Skip to main content

Thank you for visiting 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.

Electrophotocatalytic oxygenation of multiple adjacent C–H bonds


Oxygen-containing functional groups are nearly ubiquitous in complex small molecules. The installation of multiple C–O bonds by the concurrent oxygenation of contiguous C–H bonds in a selective fashion would be highly desirable but has largely been the purview of biosynthesis. Multiple, concurrent C–H bond oxygenation reactions by synthetic means presents a challenge1,2,3,4,5,6, particularly because of the risk of overoxidation. Here we report the selective oxygenation of two or three contiguous C–H bonds by dehydrogenation and oxygenation, enabling the conversion of simple alkylarenes or trifluoroacetamides to their corresponding di- or triacetoxylates. The method achieves such transformations by the repeated operation of a potent oxidative catalyst, but under conditions that are sufficiently selective to avoid destructive overoxidation. These reactions are achieved using electrophotocatalysis7, a process that harnesses the energy of both light and electricity to promote chemical reactions. Notably, the judicious choice of acid allows for the selective synthesis of either di- or trioxygenated products.

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

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Oxygenation of multiple C–H bonds.
Fig. 2: Substrate scope of electrophotocatalytic vicinal C–H dioxygenation.
Fig. 3: Electrophotocatalytic vicinal C–H trioxygenation.
Fig. 4: Vicinal C–H di- and trioxygenation of trifluoroacetamides and synthetic applications of electrophotocatalytic multiple adjacent C–H oxygenations.

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information.


  1. Company, A. & Costas, M. Applied Homogeneous Catalysis with Organometallic Compounds: A Comprehensive Handbook 3rd edn (Wiley, 2018).

  2. Irie, R. Oxidation: C-O bond formation by C-H activation. Compr. Chirality 5, 36–68 (2012).

    Article  CAS  Google Scholar 

  3. Que, L. Jr & Tolman, W. B. Biologically inspired oxidation catalysis. Nature 455, 333–340 (2008).

    Article  CAS  Google Scholar 

  4. Chen, M. S. & White, M. C. A predictably selective aliphatic C-H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

    Article  CAS  Google Scholar 

  5. Chen, M. S. & White, M. C. Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010).

    Article  CAS  Google Scholar 

  6. Horn, E. J. et al. Scalable and sustainable electrochemical allylic C-H oxidation. Nature 533, 71–81 (2016).

    Article  Google Scholar 

  7. Huang, H., Steiniger, K. A. & Lambert, T. H. Electrophotocatalysis: combining light and electricity to catalyze reactions. J. Am. Chem. Soc. 144, 12567–12583 (2022).

    Article  CAS  Google Scholar 

  8. Paddon, C. J. et al. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496, 528–532 (2013).

    Article  CAS  Google Scholar 

  9. White, M. C. & Zhao, J. Aliphatic C-H oxidations for late-stage functionalization. J. Am. Chem. Soc. 140, 13988–14009 (2018).

    Article  CAS  Google Scholar 

  10. Huang, X. & Groves, J. T. Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C-H activation. J. Biol. Inorg. Chem. 22, 185–207 (2017).

    Article  CAS  Google Scholar 

  11. Crandall, J. K. et al. Dimethyldioxirane (DDO) in Encyclopedia of Reagents for Organic Synthesis (ed. Charente, A. B.) (Wiley, 2022).

  12. Das, S., Incarvito, C. D., Crabtree, R. H. & Brudvig, G. W. Molecular recognition in the selective oxygenation of saturated C-H bonds by a dimanganese catalyst. Science 312, 1941–1943 (2006).

    Article  CAS  Google Scholar 

  13. Kawamata, Y. et al. Scalable, electrochemical oxidation of unactivated C–H bonds. J. Am. Chem. Soc. 139, 7448–7451 (2017).

    Article  CAS  Google Scholar 

  14. Moutet, J. C. & Reverdy, G. Photochemistry of cation radicals in solution-photoinduced electron-transfer reactions between alcohols and the N,N,N’,N’-tetraphenyl-para-phenylenediamine cation radical. J. Chem. Soc. Chem. Comm. 12, 654–655 (1982).

  15. Scheffold, R. & Orlinski, R. Carbon-carbon bond formation by light-assisted B-12 catalysis-nucleophilic acylation of Michael olefins. J. Am. Chem. Soc. 105, 7200–7202 (1983).

    Article  CAS  Google Scholar 

  16. Barham, J. P. & König, B. Synthetic photoelectrochemistry. Angew. Chem. Int. Ed. Engl. 59, 11732–11747 (2020).

    Article  CAS  Google Scholar 

  17. Huang, H. et al. Electrophotocatalysis with a trisaminocyclopropenium radical dication. Angew. Chem. Int. Ed. Engl. 58, 13318–13322 (2019).

    Article  CAS  Google Scholar 

  18. Huang, H., Strater, Z. M. & Lambert, T. H. Electrophotocatalytic C-H functionalization of ethers with high regioselectivity. J. Am. Chem. Soc. 142, 1698–1703 (2020).

    Article  CAS  Google Scholar 

  19. Huang, H. & Lambert, T. H. Electrophotocatalytic acetoxyhydroxylation of aryl olefins. J. Am. Chem. Soc. 143, 7247–7252 (2021).

    Article  CAS  Google Scholar 

  20. Shen, T. & Lambert, T. H. Electrophotocatalytic diamination of vicinal C–H bonds. Science 371, 620–626 (2021).

    Article  CAS  Google Scholar 

  21. Shen, T. & Lambert, T. H. C-H amination via electrophotocatalytic Ritter-type reaction. J. Am. Chem. Soc. 143, 8597–8602 (2021).

    Article  CAS  Google Scholar 

  22. Huang, H. & Lambert, T. H. Electrophotocatalytic SNAr reactions of unactivated aryl fluorides at ambient temperature and without base. Angew. Chem. Int. Ed. Engl. 59, 658–662 (2020).

    Article  CAS  Google Scholar 

  23. Wang, F. & Stahl, S. S. Merging photochemistry with electrochemistry: functional-group tolerant electrochemical amination of C(sp3)-H bonds. Angew. Chem. Int. Ed. Engl. 58, 6385–6390 (2019).

    Article  CAS  Google Scholar 

  24. Yan, H., Hou, Z.-W. & Xu, H.-C. Photoelectrochemical C-H alkylation of heteroarenes with organotrifluoroborates. Angew. Chem. Int. Ed. Engl. 58, 4592–4595 (2019).

    Article  CAS  Google Scholar 

  25. Zhang, L. et al. Photoelectrocatalytic arene C-H amination. Nat. Catal. 2, 366–373 (2019).

    Article  CAS  Google Scholar 

  26. Zhang, W., Carpenter, K. L. & Lin, S. Electrochemistry broadens the scope of flavin photocatalysis: photoelectrocatalytic oxidation of unactivated alcohols. Angew. Chem. Int. Ed. Engl. 59, 409–417 (2020).

    Article  CAS  Google Scholar 

  27. Niu, L. et al. Manganese-catalyzed oxidative azidation of C(sp3)-H bonds under electrophotocatalytic conditions. J. Am. Chem. Soc. 142, 17693–17702 (2020).

    Article  CAS  Google Scholar 

  28. Kim, H., Kim, H., Lambert, T. H. & Lin, S. Reductive electrophotocatalysis: merging electricity and light to achieve extreme reduction potentials. J. Am. Chem. Soc. 142, 2087–2092 (2020).

    Article  CAS  Google Scholar 

  29. Cowper, N. G. W., Chernowsky, C. P., Williams, O. P. & Wickens, Z. K. Potent reductants via electron-primed photoredox catalysis: unlocking aryl chlorides for radical coupling. J. Am. Chem. Soc. 142, 2093–2099 (2020).

    Article  CAS  Google Scholar 

  30. Qiu, Y., Scheremetjew, A., Finger, L. H. & Ackermann, L. Electrophotocatalytic undirected C-H trifluoromethylations of (het)arenes. Chemistry 26, 3241–3246 (2020).

    Article  CAS  Google Scholar 

  31. Yoshida, J.-i, Kataoka, K., Horcajada, R. & Nagaki, A. Modern strategies in electroorganic synthesis. Chem. Rev. 108, 2265–2299 (2008).

    Article  CAS  Google Scholar 

  32. Francke, R. & Little, R. D. Redox catalysis in organic electrosynthesis: basic principles and recent developments. Chem. Soc. Rev. 43, 2492–2521 (2014).

    Article  CAS  Google Scholar 

  33. 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 

  34. Moeller, K. D. Using physical organic chemistry to shape the course of electrochemical reactions. Chem. Rev. 118, 4817–4833 (2018).

    Article  CAS  Google Scholar 

  35. Shi, S.-H., Liang, Y. & Jiao, N. Electrochemical oxidation induced selective C-C bond cleavage. Chem. Rev. 121, 485–505 (2021).

    Article  CAS  Google Scholar 

  36. Ghosh, A. K. et al. Highly selective and potent human β-secretase 2 (BACE2) inhibitors against type 2 diabetes: design, synthesis, X-ray structure and structure–activity relationship studies. ChemMedChem 14, 545–560 (2019).

    Article  CAS  Google Scholar 

  37. Furukubo, S., Moriyama, N., Onomura, O. & Matsumura, Y. Stereoselective synthesis of azasugars by electrochemical oxidation. Tetrahedron Lett. 45, 8177–8181 (2004).

    Article  CAS  Google Scholar 

  38. Beal, H. E. & Horenstein, N. A. Comparative genomic analysis of azasugar biosynthesis. AMB Express 11, 120 (2021).

    Article  CAS  Google Scholar 

  39. Chambers, M. S. et al. Spiropiperidines as high-affinity, selective σ ligands. J. Med. Chem. 35, 2033–2039 (1992).

    Article  CAS  Google Scholar 

  40. Lund, B. W. et al. Discovery of a potent, orally available, and isoform-selective retinoic acid β2 receptor agonist. J. Med. Chem. 48, 7517–7519 (2005).

    Article  CAS  Google Scholar 

  41. Acetti, D., Brenna, E., Fuganti, C., Gatti, F. G. & Serra, S. Enzyme-catalysed approach to the preparation of triazole antifungals: synthesis of (-)-genaconazole. Tetrahedron Asymmetry 20, 2413–2420 (2009).

    Article  CAS  Google Scholar 

  42. Frank, R. et al. Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an O-containing group as vanilloid receptor ligands. Patent WO 2013068461A1 (2013).

Download references


Funding for this work was provided by the National Institutes of Health (no. R35GM127135 to T.H.L.) and the National Natural Science Foundation of China (no. 22171046 to K.-Y.Y.). We thank X.-X. Li, X. He, Y. Yu and Z. Shi from Fuzhou University for their help with X-ray single-crystal analysis. We also thank S. Liao and Q. Song from Fuzhou University for their help with gas chromatography–mass spectrometry analysis. We thank I. Keresztes (Cornell University), J. Cheng and C. Xu (both from Fuzhou University) for their help with two-dimensional nuclear magnetic resonance analysis.

Author information

Authors and Affiliations



T.H.L. conceived of and directed the project and prepared the manuscript. T.H.L., T.S. and K.-Y.Y. designed experiments. T.S. and Y.-L.L. performed experiments. Y.-L.L. synthesized key substrates. T.S. performed all reactions and collected and analysed data.

Corresponding authors

Correspondence to Ke-Yin Ye or Tristan H. Lambert.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

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

Supplementary information

Supplementary Information

Analytical methods, experimental tips, mechanistic data, challenging substrates, compound characterization, nuclear magnetic resonance spectra and X-ray data analysis.

cif File for product 84 X-ray.

cif File for product 79 X-ray.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shen, T., Li, YL., Ye, KY. et al. Electrophotocatalytic oxygenation of multiple adjacent C–H bonds. Nature (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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