The adoption of and opportunities in continuous flow synthesis ('flow chemistry') have increased significantly over the past several years. Continuous flow systems provide improved reaction safety and accelerated reaction kinetics, and have synthesised several active pharmaceutical ingredients in automated reconfigurable systems. Although continuous flow platforms are commercially available, systems constructed 'in-lab' provide researchers with a flexible, versatile, and cost-effective alternative. Herein, we describe the assembly and use of a modular continuous flow apparatus from readily available and affordable parts in as little as 30 min. Once assembled, the synthesis of a sulfonamide by reacting 4-chlorobenzenesulfonyl chloride with dibenzylamine in a single reactor coil with an in-line quench is presented. This example reaction offers the opportunity to learn several important skills including reactor construction, charging of a back-pressure regulator, assembly of stainless-steel syringes, assembly of a continuous flow system with multiple junctions, and yield determination. From our extensive experience of single-step and multistep continuous flow synthesis, we also describe solutions to commonly encountered technical problems such as precipitation of solids ('clogging') and reactor failure. Following this protocol, a nonspecialist can assemble a continuous flow system from reactor coils, syringes, pumps, in-line liquid–liquid separators, drying columns, back-pressure regulators, static mixers, and packed-bed reactors.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Flow chemistry experiments in the undergraduate teaching laboratory: synthesis of diazo dyes and disulfides
Journal of Flow Chemistry Open Access 07 October 2020
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gutmann, B., Cantillo, D. & Kappe, C.O. Continuous flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. Engl. 54, 6688–6728 (2015).
Movsisyan, M. et al. Taming hazardous chemistry by continuous flow technology. Chem. Soc. Rev. 45, 4892–4928 (2016).
Webb, D. & Jamison, T.F. Continuous flow multi-step organic synthesis. Chem. Sci. 1, 675–680 (2010).
Wiles, C. & Watts, P. Continuous flow reactors: a perspective. Green Chem. 14, 38–54 (2012).
Hartman, R.L., McMullen, J.P. & Jensen, K.F. Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. Angew. Chem. Int. Ed. Engl. 50, 7502–7519 (2011).
Ley, S.V., Fitzpatrick, D.E., Ingham, R.J. & Myers, R.M. Organic synthesis: march of the machines. Angew. Chem. Int. Ed. Engl. 54, 3449–3464 (2015).
Newman, S.G. & Jensen, K.F. The role of flow in green chemistry and engineering. Green Chem. 15, 1456–1472 (2013).
Wiles, C. & Watts, P. Continuous process technology: a tool for sustainable production. Green Chem. 16, 55–62 (2014).
Britton, J. & Raston, C.L. Multi-step continuous flow synthesis. Chem. Soc. Rev. 46, 1250–1271 (2017).
Jähnisch, K., Hessel, V., Löwe, H. & Baerns, M. Chemistry in microstructured reactors. Angew. Chem. Int. Ed. Engl. 43, 406–446 (2004).
Sahoo, H.R., Kralj, J.G. & Jensen, K.F. Multistep continuous flow microchemical synthesis involving multiple reactions and separations. Angew. Chem. Int. Ed. Engl. 119, 5806–5810 (2007).
Wörz, O., Jäckel, K.P., Richter, T. & Wolf, A. Microreactors – a new efficient tool for reactor development. Chem. Eng. Technol. 24, 138–142 (2001).
Straathof, N.J.W., Su, Y., Hessel, V. & Noel, T. Accelerated gas-liquid visible light photoredox catalysis with continuous flow photochemical microreactors. Nat. Protoc. 11, 10–21 (2016).
Su, Y., Straathof, N.J.W., Hessel, V. & Noël, T. Photochemical transformations accelerated in continuous flow reactors: basic concepts and applications. Chem. Eur. J. 20, 10562–10589 (2014).
Garlets, Z.J., Nguyen, J.D. & Stephenson, C.R.J. The development of visible-light photoredox catalysis in flow. Isr. J. Chem. 54, 351–360 (2014).
Tucker, J.W., Zhang, Y., Jamison, T.F. & Stephenson, C.R.J. Visible-light photoredox catalysis in flow. Angew. Chem. Int. Ed. Engl. 51, 4144–4147 (2012).
Porta, R., Benaglia, M. & Puglisi, A. Flow chemistry: recent developments in the synthesis of pharmaceutical products. Org. Process. Res. Dev. 20, 2–25 (2016).
Malet-Sanz, L. & Susanne, F. Continuous flow synthesis. a pharma perspective. J. Med. Chem. 55, 4062–4098 (2012).
Schaber, S.D. et al. Economic analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. Ind. Eng. Chem. Res 50, 10083–10092 (2011).
Lee, S.L. et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J. Pharm. Innov. 10, 191–199 (2015).
Roberge, D.M. et al. Microreactor technology and continuous processes in the fine chemical and pharmaceutical industry: is the revolution underway? Org. Process. Res. Dev. 12, 905–910 (2008).
Wegner, J., Ceylan, S. & Kirschning, A. Flow chemistry – a key enabling technology for (multistep) organic synthesis. Adv. Synth. Catal. 354, 17–57 (2012).
Zhang, J., Gong, C., Zeng, X. & Xie, J. Continuous flow chemistry: new strategies for preparative inorganic chemistry. Coord. Chem. Rev. 324, 39–53 (2016).
Cambié, D., Bottecchia, C., Straathof, N.J.W., Hessel, V. & Noël, T. Applications of continuous flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 116, 10276–10341 (2016).
Peng, Y. et al. Room temperature batch and continuous flow synthesis of water-stable covalent organic frameworks (COFs). Chem. Mater. 28, 5095–5101 (2016).
Liu, Z. et al. Continuous flow synthesis of ZSM-5 zeolite on the order of seconds. Proc. Natl. Acad. Sci. USA 113, 14267–14271 (2016).
Hajba, L. & Guttman, A. Continuous flow biochemical reactors: biocatalysis, bioconversion, and bioanalytical applications utilizing immobilized microfluidic enzyme reactors. J. Flow Chem. 6, 8–12 (2016).
Planchestainer, M. et al. Continuous flow biocatalysis: production and in-line purification of amines by immobilised transaminase from Halomonas elongata. Green Chem. 19, 372–375 (2017).
Tang, X., Allemann, R.K. & Wirth, T. Optimising terpene synthesis with flow biocatalysis. Eur. J. Org. Chem. 2017, 414–418 (2017).
Britton, J., Raston, C.L. & Weiss, G.A. Rapid protein immobilization for thin film continuous flow biocatalysis. Chem. Commun. 52, 10159–10162 (2016).
Britton, J. & Raston, C.L. Rapid high conversion of high free fatty acid feedstock into biodiesel using continuous flow vortex fluidics. RSC Adv. 5, 2276–2280 (2015).
Britton, J. & Raston, C.L. Continuous flow vortex fluidic production of biodiesel. RSC Adv. 4, 49850–49854 (2014).
Choedkiatsakul, I., Ngaosuwan, K., Assabumrungrat, S., Mantegna, S. & Cravotto, G. Biodiesel production in a novel continuous flow microwave reactor. Renew. Energ. 83, 25–29 (2015).
Asadi, M., Hooper, J.F. & Lupton, D.W. Biodiesel synthesis using integrated acid and base catalysis in continuous flow. Tetrahedron 72, 3729–3733 (2016).
Roberge, D.M., Ducry, L., Bieler, N., Cretton, P. & Zimmermann, B. Microreactor technology: a revolution for the fine chemical and pharmaceutical industries? Chem. Eng. Technol. 28, 318–323 (2005).
Snead, D.R. & Jamison, T.F. A three-minute synthesis and purification of ibuprofen: pushing the limits of continuous flow processing. Angew. Chem. Int. Ed. Engl. 54, 983–987 (2015).
Adamo, A. et al. On-demand continuous flow production of pharmaceuticals in a compact, reconfigurable system. Science 352, 61–67 (2016).
Snead, D.R. & Jamison, T.F. End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts. Chem. Sci. 4, 2822–2827 (2013).
Dai, C., Snead, D.R., Zhang, P. & Jamison, T.F. Continuous flow synthesis and purification of atropine with sequential in-line separations of structurally similar impurities. J. Flow Chem. 5, 133–138 (2015).
Zhang, P., Russell, M.G. & Jamison, T.F. Continuous flow total synthesis of rufinamide. Org. Process. Res. Dev. 18, 1567–1570 (2014).
Mascia, S. et al. End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. Angew. Chem. Int. Ed. Engl. 52, 12359–12363 (2013).
Heider, P.L. et al. Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical. Org. Process. Res. Dev. 18, 402–409 (2014).
Britton, J. & Jamison, T.F. A unified continuous flow assembly-line synthesis of highly substituted pyrazoles and pyrazolines. Angew. Chem. Int. Ed. Engl. 56, 8823–8827 (2017).
McTeague, T.A. & Jamison, T.F. Photoredox activation of SF6 for fluorination. Angew. Chem. Int. Ed. Engl. 55, 15072–15075 (2016).
Andrade, L.H., Kroutil, W. & Jamison, T.F. Continuous flow synthesis of chiral amines in organic solvents: immobilization of E. coli cells containing both ù-transaminase and PLP. Org. Lett. 16, 6092–6095 (2014).
Barnes, J.C. et al. Iterative exponential growth of stereo- and sequence-controlled polymers. Nat. Chem. 7, 810–815 (2015).
Wu, J. et al. Continuous flow synthesis of ketones from carbon dioxide and organolithium or Grignard reagents. Angew. Chem. Int. Ed. Engl. 53, 8416–8420 (2014).
Wu, J., Kozak, J.A., Simeon, F., Hatton, T.A. & Jamison, T.F. Mechanism-guided design of flow systems for multicomponent reactions: conversion of CO2 and olefins to cyclic carbonates. Chem. Sci. 5, 1227–1231 (2014).
Zhang, Y., Blackman, M.L., Leduc, A.B. & Jamison, T.F. Peptide fragment coupling using a continuous flow photochemical rearrangement of nitrones. Angew. Chem. Int. Ed. Engl. 52, 4251–4255 (2013).
Kleinke, A.S. & Jamison, T.F. Hydrogen-free alkene reduction in continuous flow. Org. Lett. 15, 710–713 (2013).
Shen, B. & Jamison, T.F. Rapid continuous synthesis of 5-deoxyribonucleosides in flow via Brønsted acid catalyzed glycosylation. Org. Lett. 14, 3348–3351 (2012).
Shen, B., Bedore, M.W., Sniady, A. & Jamison, T.F. Continuous flow photocatalysis enhanced using an aluminum mirror: rapid and selective synthesis of 2-deoxy and 2,3-dideoxynucleosides. Chem. Commun. 48, 7444–7446 (2012).
Webb, D. & Jamison, T.F. Diisobutylaluminum hydride reductions revitalized: a fast, robust, and selective continuous flow system for aldehyde synthesis. Org. Lett. 14, 568–571 (2012).
Leduc, A.B. & Jamison, T.F. Continuous flow oxidation of alcohols and aldehydes utilizing bleach and catalytic tetrabutylammonium bromide. Org. Process. Res. Dev. 16, 1082–1089 (2012).
Palde, P.B. & Jamison, T.F. Safe and efficient tetrazole synthesis in a continuous flow microreactor. Angew. Chem. Int. Ed. Engl. 50, 3525–3528 (2011).
Sniady, A., Bedore, M.W. & Jamison, T.F. One-flow, multistep synthesis of nucleosides by Brønsted acid-catalyzed glycosylation. Angew. Chem. Int. Ed. Engl. 50, 2155–2158 (2011).
Zhang, Y., Jamison, T.F., Patel, S. & Mainolfi, N. Continuous flow coupling and decarboxylation reactions promoted by copper tubing. Org. Lett. 13, 280–283 (2011).
Yoshida, J.-i., Nagaki, A. & Yamada, T. Flash chemistry: fast chemical synthesis by using microreactors. Chemistry 14, 7450–7459 (2008).
Yoshida, J.-i., Takahashi, Y. & Nagaki, A. Flash chemistry: flow chemistry that cannot be done in batch. Chem. Commun. 49, 9896–9904 (2013).
Browne, D.L. et al. Continuous flow reaction monitoring using an on-line miniature mass spectrometer. Rapid Commun. 26, 1999–2010 (2012).
Hall, A.M.R. et al. Practical aspects of real-time reaction monitoring using multi-nuclear high resolution FlowNMR spectroscopy. Catal. Sci. Technol. 6, 8406–8417 (2016).
Brodmann, T., Koos, P., Metzger, A., Knochel, P. & Ley, S.V. Continuous preparation of arylmagnesium reagents in flow with inline IR monitoring. Org. Process. Res. Dev. 16, 1102–1113 (2012).
J.B. acknowledges A.-C. Bédard, J. Lummiss, T.A. McTeague, M.G. Russell, and R. Hicklin for their discussions during the preparation of the manuscript. J.B and T.F.J. thank the Defense Advanced Research Project Agency (DARPA) for support.
T.F.J. is a cofounder of Snapdragon Chemistry, Inc., and a scientific adviser for Zaiput Flow Technologies, Continuus Pharmaceuticals, Paraza Pharma, Inc., and Asymchem. J.B. declares no competing financial interests.
Supplementary Equations. Calculation of required reactor-coil length for a specific residence time and calculation of residence time. (XLSX 10 kb)
Supplementary Video 7. Assembly of a packed-bed reactor (Swagelok fitting and insertion of the metal frit). (MP4 14363 kb)
Supplementary Video 8. Assembly of a packed-bed reactor (loading the metal nut and ferrule set onto the PFA tubing and tightening into the Swagelok union). (MP4 3763 kb)
Supplementary Video 9. Assembly of a packed-bed reactor (loading of the sand into the packed-bed reactor). (MP4 1557 kb)
About this article
Cite this article
Britton, J., Jamison, T. The assembly and use of continuous flow systems for chemical synthesis. Nat Protoc 12, 2423–2446 (2017). https://doi.org/10.1038/nprot.2017.102
This article is cited by
Flow chemistry experiments in the undergraduate teaching laboratory: synthesis of diazo dyes and disulfides
Journal of Flow Chemistry (2021)
Development of a packed-bed flow process for the production scale hydrogenation of 7-oxo-lithocholic acid to ursodeoxycholic acid
Journal of Flow Chemistry (2020)
Self-sustaining closed-loop multienzyme-mediated conversion of amines into alcohols in continuous reactions
Nature Catalysis (2018)