556CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Laboratory for Organic ChemistrySwiss Federal Institute of Technology (ETH) ZurichZurichSwitzerland

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