Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst

Nature Chemistry volume 11, pages 129–135 (2019)Cite this article

Subjects

Abstract

Chemists extensively use free radical reactivity for applications in organic synthesis, materials science, and life science. Traditionally, generating radicals requires strategies that exploit the bond dissociation energy or the redox properties of the precursors. Here, we disclose a photochemical catalytic approach that harnesses different physical properties of the substrate to form carbon radicals. We use a nucleophilic dithiocarbamate anion catalyst, adorned with a well-tailored chromophoric unit, to activate alkyl electrophiles via an SN2 pathway. The resulting photon-absorbing intermediate affords radicals upon homolytic cleavage induced by visible light. This catalytic SN2-based strategy, which exploits a fundamental mechanistic process of ionic chemistry, grants access to open-shell intermediates from a variety of substrates that would be incompatible with or inert to classical radical-generating strategies. We also describe how the method’s mild reaction conditions and high functional group tolerance could be advantageous for developing C–C bond-forming reactions, for streamlining the preparation of a marketed drug, for the late-stage elaboration of biorelevant compounds and for enantioselective radical catalysis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Strategies for generating radicals.
Fig. 2: Design plan and reaction development.
Fig. 3: Reaction scope.
Fig. 4: Synthetic applications of the method.
Fig. 5: Application in enantioselective radical catalysis.

Similar content being viewed by others

Data availability:

The data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for Br-11, an analogue of the major diastereoisomer of compound 11, have been deposited with the Cambridge Crystallographic Data Centre, accession number CCDC 1839232.

References

  1. Renaud, P. & Sibi, M. P. (eds) Radicals in Organic Synthesis (Wiley-VCH, Weinheim, Germany, 2001).

  2. Yan, M., Lo, J. C., Edwards, J. T. & Baran, P. S. Radicals: reactive intermediates with translational potential. J. Am. Chem. Soc. 138, 12692–12714 (2016).

    Article  CAS  Google Scholar 

  3. Lalevée, J. & Fouassier, J. P. in Encyclopedia of Radicals in Chemistry, Biology and Materials, Vol 1 (eds Chatgilialoglu, C. & Studer, A.) (John Wiley & Sons, Weinheim, 2012).

  4. Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical methods since 2000: on the verge of a renaissance. Chem. Rev. 117, 13230–13319 (2017).

    Article  CAS  Google Scholar 

  5. Barton, D. H. R. & McCombie, S. W. A new method for the deoxygenation of secondary alcohols. J. Chem. Soc. Perkin Trans. 1, 1574–1585 (1975).

    Article  Google Scholar 

  6. Barton, D. H. R., Crich, D. & Motherwell, W. B. New and improved methods for the radical decarboxylation of acids. J. Chem. Soc. Chem. Commun. https://doi.org/10.1039/C39830000939 (1983).

  7. Barton, D. H. R. & Zard, S. Z. Invention of new reactions useful in the chemistry of natural products. Pure Appl. Chem. 58, 675–684 (1986).

    Article  CAS  Google Scholar 

  8. Delduc, P., Tailhan, C. & Zard, S. Z. A convenient source of alkyl and acyl radicals. J. Chem. Soc. Chem. Commun. https://doi.org/10.1039/C39880000308 (1988).

  9. Zard, S. Z. On the trail of xanthates: some new chemistry from an old functional group. Angew. Chem. Int. Ed. 36, 672–685 (1997).

    Article  Google Scholar 

  10. Studer, A. & Curran, D. P. Catalysis of radical reactions: a radical chemistry perspective. Angew. Chem. Int. Ed. 55, 58–102 (2016).

    Article  CAS  Google Scholar 

  11. Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).

    Article  CAS  Google Scholar 

  12. Matsui, J. K., Lang, S. B., Heitz, D. R. & Molander, G. A. Photoredox-mediated routes to radicals: the value of catalytic radical generation in synthetic methods development. ACS Catal. 7, 2563–2575 (2017).

    Article  CAS  Google Scholar 

  13. Tzirakis, M. D., Lykakis, I. N. & Orfanopoulos, M. Decatungstate as an efficient photocatalyst in organic chemistry. Chem. Soc. Rev. 38, 2609–2621 (2009).

    Article  CAS  Google Scholar 

  14. Roth, H. G., Romero, N. A. & Nicewicz, D. A. Experimental and calculated electrochemical potentials of common organic molecules for applications to single-electron redox chemistry. Synlett. 27, 714–723 (2016).

    CAS  Google Scholar 

  15. Lalevée, J., Blanchard, N., El-Roz, M., Allonas, X. & Fouassier, J. P. New photoiniferters: respective role of the initiating and persistent radicals. Macromolecules 41, 2347–2352 (2008).

    Article  Google Scholar 

  16. Dag, O., Yaman, S. O., Onal, A. M. & Isci, H. Spectroelectrochemistry of potassium ethylxanthate, bis(ethylxanthato)nickel(II) and tetraethylammonium tris(ethylxanthato)nickelate(II). J. Chem. Soc. Dalton Trans. https://doi.org/10.1039/B105683M (2001).

  17. Bahtia, K. & Schuler, R. H. Oxidation of hydroxycyclohexadienyl radical by metal ions. J. Phys. Chem. 78, 2335–2338 (1974).

    Article  Google Scholar 

  18. Duan, X.-H., Maji, B. & Mayr, H. Characterization of the nucleophilic reactivities of thiocarboxylate, dithiocarbonate and dithiocarbamate anions. Org. Biomol. Chem. 9, 8046–8050 (2011).

    Article  CAS  Google Scholar 

  19. Barton, D. H. R., George, M. V. & Tomoeda, M. 369. Photochemical transformations. Part XIII. A new method for the production of acyl radicals. J. Chem. Soc. https://doi.org/10.1039/JR9620001967 (1962).

  20. Grainger, R. S. & Welsh, E. J. Formal synthesis of (−)-Aphanorphine using sequential photomediated radical reactions of dithiocarbamates. Angew. Chem. Int. Ed. 46, 5377–5380 (2007).

    Article  CAS  Google Scholar 

  21. Davies, J., Svejstrup, T. D., Fernandez Reina, D., Sheikh, N. S. & Leonori, D. Visible-light-mediated synthesis of amidyl radicals: transition-metal-free hydroamination and N-arylation reactions. J. Am. Chem. Soc. 138, 8092–8095 (2016).

    Article  CAS  Google Scholar 

  22. Giese, B. Formation of C–C bonds by addition of free radicals to alkenes. Angew. Chem. Int. Ed. 22, 753–764 (1983).

    Article  Google Scholar 

  23. Proinsias, K. ó, Jackowska, A., Radzewicz, K., Giedyk, M. & Gryko, D. Vitamin B12 catalyzed atom transfer radical addition. Org. Lett. 20, 296–299 (2018).

    Article  CAS  Google Scholar 

  24. Gualandi, A. et al. Photocatalytic radical alkylation of electrophilic olefins by benzylic and alkylic zinc-sulfinates. ACS Catal. 7, 5357–5362 (2017).

    Article  CAS  Google Scholar 

  25. Ueda, M. et al. Benzyl radical addition reaction through the homolytic cleavage of a benzylic C–H bond. Org. Biomol. Chem. 9, 2062–2064 (2011).

    Article  CAS  Google Scholar 

  26. Capaldo, L., Buzzetti, L., Merli, D., Fagnoni, M. & Ravelli, D. Smooth photocatalyzed benzylation of electrophilic olefins via decarboxylation of arylacetic acids. J. Org. Chem. 81, 7102–7109 (2016).

    Article  CAS  Google Scholar 

  27. Isse, A. A., Falciola, L., Mussini, P. R. & Gennaro, A. Relevance of electron transfer mechanism in electrocatalysis: the reduction of organic halides at silver electrodes. Chem. Commun. https://doi.org/10.1039/B513801A (2006).

  28. Brasholz, M. “Super-reducing” photocatalysis: consecutive energy and electron transfers with polycyclic aromatic hydrocarbons. Angew. Chem. Int. Ed. 56, 10280–10281 (2017).

    Article  CAS  Google Scholar 

  29. Clayden, J., Greeves, N. & Warren, S. in Organic Chemistry (ed. Wothers, P.) Ch. 17 (Oxford University Press, Oxford, 2001).

  30. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  Google Scholar 

  31. Chen, J.-R., Yu, X.-Y. & Xiao, W.-J. Tandem radical cyclization of N-arylacrylamides: an emerging platform for the construction of 3,3-disubstituted oxindoles. Synthesis 47, 604–629 (2015).

    Article  CAS  Google Scholar 

  32. Fujiwara, Y. & Baran, P. S. in New Horizons of Process Chemistry (eds Tomioka K., Shioiri T. & Sajiki H.) (Springer Nature, Singapore, 2017).

  33. Carson, J. R. Uncatalyzed aroylation of 1-alkylpyrrole-2-acetic acid derivatives. US Patent US3998844A (1976).

  34. Liu, Z.-Q. & Li, Z. Radical-promoted site-specific cross dehydrogenative coupling of heterocycles with nitriles. Chem. Commun. 52, 14278–14281 (2016).

    Article  CAS  Google Scholar 

  35. 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).

    Article  Google Scholar 

  36. Nicewicz, D. & MacMillan, D. W. C. Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008).

    Article  CAS  Google Scholar 

  37. Silvi, M. & Melchiorre, P. Enhancing the potential of enantioselective organocatalysis with light. Nature 554, 41–49 (2018).

    Article  CAS  Google Scholar 

  38. Neumann, M., Füldner, S., König, B. & Zeitler, K. Metal-free, cooperative asymmetric organophotoredox catalysis with visible light. Angew. Chem. Int. Ed. 50, 951–954 (2011).

    Article  CAS  Google Scholar 

  39. Gualandi, A. et al. Organocatalytic enantioselective alkylation of aldehydes with [Fe(bpy)3]Br2 catalyst and visible light. ACS Catal. 5, 5927–5931 (2015).

    Article  CAS  Google Scholar 

  40. Brimioulle, R., Lenhart, D., Maturi, M. M. & Bach, T. Enantioselective catalysis of photochemical reactions. Angew. Chem. Int. Ed. 54, 3872–3890 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank ICIQ and the European Research Council (ERC 681840 - CATA-LUX) for financial support. E.P.B. thanks MINECO (CTQ2016-75520-P) for a predoctoral fellowship.

Author information

Author notes

  1. Paolo Melchiorre

    Present address: Italian Institute of Technology, IIT, Laboratory of Asymmetric Catalysis and Photochemistry, Genoa, Italy

Authors and Affiliations

  1. ICIQ, Institute of Chemical Research of Catalonia—the Barcelona Institute of Science and Technology, Tarragona, Spain

    Bertrand Schweitzer-Chaput, Matthew A. Horwitz, Eduardo de Pedro Beato & Paolo Melchiorre

  2. ICREA, Catalan Institution for Research and Advanced Studies, Barcelona, Spain

    Paolo Melchiorre

Authors
  1. Bertrand Schweitzer-Chaput
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew A. Horwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eduardo de Pedro Beato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Melchiorre
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.S.-C. was involved in the discovery and initial development of the radical generation strategy. B.S.-C., M.A.H., and E.P.B. performed the experiments. All the authors analyzed the data and designed the experiments. P.M directed the project and wrote the manuscript with contributions from all the authors.

Corresponding author

Correspondence to Paolo Melchiorre.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary information

General information, catalyst synthesis, experimental set-up, mechanistic studies, synthetic procedures, additional references and chemical compound characterization data

Crystallographic data

CIF for Br-11, an analogue of the major diastereoisomer of compound 11; CCDC reference: 1839232

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schweitzer-Chaput, B., Horwitz, M.A., de Pedro Beato, E. et al. Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst. Nature Chem 11, 129–135 (2019). https://doi.org/10.1038/s41557-018-0173-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-018-0173-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing