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Flow Process Development and Optimization of A Suzuki-Miyaura Cross Coupling Reaction using Response Surface Methodology

1Department of Chemical Engineering, Dayananda Sagar College of Engineering, Bengaluru, India

2Syngene International Ltd, Bengaluru, India

Received: 22 Jun 2020; Revised: 24 Jul 2020; Accepted: 25 Jul 2020; Available online: 15 Aug 2020; Published: 28 Dec 2020.
Editor(s): Istadi Istadi
Open Access Copyright (c) 2020 by Authors, Published by BCREC Group under

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A custom-made tubular flow reactor was utilized to develop a mathematical model and optimize the Suzuki-Miyaura cross coupling reaction. In this study, the experimentation was designed and executed through the statistical design of experiments (DoE) approach via response surface methodology. The effect of molar ratios of phenylboronic acid (1) and 4-bromophenol (2), temperature, the catalyst tetrakis(triphenylphosphine)palladium, and equivalence of aqueous tripotassium phosphate was studied in detail. The flow reactor profile was in good agreement with batch conditions and significant improvements to the overall reaction time and selectivity towards desired [1-1-biphenyl]-4-ol (3) was achieved. The Suzuki coupling reaction in batch condition would take on an average of 4 to 6 hours to complete, which was effectively accomplished in 60 to 70 minutes in this tubular reactor setup and could be operated continuously. The reaction model is in good agreement with the reaction conditions. Copyright © 2021 by Authors, Published by BCREC Group. This is an open access article under the CC BY-SA License (

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Keywords: Continuous flow chemistry; Suzuki coupling reaction; Customized flow reactor; Tubular reactor; Design of experiments (DoE)
Funding: Syngene International Ltd, Bengaluru, India

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  1. Yin, L., Liebscher, J. (2007). Carbon-carbon coupling reactions catalyzed by heterogeneous palladium catalysts. Chemical Reviews, 107, 133−173
  2. Agrofoglio, L.A., Gillaizeau, I., Saito, Y. (2003). Palladium-assisted routes to nucleosides. Chemical Reviews, 103, 1875−1916
  3. Crawford, K.A. (2014). Direct comparison of homogeneous and heterogeneous palladium (II) catalysts for Suzuki-Miyaura cross-coupling reactions. PhD Thesis, The University of Texas at Austin, USA
  4. Barnard, B.C. (2008). Palladium-catalyzed C‐C Coupling: Then and Now. Platinum Metals Review, 52, 38−45
  5. Johansson Seechurn, C.C., Kitching, M.O., Colacot, T.J., Snieckus, V. (20120. Palladium‐catalyzed cross‐coupling: a historical contextual perspective to the 2010 Nobel Prize. Angewandte Chemie International Edition, 51, 5062−5085
  6. Len, C., Bruniaux, S., Delbecq, F., Parmar, V.S. (2017). Palladium-catalyzed Suzuki–Miyaura cross-coupling in continuous flow. Catalysts, 7, 146
  7. Paterson, I., Davies, R.D., Marquez, R. (2001). Total synthesis of the callipeltoside aglycon. Angewandte Chemie, 113, 623−627
  8. Hiyama, T., Hatanaka, Y. (1994). Palladium-catalyzed cross-coupling reaction of organometalloids through activation with fluoride ion. Pure and applied chemistry, 66, 1471−1478
  9. Haswell, S.J., Watts, P. (2003). Green chemistry: synthesis in micro reactors. Green Chemistry, 5, 240−249
  10. Wiles, C., Watts, P. (2012). Continuous flow reactors: a perspective. Green Chemistry, 14, 138−154
  11. Newman, S.G., Jensen, K.F. (2013). The role of flow in green chemistry and engineering. Green chemistry, 15, 1456−1472
  12. Wiles, C., Watts, P. (2014). Continuous process technology: a tool for sustainable production. Green Chemistry, 16, 55−62
  13. Vaccaro, L., Lanari, D., Marrocchi, A., Strappaveccia, G. (2014). Flow approaches towards sustainability. Green Chemistry, 16, 3680−3704
  14. Falß, S., Tomaiuolo, G., Perazzo, A., Hodgson, P., Yaseneva, P., Zakrzewski, J., Guido, S., Lapkin, A., Woodward, R., Meadows, R.E. (2016). A continuous process for Buchwald–Hartwig amination at micro-, lab-, and mesoscale using a novel reactor concept. Organic Process Research & Development, 20, 558−567
  15. Suzuki, A. (2011). Cross‐coupling reactions of organoboranes: an easy way to construct C−C bonds (Nobel Lecture). Angewandte Chemie International Edition, 50, 6722−6737
  16. Shu, W., Pellegatti, L., Oberli, M.A., Buchwald, S.L. (2011). Continuous‐Flow Synthesis of Biaryls Enabled by Multistep Solid‐Handling in a Lithiation/Borylation/Suzuki–Miyaura Cross‐Coupling Sequence. Angewandte Chemie, 123, 10853−10857
  17. Kobayashi, S. (2016). Flow “fine” synthesis: high yielding and selective organic synthesis by flow methods. Chemistry–An Asian Journal, 11, 425−436
  18. Geyer, K., Codee, J.D., Seeberger, P.H. (2006). Microreactors as tools for synthetic chemists—the chemists' round‐bottomed flask of the 21st century?. Chemistry–A European Journal, 12, 8434−8442
  19. Delville, M.M., Nieuwland, P.J., Janssen, P., Koch, K., van Hest, J.C., Rutjes, F.P. (2011). Continuous flow azide formation: Optimization and scale-up. Chemical engineering journal, 167, 556−559
  20. Zhang, C., Zhang, J., Luo, G. (2016). Kinetic study and intensification of acetyl guaiacol nitration with nitric acid—acetic acid system in a microreactor. Journal of Flow Chemistry, 6, 309−314
  21. Anxionnaz, Z., Cabassud, M., Gourdon, C., Tochon, P. (2008). Heat exchanger/reactors (HEX reactors): concepts, technologies: state-of-the-art. Chemical Engineering and Processing: Process Intensification, 47, 2029−2050
  22. Koch, K., van Weerdenburg, B.J., Verkade, J.M., Nieuwland, P.J., Rutjes, F.P., van Hest, J.C. (2009). Optimizing the deprotection of the amine protecting p-methoxyphenyl group in an automated microreactor platform. Organic Process Research & Development, 13, 1003−1006
  23. Becker, R., van den Broek, S.B.A., Nieuwland, P.J., Koch, K., Rutjes, F.P. (2012). Optimisation and Scale-up of α-Bromination of Acetophenone in a Continuous Flow Microreactor. Journal of Flow Chemistry, 2, 87−91
  24. Fabry, D.C., Sugiono, E., Rueping, M., Meunier, F.C. (2016). Reaction Chemistry & Engineering. Chem. Eng., 1, 165
  25. Nieuwland, P.J., Koch, K., van Harskamp, N., Wehrens, R., van Hest, J.C., Rutjes, F.P. (2010). Flash Chemistry Extensively Optimized: High‐Temperature Swern–Moffatt Oxidation in an Automated Microreactor Platform. Chemistry–An Asian Journal, 5, 799−805
  26. Nagaki, A., Kim, H., Usutani, H., Matsuo, C., Yoshida, J.I. (2010). Generation and reaction of cyano-substituted aryllithium compounds using microreactors. Organic & biomolecular chemistry, 8, 1212−1217
  27. Hafner, A., Filipponi, P., Piccioni, L., Meisenbach, M., Schenkel, B., Venturoni, F., Sedelmeier, J. (2016). A simple scale-up strategy for organolithium chemistry in flow mode: From feasibility to kilogram quantities. Organic process research & development, 20, 1833−1837
  28. Gioiello, A., Mancino, V., Filipponi, P., Mostarda, S., Cerra, B. (2016). Concepts and optimization strategies of experimental design in continuous-flow processing. Journal of Flow Chemistry, 6, 167−180
  29. Nunn, C., DiPietro, A., Hodnett, N., Sun, P., Wells, K.M. (2018). High-Throughput Automated Design of Experiment (DoE) and Kinetic Modeling to Aid in Process Development of an API. Organic Process Research & Development, 22, 54−61
  30. Afzal, a., Muhammad, I.A., Muhammad, Y., Hayat, K., Mansoor, u.H.S. (2013). A comparative study of alkaline hydrolysis of ethyl acetate using design of experiments. Iranian journal of chemistry and chemical engineering, 32, 33−47
  31. Asprey, S.P., Macchietto, S. (2000). Statistical tools for optimal dynamic model building. Computers & Chemical Engineering, 24, 1261−1267
  32. Montgomery, D.C. (2017). Design and Analysis of Experiments. New York: John Wiley & sons
  33. Lazic, Z.R. (2006). Design of Experiments in Chemical Engineering: A Practical Guide. New Jersey: John Wiley & Sons
  34. Franceschini, G., Macchietto, S. (2008). Model-based design of experiments for parameter precision: State of the art. Chemical Engineering Science, 63, 4846−4872
  35. Atkinson, A.C., Bogacka, B., Bogacki, M.B. (1998). D-and T-optimum designs for the kinetics of a reversible chemical reaction. Chemometrics and Intelligent Laboratory Systems, 43, 185−198
  36. Gupta, A., Balomajumder, C. (2015). Residence time distribution study for continuous column packed with tea waste biomass. Integrated Research Advances, 2, 5−10
  37. Anderson, N.G. (2001). Practical use of continuous processing in developing and scaling up laboratory processes. Organic Process Research & Development, 5, 613−621
  38. Garcia-Serna, J., García-Verdugo, E., Hyde, J.R., Fraga-Dubreuil, J., Yan, C., Poliakoff, M., Cocero, M.J. (2007). Modelling residence time distribution in chemical reactors: A novel generalised n-laminar model: Application to supercritical CO2 and subcritical water tubular reactors. The Journal of Supercritical Fluids, 41, 82−91
  39. Klose, F., Wolff, T., Thomas, S., Seidel-Morgenstern, A. (2003). Concentration and residence time effects in packed bed membrane reactors. Catalysis today, 82, 25−40
  40. Istadi, I., Suherman, S., Buchori, L. (2010). Optimization of reactor temperature and catalyst weight for plastic cracking to fuels using response surface methodology. Bulletin of Chemical Reaction Engineering & Catalysis, 5 (2), 103-111, DOI: 10.9767/bcrec.5.2.797.103-111

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