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A general arene C–H functionalization strategy via electron donor–acceptor complex photoactivation


The photoactivation of electron donor–acceptor complexes has emerged as a sustainable, selective and versatile strategy for the generation of radical species. However, when it comes to aryl radical formation, this strategy remains hamstrung by the electronic properties of the aromatic radical precursors, and electron-deficient aryl halide acceptors are required. This has prevented the implementation of a general synthetic platform for aryl radical formation. Our study introduces triarylsulfonium salts as acceptors in photoactive electron donor–acceptor complexes, used in combination with catalytic amounts of newly designed amine donors. The sulfonium salt label renders inconsequential the electronic features of the aryl radical precursor and, more importantly, it is installed regioselectively in native aromatic compounds by C–H sulfenylation. Using this general, site-selective aromatic C–H functionalization approach, we developed metal-free protocols for the alkylation and cyanation of arenes, and showcased their application in both the synthesis and the late-stage modification of pharmaceuticals and agrochemicals.

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Fig. 1: Photoactivation of EDA complexes drives the metal-free radical C–H functionalization of arenes.
Fig. 2: Development of the photochemical C–H alkylation protocol.
Fig. 3: Synthesis and late-stage functionalization of pharmaceuticals and agrochemicals.
Fig. 4: Mechanistic studies and proposed reaction pathway.

Data availability

Materials and methods, experimental procedures, useful information, mechanistic studies, 1H NMR spectra, 13C NMR spectra and mass spectrometry data are available in the Supplementary Information. Crystallographic data for compounds 2, 31, 33, 44, 64 and 69 have been deposited with the Cambridge Crystallographic Data Centre, with deposition numbers CCDC 2120242, 2120244, 2120243, 2122516, 2122517 and 2120245, respectively. Correspondence and requests for materials/raw data should be addressed to the corresponding author).


  1. Sumida, Y. & Ohmiya, H. Direct excitation strategy for radical generation in organic synthesis. Chem. Soc. Rev. 50, 6320–6332 (2021).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Genzink, M. J., Kidd, J. B., Swords, W. B. & Yoon, T. P. Chiral photocatalyst structures in asymmetric photochemical synthesis. Chem. Rev. 122, 1654–1716 (2022).

    Article  CAS  Google Scholar 

  4. Sandoval, B. A. et al. Photoenzymatic reductions enabled by direct excitation of flavin-dependent ‘ene’-reductases. J. Am. Chem. Soc. 143, 1735–1739 (2021).

    Article  CAS  Google Scholar 

  5. Romero, N. A. & Nicewicz, D. A. Organic photoredox catalysis. Chem. Rev. 116, 10075–10166 (2016).

    Article  CAS  Google Scholar 

  6. 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 

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

    Article  CAS  Google Scholar 

  8. Crisenza, G. E. M., Mazzarella, D. & Melchiorre, P. Synthetic methods driven by the photoactivity of electron donor−acceptor complexes. J. Am. Chem. Soc. 142, 5461–5476 (2020).

    Article  CAS  Google Scholar 

  9. Wu, J., Grant, P. S., Li, X., Noble, A. & Aggarwal, V. K. Catalyst free deaminative functionalizations of primary amines by photoinduced single-electron transfer. Angew. Chem. Int. Ed. 58, 5697–5701 (2019).

    Article  CAS  Google Scholar 

  10. Fu, M.-C., Shang, R., Zhao, B., Wang, B. & Fu, Y. Photocatalytic decarboxylative alkylations mediated by triphenylphosphine and sodium iodide. Science 363, 1429–1434 (2019).

    Article  CAS  Google Scholar 

  11. de Pedro Beato, E., Spinnato, D., Zhou, W. & Melchiorre, P. A general organocatalytic system for electron donor−acceptor complex photoactivation and its use in radical processes. J. Am. Chem. Soc. 143, 12304–12314 (2021).

    Article  Google Scholar 

  12. Davies, J., Booth, S. G., Essafi, S., Dryfe, R. A. W. & Leonori, D. Visible-light-mediated generation of nitrogen-centered radicals: metal-free hydroimination and iminohydroxylation cyclization reactions. Angew. Chem. Int. Ed. 54, 14017–14021 (2015).

    Article  CAS  Google Scholar 

  13. Tobisu, M., Furukawa, T. & Chatani, N. Visible light-mediated direct arylation of arenes and heteroarenes using diaryliodonium salts in the presence and absence of a photocatalyst. Chem. Lett. 42, 1203–1205 (2013).

    Article  CAS  Google Scholar 

  14. Liu, B., Lim, C.-H. & Miyake, G. M. Visible-light-promoted C-S cross-coupling via intermolecular charge transfer. J. Am. Chem. Soc. 139, 13616–13619 (2017).

    Article  CAS  Google Scholar 

  15. Berger, F. et al. Site-selective and versatile aromatic C−H functionalization by thianthrenation. Nature 567, 223–228 (2019).

    Article  CAS  Google Scholar 

  16. Aukland, M. H., Šiaučiulis, M., West, A., Perry, G. J. P. & Procter, D. J. Metal-free photoredox-catalyzed formal C-H/C-H coupling of arenes enabled by interrupted Pummerer activation. Nat. Catal. 3, 163–169 (2020).

    Article  CAS  Google Scholar 

  17. Péter, Á., Perry, G. J. P. & Procter, D. J. Radical C–C bond formation using sulfonium salts and light. Adv. Synth. Catal. 362, 2135–2142 (2020).

    Article  Google Scholar 

  18. Juliá, F. et al. High site selectivity in electrophilic aromatic substitutions: mechanism of C–H thianthrenation. J. Am. Chem. Soc. 143, 16041–16054 (2021).

    Article  Google Scholar 

  19. Pulis, A. P. & Procter, D. J. C–H coupling reactions directed by sulfoxides: teaching an old functional group new tricks. Angew. Chem. Int. Ed. 55, 9842–9860 (2016).

    Article  CAS  Google Scholar 

  20. Trudel, V., Tien, C.-H., Trofimove, A. & Yudin, A. K. Interrupted reactions in chemical synthesis. Nat. Rev. Chem. 5, 604–623 (2021).

    Article  CAS  Google Scholar 

  21. Spell, M. L. et al. A visible-light-promoted O-glycosylation with a thioglycoside donor. Angew. Chem. Int. Ed. 55, 6515–6519 (2016).

    Article  CAS  Google Scholar 

  22. Chen, C., Wang, Z.-J., Lu, H., Zhao, Y. & Shi, Z. Generation of non-stabilized alkyl radicals from thianthrenium salts for C-B and C-C bond formation. Nat. Commun. 12, 4526 (2021).

    Article  CAS  Google Scholar 

  23. Hamann, B. C. & Hartwig, J. F. Palladium-catalyzed direct α-arylation of ketones. Rate acceleration by sterically hindered chelating ligands and reductive elimination from a transition metal enolate complex. J. Am. Chem. Soc. 119, 12382–12383 (1997).

    Article  CAS  Google Scholar 

  24. Escudero-Casao, M., Licini, G. & Orlandi, M. Enantioselective α-arylation of ketones via a novel Cu(I)–bis(phosphine) dioxide catalytic system. J. Am. Chem. Soc. 143, 3289–3294 (2021).

    Article  CAS  Google Scholar 

  25. Zhao, D., Xu, P. & Ritter, T. Palladium-catalyzed late-stage direct arene cyanation. Chem 5, 97–107 (2019).

    Article  CAS  Google Scholar 

  26. McManus, J. B. & Nicewicz, D. A. Direct C−H cyanation of arenes via organic photoredox catalysis. J. Am. Chem. Soc. 139, 2880–2883 (2017).

    Article  CAS  Google Scholar 

  27. McCarthy, B. G. et al. Structure−property relationships for tailoring phenoxazines as reducing photoredox catalysts. J. Am. Chem. Soc. 140, 5088–5101 (2018).

    Article  CAS  Google Scholar 

  28. Sreenath, K., Veettil Suneesh, C., Gopidas, K. R. & Flowers, R. A. II Generation of triarylamine radical cations through reaction of triarylamines with Cu(II) in acetonitrile. A kinetic investigation of the electron-transfer reaction. J. Phys. Chem. A 113, 6477–6483 (2009).

    Article  CAS  Google Scholar 

  29. Lei, J., Huang, J. & Zhu, Q. Recent progress in imidoyl radical-involved reactions. Org. Biomol. Chem. 14, 2593–2602 (2016).

    Article  CAS  Google Scholar 

  30. Stork, G. & Sher, P. M. Regiospecific trapping of radicals from cyclization reactions. Cyclic nitriles via isocyanide trapping. J. Am. Chem. Soc. 105, 6765–6766 (1983).

    Article  CAS  Google Scholar 

  31. Leardini, R., Nanni, D. & Zanardi, G. Radical addition to isonitriles: a route to polyfunctionalized alkenes through a novel three-component radical cascade reaction. J. Org. Chem. 65, 2763–2772 (2000).

    Article  CAS  Google Scholar 

  32. Pimparkar, S. et al. C–CN bond formation: an overview of diverse strategies. Chem. Commun. 57, 2210–2232 (2021).

    Article  CAS  Google Scholar 

  33. Guillemard, L., Kaplaneris, N., Ackermann, L. & Johansson, M. J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 5, 522–545 (2021).

    Article  CAS  Google Scholar 

  34. Berger, F. & Ritter, T. Site-selective late-stage C–H functionalization via thianthrenium salts. Synlett 33, 339–345 (2022).

    Article  CAS  Google Scholar 

  35. Zhou, G., Liu, X. A process for preparing febuxostat. CN patent 102964313A (2013).

  36. Buzzetti, L., Crisenza, G. E. M. & Melchiorre, P. Mechanistic studies in photocatalysis. Angew. Chem. Int. Ed. 58, 3730–3747 (2019).

    Article  CAS  Google Scholar 

  37. Buglioni, L., Mastandrea, M. M., Frontera, A. & Pericàs, M. A. Anion–π interactions in light-induced reactions: role in the amidation of (hetero)aromatic systems with activated N-aryloxyamides. Chem. Eur. J. 25, 11785–11790 (2019).

    Article  CAS  Google Scholar 

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We thank EPSRC (PhD Studentship to L.v.D. and PDRA funding to A.D. (EP/T013419/1)), the Leverhulme Trust (PDRA funding to J.A.R.-A. (RPG-2016-360)) and the University of Manchester (Lectureship to G.E.M.C.) for their generous support. Additionally, we thank the Natrajan group for their assistance with the photophysical studies, and the Leonori group for insightful discussion.

Author information

Authors and Affiliations



J.A.R.-A., G.E.M.C. and D.J.P. conceived the project. L.v.D. and A.D. designed and performed the experimental work, with contributions from J.A.R.-A., E.G. and G.E.M.C. All the authors contributed to the analysis and interpretation of data. G.E.M.C. and D.J.P. wrote the manuscript with input from all the authors.

Corresponding author

Correspondence to David J. Procter.

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The authors declare no competing interests.

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Peer review information

Nature Chemistry thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–5, Schemes 1–3, discussion and Tables 1–17.

Supplementary Data 1

Crystallographic data for compound 2; CCDC reference 2120242.

Supplementary Data 2

Crystallographic data for compound 31; CCDC reference 2120244.

Supplementary Data 3

Crystallographic data for compound 33; CCDC reference 2120243.

Supplementary Data 4

Crystallographic data for compound 44; CCDC reference 2122516.

Supplementary Data 5

Crystallographic data for compound 69; CCDC reference 2120245.

Supplementary Data 6

Crystallographic data for compound 64; CCDC reference 2122517.

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Dewanji, A., van Dalsen, L., Rossi-Ashton, J.A. et al. A general arene C–H functionalization strategy via electron donor–acceptor complex photoactivation. Nat. Chem. 15, 43–52 (2023).

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