I recently helped some colleagues and customers with literature references on the use of real time in situ mid-IR spectroscopy (ATR-FTIR) applied to flow chemistry. Considering all the reaction condition improvements (yields, purity, simplicity) described in these papers, I thought I would share the list with the chemical community. The papers are from a variety of academic research groups including Klavs Jensen at MIT (USA), Steven Ley and Ian Baxendale at the University of Cambridge (UK), Paul Knochel in Munich (Germany) and Floris Rutjes in the Netherlands. There are also a few papers from Industry, e.g. Merck (USA), and Pfizer (USA).
Combining home-made and commercial flow chemistry units, from companies such as Vapourtec, ThalesNano, Syrris, HEL, Uniqsis, Dow Corning and others, together with online ATR-FTIR spectroscopy provides the best of both worlds: flow synthesis linked to super-fast analytical feedback. Scientists can be more productive in a variety of chemical research and development areas including screening of catalysts and reaction conditions and route scouting, as well as producing more rapidly the first few batches of material for proof of concept (drug development, new material…).
It’s not a comprehensive list but it’s a pretty good overview. Please take advantage, enjoy reading, and let me know if you found other references.
1. Synthesis of acetal protected building blocks using flow chemistry with flow I.R. analysis: preparation of butane-2,3-diacetal tartratesCarter, C. F.; Baxendale, I. R.; O’Brien, M.; Pavey, J.B. J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, 4594–4597
2. The continuous flow synthesis of butane-2,3-diacetal protected building blocks using microreactors, Carter, C. F.; Baxendale, I. R.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2010, 8, 1588–1595
3. ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing 1 C.F. Carter, H. Lange, S.V. Ley, I.R. Baxendale, B. Wittkamp J. G. Goode, N. L. Gaunt, Org. Proc. Res. Dev., 2010, 14, 393-404.
4. A Continuous Flow Process Using a Sequence of Microreactors with In-line IR Analysis for the Preparation of N,N-Diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide as a Potent and Highly Selective d-Opioid Receptor Agonist, Z. Qian, I.R. Baxendale, S.V. Ley, Chem. Eur. J.,
2010, 16, 12342-12348.
5. Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor Malet-Sanz, L.; Madrzak, J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324–5332
6. A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles, Smith, C. J.; Nikbin, N.; Ley, S. V.; Lange, H.; Baxendale, I. R. Org. Biomol. Chem. 2011, 9, 1938–1947
7. A Breakthrough Method for the Accurate Addition of Reagents in Multi-step Segmented Flow Processing H. Lange, C.F. Carter, M.D. Hopkin, A. Burke, J.G. Goode, I.R. Baxendale and S.V. Ley, Chem. Sci., 2011, 2, 765-769.
8. Teflon AF-2400 mediated gas–liquid contact in continuous flow methoxycarbonylations and inline FTIR measurement of CO concentration, P. Koos, U. Gross, A. Polyzos, M. O’Brien, I.R. Baxendale and S.V. Ley, Org. Biomol. Chem., 2011, 9, 6903-6908
9. Lab of the Future: The Importance of Remote Monitoring and Control, M.D. Hopkin, I.R. Baxendale and S.V. Ley, Chim. Oggi./Chemistry Today, 2011, 29, 28-32.
10. Microreactor System for High-Pressure Continuous Flow Homogeneous Catalysis Measurements, J. Keybl and K. F. Jensen, Ind. Eng. Chem. Res. 2011, 50, 11013–11022
11. ReactNMR and ReactIR as Reaction Monitoring and Mechanistic Elucidation Tools – The NCS Mediated Cascade Reaction of alpha-Thioamides to alpha-Thio-beta-Chloroacrylamides Foley, D. A.; Doecke, C. W.; Buser, J. Y.; Merritt, J. M.; Murphy, L.; Kissane, M.; Collins, S. G.; Maguire, A. R.; Kaerner, A. J. Org. Chem. 2011, 76, 9630–9640
12. Continuous Stream Processing: A Prototype Magnetic Field Induced Flow Mixer , P. Koos, D.L. Browne and S.V. Ley, Green Process. and Synth., 2012, 1, 11-18.
13. On-line FTIR Monitoring and Simultaneous Optimization of a Strecker Reaction Performed in a Laboratory Scale Flow-Through Reactor. Skrdla et al. American Pharmaceutical Review, Jan 2012
14. Continuous Preparation of Arylmagnesium Reagents in Flow with In-line IR Monitoring, T. Brodmann, P. Koos, A. Metzger, P. Knochel, and S. V. Ley, Org. Proc. Res. Dev,. 2012, 16 (5), pp 1102–1113
15. Continuous Flow Production of Thermally Unstable Intermediates in a Microreactor with Inline IR-Analysis: Controlled Vilsmeier−Haack Formylation of Electron-Rich Arenes, Sebastiaan (Bas) A. M. W. van den Broek, Jeroen R. Leliveld, René Becker, Marielle M. E. Delville, Pieter J. Nieuwland, Kaspar Koch, and Floris P. J. T. Rutjes, Org. Proc. Res. Dev., 2012, 16 (5), 934–938
16. Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis, Magnus Rueping*, Teerawut Bootwicha and Erli Sugiono, Beilstein J. Org. Chem. 2012, 8, 300–307.
17. Automated Multitrajectory Method for Reaction Optimization in a Microfluidic System using Online IR Analysis, Moore, J. S., & Jensen, K. F. Organic Process Research & Development, 16(8), 1409–1415 2012
18. Process Analytical Technology (PAT) for enhanced development and control of continuous processes, Goode, J.G. & Hebrault, D. Chimica oggi/Chemistry Today Vol. 30 No. 6 Nov/Dec, 20-24 2012
19. Using Process Analytical Technology ( PAT ) Tools to Support Flow Chemistry Development and Production. Vanalsten et al. American Pharmaceutical Review, May 2012.
20. Single Operation Stereoselective Synthesis of Aerangis Lactones: Combining Continuous Flow Hydrogenation and Biocatalysts in a Chemoenzymatic SequenceChem, Fink, M. J. et al. CatChem 2013, 5, 724 – 727