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Automated radial synthesis of organic molecules


Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative1,2,3,4 or linear processes5,6,7,8,9, and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide10, synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon–nitrogen cross-couplings11 in a photochemical module—all without instrument reconfiguration.

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Fig. 1: Approaches to organic synthesis.
Fig. 2: The radial synthesizer.
Fig. 3: Direct comparison of synthetic routes towards rufinamide.
Fig. 4: Generation of a library of rufinamide derivatives.
Fig. 5: Modular expansion of the capabilities of the system.

Data availability

All data generated or analysed during this study are included in this Article and its Supplementary Information file.

Code availability

The complete software package and instructions necessary for assembling and operating the radial synthesizer are freely available to academic users by request at


  1. 1.

    Merrifield, R. B. Automated synthesis of peptides. Science 150, 178–185 (1965).

    CAS  ADS  Article  Google Scholar 

  2. 2.

    Caruthers, M. H. Gene synthesis machines: DNA chemistry and its uses. Science 230, 281–285 (1985).

    CAS  ADS  Article  Google Scholar 

  3. 3.

    Plante, O. J., Palmacci, E. R. & Seeberger, P. H. Automated solid-phase synthesis of oligosaccharides. Science 291, 1523–1527 (2001).

    CAS  ADS  Article  Google Scholar 

  4. 4.

    Li, J. et al. Synthesis of many different types of organic small molecules using one automated process. Science 347, 1221–1226 (2015).

    CAS  ADS  Article  Google Scholar 

  5. 5.

    Zhang, P. et al. Advanced continuous flow platform for on-demand pharmaceutical manufacturing. Chem. Eur. J. 24, 2776–2784 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Adamo, A. et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 352, 61–67 (2016).

    CAS  ADS  Article  Google Scholar 

  7. 7.

    Bédard, A. C. et al. Reconfigurable system for automated optimization of diverse chemical reactions. Science 361, 1220–1225 (2018).

    ADS  Article  Google Scholar 

  8. 8.

    Ghislieri, D., Gilmore, K. & Seeberger, P. H. Chemical assembly systems: layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients. Angew. Chem. Int. Ed. 54, 678–682 (2015).

    CAS  Google Scholar 

  9. 9.

    Britton, J. & Jamison, T. F. A unified continuous flow assembly-line synthesis of highly subsituted pyrazoles and pyrazolines. Angew. Chem. Int. Ed. 56, 8823–8827 (2017).

    CAS  Article  Google Scholar 

  10. 10.

    Padmaja, R. D. & Chanda, K. A short review on synthetic advances towards the synthesis of rufinamide, an entiepileptic drug. Org. Process Res. Dev. 22, 457–466 (2018).

    CAS  Article  Google Scholar 

  11. 11.

    Corcoran, E. B. et al. Aryl amination using ligand-free Ni(ii) salts and photoredox catalysis. Science 353, 279–283 (2016).

    CAS  ADS  Article  Google Scholar 

  12. 12.

    Plutschack, M. B., Pieber, B., Gilmore, K. & Seeberger, P. H. The hitchhiker’s guide to flow chemistry. Chem. Rev. 117, 11796–11893 (2017).

    CAS  Article  Google Scholar 

  13. 13.

    Britton, J. & Raston, C. L. Multi-step continuous-flow synthesis. Chem. Soc. Rev. 46, 1250–1271 (2017).

    CAS  Article  Google Scholar 

  14. 14.

    Gérardy, R. et al. Continuous flow organic chemistry: successes and pitfalls at the interface with current societal challenges. Eur. J. Org. Chem. 2018, 2301–2351 (2018).

  15. 15.

    Pastre, J. C., Browne, D. L. & Ley, S. V. Flow chemistry syntheses of natural products. Chem. Soc. Rev. 42, 8849–8869 (2013).

    CAS  Article  Google Scholar 

  16. 16.

    Malet-Sanz, L. & Susanne, F. Continuous flow synthesis. A pharma perspective. J. Med. Chem. 55, 4062–4098 (2012).

    CAS  Article  Google Scholar 

  17. 17.

    Gutmann, B., Cantillo, D. & Kappe, C. O. Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. 54, 6688–6728 (2015).

    CAS  Article  Google Scholar 

  18. 18.

    Steiner, S. et al. Organic synthesis in a modular robotic system driven by a chemical programming language. Science 363, eaav2211 (2019).

    CAS  Article  Google Scholar 

  19. 19.

    Schotten, C., Leist, L. G. T., Semrau, A. L. & Browne, D. L. A machine-assisted approach for the preparation of follow-on pharmaceutical compound libraries. React. Chem. Eng. 3, 210–215 (2018).

    CAS  Article  Google Scholar 

  20. 20.

    Hwang, Y. J. et al. A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets. Chem. Commun. 53, 6649–6652 (2017).

    CAS  Article  Google Scholar 

  21. 21.

    Hepler, L. G. Correct calculation of ΔH°, ΔC°P, and ΔV° from temperature and pressure dependences of equilibrium constants: the importance of thermal expansion and compressibility of the solvent. Thermochim. Acta 50, 69–72 (1981).

    CAS  Article  Google Scholar 

  22. 22.

    Fitzpatrick, D. E., Maujean, T., Evans, A. C. & Ley, S. V. Across-the-world automated optimization and continuous-flow synthesis of pharmaceutical agents operating through a cloud-based server. Angew. Chem. Int. Ed. 57, 15128–15132 (2018).

    CAS  Article  Google Scholar 

  23. 23.

    Twilton, J. et al. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).

    CAS  Article  Google Scholar 

  24. 24.

    Milligan, J. A., Phelan, J. P., Badir, S. O. & Molander, G. A. Alkyl carbon–carbon bond formation by nickel/photoredox cross-coupling. Angew. Chem. Int. Ed. 58, 6152–6163 (2019).

    CAS  Article  Google Scholar 

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We acknowledge financial support from the Max-Planck Society, the Army Research Office under contract W911NF-16-1-0557, and the DFG InCHeM (FOR 2177). We thank B. Pieber, J. Malik, S. Moon and F. Hentschel for suggestions and support; J. von Szada-Borryszkowski and J. Petersen for construction of the instrument housing; and Vapourtec for software support with the incorporation of their equipment.

Author information




K.G. designed the approach and system, and refined the instrument and chemistries. M.G. and K.G. wrote the draft of the manuscript, and all authors participated in revising the manuscript. S.C. designed, wrote and developed the software, controls, user interface and hardware layout. M.G. developed chemistry, designed and executed optimizations, developed pathways for multistep processes and refined the system. P.H.S. and K.G. provided oversight to the project and secured funding.

Corresponding author

Correspondence to Kerry Gilmore.

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Competing interests

The Max-Planck Society has been granted patent EP3386628B1, which covers the system described here and lists S.C., P.H.S. and K.G. as inventors.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1–S146, Supplementary Tables S1–S23 and Supplementary Schemes S1–S34.

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Chatterjee, S., Guidi, M., Seeberger, P.H. et al. Automated radial synthesis of organic molecules. Nature 579, 379–384 (2020).

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