A microfluidic platform for screening and optimization of organic reactions in droplets


We report an automated microfluidic system for screening and optimization of chemical reactions performed inside microliter liquid droplets. The system offers precise control over generation, merging and flow of droplet “micro-reactors” and over reaction conditions, including the volumes of the reagents, temperature and time. The high level of control coupled with the ability to quickly screen multiple reaction conditions allow us to thoroughly monitor the impact of input parameters on the yield of the reaction. In addition, the reagent consumption is kept remarkably low. As an exemplary use of our system we demonstrate a comprehensive study of acid-catalyzed (para-toluenesulfonic acid, p-TsOH) model imine formation (condensation of ortho-nitrobenzaldehyde and phenylethylamine) in an organic solvent (ethanol). By use of novel screening methods described herein, we unfold that the acid-catalyzed model imine formation in the organic medium can be considered as an assembly of acid-mediated and non-catalyzed reactions, both of which accelerate with increasing temperature.

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  1. 1.

    Wirth T (ed) (2013) Microreactors in organic synthesis and catalysis. Wiley-VCH, Weinheim

    Google Scholar 

  2. 2.

    Wiles C, Watts P (2011) Micro reaction technology in organic synthesis. CRC Press, Boca Raton

    Google Scholar 

  3. 3.

    Ramshaw C (1995) The incentive for process intensification. Paper presented at the 1st Intl Conf Proc Intensif for Chem Ind, London

  4. 4.

    Schwalbe T, Autze V, Wille G (2002) Chemical synthesis in microreactors. Chimia 56(11):636–646

    CAS  Article  Google Scholar 

  5. 5.

    Stazi F, Cancogni D, Turco L, Westerduin P, Bacchi S (2010) Highly efficient and safe procedure for the synthesis of aryl 1,2,3-triazoles from aromatic amine in a continuous flow reactor. Tetrahedron Lett 51(41):5385–5387

    CAS  Article  Google Scholar 

  6. 6.

    Fernandez Rivas D, Cintas P, Gardeniers HJGE (2012) Merging microfluidics and sonochemistry: towards greener and more efficient micro-sono-reactors. Chem Commun 48(89):10935–10947

    CAS  Article  Google Scholar 

  7. 7.

    Ji J, Nie L, Qiao L, Li Y, Guo L, Liu B, Yang P, Girault HH (2012) Proteolysis in microfluidic droplets: an approach to interface protein separation and peptide mass spectrometry. Lab Chip 12(15):2625–2629

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Lebedev A, Miraghaie R, Kotta K, Ball CE, Zhang J, Buchsbaum MS, Kolb HC, Elizarov A (2013) Batch-reactor microfluidic device: first human use of a microfluidically produced PET radiotracer. Lab Chip 13(1):136–145

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Watts P, Wiles C (2007) Recent advances in synthetic micro reaction technology. Chem Commun 5:443–467

    Article  Google Scholar 

  10. 10.

    Geyer K, Codee JD, Seeberger PH (2006) Microreactors as tools for synthetic chemists-the chemists round-bottomed flask of the 21st century? Chem Eur J 12(33):8434–8442

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Schwalbe T, Autze V, Hohmann M, Stirner W (2004) Novel innovation systems for a cellular approach to continuous process chemistry from discovery to market. Org Process Res Dev 8(3):440–454

    CAS  Article  Google Scholar 

  12. 12.

    Kumar V, Paraschivoiu M, Nigam KDP (2011) Single-phase fluid flow and mixing in microchannels. Chem Eng Sci 66(7):1329–1373

    CAS  Article  Google Scholar 

  13. 13.

    Hochlowski JE, Searle PA, Tu NP, Pan JY, Spanton SG, Djuric SW (2011) An integrated synthesis–purification system to accelerate the generation of compounds in pharmaceutical discovery. J Flow Chem 1(2):56–61

    CAS  Article  Google Scholar 

  14. 14.

    Carlson R, Carlson JE (2005) Design and optimization in organic synthesis. Elsevier, Amsterdam

    Google Scholar 

  15. 15.

    Pollard M (2001) Process development automation: an evolutionary approach. Org Process Res Dev 5(3):273–282

    CAS  Article  Google Scholar 

  16. 16.

    Guzowski J, Jakiela S, Korczyk PM, Garstecki P (2013) Custom tailoring multiple droplets one-by-one. Lab Chip 13(22):4308–4311

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Churski K, Korczyk P, Garstecki P (2010) High-throughput automated droplet microfluidic system for screening of reaction conditions. Lab Chip 10(7):816–818

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Becker R, Koch K, Nieuwland PJ, Rutjes FPJT (2011) Flow chemistry today: practical approaches for optimisation and scale-up. Chim Oggi 29(3):47–49

    CAS  Google Scholar 

  19. 19.

    Leung SA, Winkle RF, Wootton RC, deMello AJ (2005) A method for rapid reaction optimisation in continuous-flow microfluidic reactors using online Raman spectroscopic detection. Analyst 130(1):46–51

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    McMullen JP, Jensen KF (2010) An automated microfluidic system for online optimization in chemical synthesis. Org Process Res Dev 14(5):1169–1176

    CAS  Article  Google Scholar 

  21. 21.

    McMullen JP, Stone MT, Buchwald SL, Jensen KF (2010) An integrated microreactor system for self-optimization of a Heck reaction: from micro- to mesoscale flow systems. Angew Chem Int Ed 49(39):7076–7080

    CAS  Article  Google Scholar 

  22. 22.

    Moore JS, Jensen KF (2012) Automated multitrajectory method for reaction optimization in a microfluidic system using online IR analysis. Org Process Res Dev 16(8):1409–1415

    CAS  Article  Google Scholar 

  23. 23.

    Churski K, Kaminski TS, Jakiela S, Kamysz W, Baranska-Rybak W, Weibel DB, Garstecki P (2012) Rapid screening of antibiotic toxicity in an automated microdroplet system. Lab Chip 12(9):1629–1637

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Chen DL, Ismagilov RF (2006) Microfluidic cartridges preloaded with nanoliter plugs of reagents: an alternative to 96-well plates for screening. Curr Opin Chem Biol 10(3):226–231

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Hatakeyama T, Chen DL, Ismagilov RF (2006) Microgram-scale testing of reaction conditions in solution using nanoliter plugs in microfluidics with detection by MALDI-MS. J Am Chem Soc 128(8):2518–2519

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Wheeler RC, Benali O, Deal M, Farrant E, MacDonald SJF, Warrington BH (2007) Mesoscale flow chemistry: a plug-flow approach to reaction optimisation. Org Process Res Dev 11(4):704–710

    CAS  Article  Google Scholar 

  27. 27.

    Benali O, Deal M, Farrant E, Tapolczay D, Wheeler R (2008) Continuous flow microwave-assisted reaction optimization and scale-up using fluorous spacer technology. Org Process Res Dev 12(5):1007–1011

    CAS  Article  Google Scholar 

  28. 28.

    Davoren JE, Bundesmann MW, Yan QT, Collantes EM, Mente S, Nason DM, Gray DL (2012) Measurement of atropisomer racemization kinetics using segmented flow technology. ACS Med Chem Lett 3(5):433–435

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Reizman BJ, Jensen KF (2015) Simultaneous solvent screening and reaction optimization in microliter slugs. Chem Commun 51(68):13290–13293

    CAS  Article  Google Scholar 

  30. 30.

    Reizman BJ, Wang YM, Buchwald SL, Jensen KF (2016) Suzuki-Miyaura cross-coupling optimization enabled by automated feedback. React Chem Eng 1(6):658–666

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Hwang YJ, Coley CW, Abolhasani M, Marzinzik AL, Koch G, Spanka C, Lehmann H, Jensen KF (2017) A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets. Chem Commun 53(49):6649–6652

    CAS  Article  Google Scholar 

  32. 32.

    Hsieh H-W, Coley CW, Baumgartner LM, Jensen KF, Robinson RI (2018) Photoredox iridium–nickel dual-catalyzed decarboxylative arylation cross-coupling: from batch to continuous flow via self-optimizing segmented flow reactor. Org Process Res Dev 22(4):542–550

    CAS  Article  Google Scholar 

  33. 33.

    Coley CW, Abolhasani M, Lin H, Jensen KF (2017) Material-efficient microfluidic platform for exploratory studies of visible-light photoredox catalysis. Angew Chem Int Ed 56(33):9847–9850

    CAS  Article  Google Scholar 

  34. 34.

    Perera D, Tucker JW, Brahmbhatt S, Helal CJ, Chong A, Farrell W, Richardson P, Sach NW (2018) A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow. Science 359(6374):429–434

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Churski K, Nowacki M, Korczyk PM, Garstecki P (2013) Simple modular systems for generation of droplets on demand. Lab Chip 13(18):3689–3697

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Jakiela S, Debski PR, Dabrowski B, Garstecki P (2014) Generation of nanoliter droplets on demand at Hundred-Hz frequencies. Micromachines 5(4):1002–1011

    Article  Google Scholar 

  37. 37.

    Song H, Tice JD, Ismagilov RF (2003) A microfluidic system for controlling reaction networks in time. Angew Chem Int Ed 42(7):768–772

    CAS  Article  Google Scholar 

  38. 38.

    Lough WJ, Wainer IW (1995) High performance liquid chromatography: fundamental principles and practice. CRC Press

  39. 39.

    Smith MB (2013) March’s advanced organic chemistry: reactions, mechanisms, and structure.7th edn. Wiley, New York/Hoboken

    Google Scholar 

  40. 40.

    Hupe DJ (1984) Chapter 8: enzyme reactions involving imine formation. In: Michael IP (ed) New comprehensive biochemistry, vol 6. Elsevier, pp 271–301

  41. 41.

    Sidhu A, Sidhu S, Vineet RM (2011) Synthesis, in vitro antifungal evaluation and structure activity relation of the Schiff bases of some primary amines against Ustilago Tritici. Pestic Res J 23(1):88–95

    CAS  Google Scholar 

  42. 42.

    Jones RAY (1979) Physical and mechanistic organic chemistry. Cambridge texts in chemistry and biochemistry1st edn. Cambridge University Press

  43. 43.

    Ciaccia M, Di Stefano S (2015) Mechanisms of imine exchange reactions in organic solvents. Org Biomol Chem 13(3):646–654

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Guthrie JP (1978) Hydrolysis of esters of oxy acids – Pka values for strong acids – Bronsted relationship for attack of water at methyl – free-energies of hydrolysis of esters of oxy acids – and a linear relationship between free-energy of hydrolysis and Pka holding over a range of 20 Pk units. Can J Chem 56(17):2342–2354

    CAS  Article  Google Scholar 

  45. 45.

    Ciaccia M, Cacciapaglia R, Mencarelli P, Mandolini L, Di Stefano S (2013) Fast transimination in organic solvents in the absence of proton and metal catalysts. A key to imine metathesis catalyzed by primary amines under mild conditions. Chem Sci 4(5):2253–2261

    CAS  Article  Google Scholar 

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The research was supported by the European Research Council Starting Grant 279647. PG acknowledges support from the Foundation for Polish Science within the Idee dla Polski program.

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Correspondence to Pawel Jankowski or Piotr Garstecki.

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Article Highlights

• A benchtop microfluidic system for chemical screening in microdroplets; made of inexpensive elements; easily reproducible.

• Droplet on Demand encapsulates each individual reaction in a droplet, spending < 1 mg of limiting reagent per reaction.

• Microfluidic screening of model reaction accurately reflects the classical batch conditions.

Electronic supplementary material

Online Resource 1

ESM1.pdf — microfluidic system’s construction details, HPLC analyses, NMR spectra, heating rates in the microreactor, quantitative analysis of screening data (PDF 3617 kb)

Online Resource 2

ESM2.wmv — video showing system operation (WMV 12100 kb)

Online Resource 3

ESM3.wmv — video showing droplet mixing (WMV 3835 kb)

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Jankowski, P., Kutaszewicz, R., Ogończyk, D. et al. A microfluidic platform for screening and optimization of organic reactions in droplets. J Flow Chem 10, 397–408 (2020). https://doi.org/10.1007/s41981-019-00055-8

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  • Multiphase flow
  • Droplet on demand
  • Screening and optimization
  • Droplet microfluidics
  • Lab-on-a-chip