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:

Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids

Nature Chemistry volume 15, pages 1683–1692 (2023)Cite this article

Subjects

A Publisher Correction to this article was published on 23 November 2023

This article has been updated

Abstract

Incorporation of fluoroalkyl motifs in pharmaceuticals can enhance the therapeutic profiles of the parent molecules. The hydrofluoroalkylation of alkenes has emerged as a promising route to diverse fluoroalkylated compounds; however, current methods require superstoichiometric oxidants, expensive/oxidative fluoroalkylating reagents and precious metals, and often exhibit limited scope, making a universal protocol that addresses these limitations highly desirable. Here we report the hydrofluoroalkylation of alkenes with cheap, abundant and available fluoroalkyl carboxylic acids as the sole reagents. Hydrotrifluoro-, difluoro-, monofluoro- and perfluoroalkylation are all demonstrated, with broad scope, mild conditions (redox neutral) and potential for late-stage modification of bioactive molecules. Critical to success is overcoming the exceedingly high redox potential of feedstock fluoroalkyl carboxylic acids such as trifluoroacetic acid by leveraging cooperative earth-abundant, inexpensive iron and redox-active thiol catalysis, enabling these reagents to be directly used as hydroperfluoroalkylation donors without pre-activation. Preliminary mechanistic studies support the radical nature of this cooperative process.

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: Hydrofluoroalkylation of alkenes for accessing valuable fluorinated molecules.
Fig. 2: Mechanistic studies and deuterium labelling experiments.

Similar content being viewed by others

Data availability

The authors declare that all the data supporting the findings of this research are available within the Article and its Supplementary Information.

Change history

References

  1. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    Article  PubMed  Google Scholar 

  2. O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).

    Article  PubMed  Google Scholar 

  3. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    Article  PubMed  CAS  Google Scholar 

  4. Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem. Rev. 114, 2432–2506 (2014).

    Article  PubMed  CAS  Google Scholar 

  5. Ni, C. & Hu, J. The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations. Chem. Soc. Rev. 45, 5441–5454 (2016).

    Article  PubMed  CAS  Google Scholar 

  6. Inoue, M., Sumii, Y. & Shibata, N. Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 5, 10633–10640 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Börgel, J. & Ritter, T. Late-stage functionalization. Chem 6, 1877–1887 (2020).

    Article  Google Scholar 

  8. Wu, X., Chu, L. & Qing, F.-L. Silver-catalyzed hydrotrifluoromethylation of unactivated alkenes with CF3SiMe3. Angew. Chem. Int. Ed. 52, 2198–2202 (2013).

    Article  CAS  Google Scholar 

  9. Mizuta, S. et al. Catalytic hydrotrifluoromethylation of unactivated alkenes. J. Am. Chem. Soc. 135, 2505–2508 (2013).

    Article  PubMed  CAS  Google Scholar 

  10. Wilger, D. J., Gesmundo, N. J. & Nicewicz, D. A. Catalytic hydrotrifluoromethylation of styrenes and unactivated aliphatic alkenes via an organic photoredox system. Chem. Sci. 4, 3160–3165 (2013).

    Article  CAS  Google Scholar 

  11. Pitre, S. P., McTiernan, C. D., Ismaili, H. & Scaiano, J. C. Metal-free photocatalytic radical trifluoromethylation utilizing methylene blue and visible light irradiation. ACS Catal. 4, 2530–2535 (2014).

    Article  CAS  Google Scholar 

  12. Choi, S. et al. Hydrotrifluoromethylation and iodotrifluoromethylation of alkenes and alkynes using an inorganic electride as a radical generator. Nat. Commun. 5, 4881 (2014).

    Article  PubMed  CAS  Google Scholar 

  13. Egami, H., Usui, Y., Kawamura, S., Nagashima, S. & Sodeoka, M. Product control in alkene trifluoromethylation: hydrotrifluoromethylation, vinylic trifluoromethylation, and iodotrifluoromethylation using Togni reagent. Chem. Asian J. 10, 2190–2199 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Straathof, N. J. W., Cramer, S. E., Hessel, V. & Noël, T. Practical photocatalytic trifluoromethylation and hydrotrifluoromethylation of styrenes in batch and flow. Angew. Chem. Int. Ed. 55, 15549–15553 (2016).

    Article  CAS  Google Scholar 

  15. Cheng, Y. & Yu, S. Hydrotrifluoromethylation of unactivated alkenes and alkynes enabled by an electron-donor–acceptor complex of Togni’s reagent with a tertiary amine. Org. Lett. 18, 2962–2965 (2016).

    Article  PubMed  CAS  Google Scholar 

  16. Cui, B. et al. Mn(OAc)3-mediated hydrotrifluoromethylation of unactivated alkenes using CF3SO2Na as the trifluoromethyl source. J. Org. Chem. 83, 6015–6024 (2018).

  17. Zhang, W. et al. Leaving group assisted strategy for photoinduced fluoroalkylations using N-hydroxybenzimidoyl chloride esters. Angew. Chem. Int. Ed. 58, 624–627 (2019).

    Article  CAS  Google Scholar 

  18. Jia, H., Häring, A. P., Berger, F., Zhang, L. & Ritter, T. Trifluoromethyl thianthrenium triflate: a readily available trifluoromethylating reagent with formal CF3+, CF3•, and CF3– reactivity. J. Am. Chem. Soc. 143, 7623–7628 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Tang, X.-J., Zhang, Z. & Dolbier, W. R. Jr. Direct photoredox-catalyzed reductive difluoromethylation of electron-deficient alkenes. Chem. Eur. J. 21, 18961–18965 (2015).

    Article  PubMed  CAS  Google Scholar 

  20. Lin, Q.-Y., Xu, X.-H., Zhang, K. & Qing, F.-L. Visible-light-induced hydrodifluoromethylation of alkenes with a bromodifluoromethylphosphonium bromide. Angew. Chem. Int. Ed. 55, 1479–1483 (2016).

    Article  CAS  Google Scholar 

  21. Meyer, C. F., Hell, S. M., Misale, A., Trabanco, A. A. & Gouverneur, V. Hydrodifluoromethylation of alkenes with difluoroacetic acid. Angew. Chem. Int. Ed. 58, 8829–8833 (2019).

    Article  CAS  Google Scholar 

  22. Zhang, Z.-Q. et al. Difluoromethylation of unactivated alkenes using Freon-22 through tertiary amine-borane-triggered halogen atom transfer. J. Am. Chem. Soc. 144, 14288–14296 (2022).

    Article  PubMed  CAS  Google Scholar 

  23. Yu, C., Iqbal, N., Park, S. & Cho, E. J. Selective difluoroalkylation of alkenes by using visible light photoredox catalysis. Chem. Commun. 50, 12884–12887 (2014).

    Article  CAS  Google Scholar 

  24. Sumino, S. et al. Photoredox-catalyzed hydrodifluoroalkylation of alkenes using difluorohaloalkyl compounds and a Hantzsch ester. J. Org. Chem. 82, 5469–5474 (2017).

    Article  PubMed  CAS  Google Scholar 

  25. Supranovich, V. I., Levin, V. V., Struchkova, M. I., Korlyukov, A. A. & Dilman, A. D. Radical silyldifluoromethylation of electron-deficient alkenes. Org. Lett. 19, 3215–3218 (2017).

    Article  PubMed  CAS  Google Scholar 

  26. Yu, Y.-J. et al. Sequential C–F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts. Science 371, 1232–1240 (2021).

    Article  PubMed  CAS  Google Scholar 

  27. Campbell, M. W. et al. Photochemical C–F activation enables defluorinative alkylation of trifluoroacetates and -acetamides. J. Am. Chem. Soc. 143, 19648–19654 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Yue, W.-J., Day, C. S., Brenes Rucinski, A. J. & Martin, R. Catalytic hydrodifluoroalkylation of unactivated olefins. Org. Lett. 24, 5109–5114 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Hell, S. M. et al. Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond. Chem. Sci. 12, 12149–12155 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Wu, B.-B. et al. A general and efficient solution to monofluoroalkylation: divergent synthesis of aliphatic monofluorides with modular synthetic scaffolds. Angew. Chem. Int. Ed. 61, e202208938 (2022).

    Article  CAS  Google Scholar 

  31. Hu, C.-M. & Qiu, Y.-L. Co/Zn bimetal redox system promoted hydroperfluoroalkylation of acrylates with perfluoroalkyl iodides. Tetrahedron Lett. 32, 4001–4002 (1991).

    Article  CAS  Google Scholar 

  32. Dolbier, W. R. Structure, reactivity, and chemistry of fluoroalkyl radicals. Chem. Rev. 96, 1557–1584 (1996).

    Article  PubMed  CAS  Google Scholar 

  33. Barata-Vallejo, S. & Postigo, A. (Me3Si)3SiH-mediated intermolecular radical perfluoroalkylation reactions of olefins in water. J. Org. Chem. 75, 6141–6148 (2010).

    Article  PubMed  CAS  Google Scholar 

  34. Haszeldine, R. N. 603. The reactions of fluorocarbon radicals. Part I. The reaction of iodotrifluoromethane with ethylene and tetrafluoroethylene. J. Chem. Soc. (Resumed) 1949, 2856–2861 (1949).

  35. Kamigata, N., Fukushima, T., Terakawa, Y., Yoshida, M. & Sawada, H. Novel perfluoroalkylation of alkenes with perfluoroalkanesulphonyl chlorides catalysed by a ruthenium(II) complex. J. Chem. Soc. Perkin Trans. 1, 627–633 (1991).

    Article  Google Scholar 

  36. Langlois, B. R., Laurent, E. & Roidot, N. Trifluoromethylation of aromatic compounds with sodium trifluoromethanesulfinate under oxidative conditions. Tetrahedron Lett. 32, 7525–7528 (1991).

    Article  CAS  Google Scholar 

  37. Li, M., Wang, Y., Xue, X.-S. & Cheng, J.-P. A systematic assessment of trifluoromethyl radical donor abilities of electrophilic trifluoromethylating reagents. Asian J. Org. Chem. 6, 235–240 (2017).

    Article  CAS  Google Scholar 

  38. Zhao, Y., Huang, W., Zhu, L. & Hu, J. Difluoromethyl 2-pyridyl sulfone: a new gem-difluoroolefination reagent for aldehydes and ketones. Org. Lett. 12, 1444–1447 (2010).

    Article  PubMed  CAS  Google Scholar 

  39. Han, J. et al. Photoinduced manganese-catalysed hydrofluorocarbofunctionalization of alkenes. Nat. Synth. 1, 475–486 (2022).

    Article  Google Scholar 

  40. Chen, M. & Buchwald, S. L. Rapid and efficient trifluoromethylation of aromatic and heteroaromatic compounds using potassium trifluoroacetate enabled by a flow system. Angew. Chem. Int. Ed. 52, 11628–11631 (2013).

    Article  CAS  Google Scholar 

  41. Depecker, C., Marzouk, H., Trevin, S. P. & Devynck, J. Trifluoromethylation of aromatic compounds via Kolbe electrolysis in pure organic solvent. Study on laboratory and pilot scale. New J. Chem. 23, 739–742 (1999).

    Article  CAS  Google Scholar 

  42. Beatty, J. W., Douglas, J. J., Cole, K. P. & Stephenson, C. R. J. A scalable and operationally simple radical trifluoromethylation. Nat. Commun. 6, 7919 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kochi, J. K. Photolyses of metal compounds: cupric chloride in organic media. J. Am. Chem. Soc. 84, 2121–2127 (1962).

    Article  CAS  Google Scholar 

  44. Abderrazak, Y., Bhattacharyya, A. & Reiser, O. Visible-light-induced homolysis of earth-abundant metal-substrate complexes: a complementary activation strategy in photoredox catalysis. Angew. Chem. Int. Ed. 60, 21100–21115 (2021).

    Article  CAS  Google Scholar 

  45. Juliá, F. Ligand-to-metal charge transfer (LMCT) photochemistry at 3d-metal complexes: an emerging tool for sustainable organic synthesis. ChemCatChem 14, e202200916 (2022).

    Article  Google Scholar 

  46. Hossain, A., Bhattacharyya, A. & Reiser, O. Copper’s rapid ascent in visible-light photoredox catalysis. Science 364, eaav9713 (2019).

    Article  PubMed  Google Scholar 

  47. de Groot, L. H. M., Ilic, A., Schwarz, J. & Wärnmark, K. Iron photoredox catalysis–past, present, and future. J. Am. Chem. Soc. 145, 9369–9388 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Chábera, P. et al. A low-spin Fe(iii) complex with 100-ps ligand-to-metal charge transfer photoluminescence. Nature 543, 695–699 (2017).

    Article  PubMed  Google Scholar 

  49. Li, Z., Wang, X., Xia, S. & Jin, J. Ligand-accelerated iron photocatalysis enabling decarboxylative alkylation of heteroarenes. Org. Lett. 21, 4259–4265 (2019).

    Article  PubMed  CAS  Google Scholar 

  50. Feng, G., Wang, X. & Jin, J. Decarboxylative C–C and C–N bond formation by ligand-accelerated iron photocatalysis. Eur. J. Org. Chem. 2019, 6728–6732 (2019).

    Article  CAS  Google Scholar 

  51. Zhang, Y., Qian, J., Wang, M., Huang, Y. & Hu, P. Visible-light-induced decarboxylative fluorination of aliphatic carboxylic acids catalyzed by iron. Org. Lett. 24, 5972–5976 (2022).

    Article  PubMed  CAS  Google Scholar 

  52. Tu, J.-L. et al. Iron-catalyzed ring-opening of cyclic carboxylic acids enabled by photoinduced ligand-to-metal charge transfer. Green Chem. 24, 5553–5558 (2022).

    Article  CAS  Google Scholar 

  53. Lu, Y.-C. & West, J. G. Chemoselective decarboxylative protonation enabled by cooperative Earth-abundant element catalysis. Angew. Chem. Int. Ed. 62, e202213055 (2023).

    Article  CAS  Google Scholar 

  54. Xu, P., López-Rojas, P. & Ritter, T. Radical decarboxylative carbometalation of benzoic acids: a solution to aromatic decarboxylative fluorination. J. Am. Chem. Soc. 143, 5349–5354 (2021).

    Article  PubMed  CAS  Google Scholar 

  55. Chen, T. Q. et al. A unified approach to decarboxylative halogenation of (hetero)aryl carboxylic acids. J. Am. Chem. Soc. 144, 8296–8305 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Li, Q. Y. et al. Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(ii) carboxylates. Nat. Chem. 14, 94–99 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Bian, K.-J., Kao, S.-C., Nemoto, D., Chen, X.-W. & West, J. G. Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer. Nat. Commun. 13, 7881 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Glüge, J. et al. An overview of the uses of per- and polyfluoroalkyl substances (PFAS). Environ. Sci. Process. Impacts 22, 2345–2373 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Dénès, F., Pichowicz, M., Povie, G. & Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev. 114, 2587–2693 (2014).

    Article  PubMed  Google Scholar 

  60. Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

J.G.W. acknowledges financial support from the Cancer Prevention and Research Institute of Texas (CPRIT) (RR190025), the National Institutes of Health (NIH) (R35GM142738) and the Welch Foundation (C-2085). J.G.W. is a CPRIT Scholar in Cancer Research. We acknowledge Y. H. Rezenom (Texas A&M University Laboratory for Biological Mass Spectrometry (TAMU/LBMS)), I. M. Riddington (University of Texas (UT) Austin Mass Spectrometry Facility) and C. L. Pennington (Rice University Mass Spectrometry Facility) for assistance with mass spectrometry analysis.

Author information

Author notes

  1. These authors contributed equally: Kang-Jie Bian, Yen-Chu Lu.

Authors and Affiliations

  1. Department of Chemistry, Rice University, Houston, TX, USA

    Kang-Jie Bian, Yen-Chu Lu, David Nemoto Jr, Shih-Chieh Kao, Xiaowei Chen & Julian G. West

Authors
  1. Kang-Jie Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yen-Chu Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Nemoto Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shih-Chieh Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaowei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julian G. West
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.-J.B. and Y.-C.L. designed the project. K.-J.B., Y.-C.L., D.N. Jr, S.-C.K. and X.C. performed the experiments. K.-J.B., Y.-C.L. and J.G.W. wrote the manuscript. J.G.W. directed the project. All authors interpreted the results in the manuscript.

Corresponding author

Correspondence to Julian G. West.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Eun Jin Cho and the other, anonymous, reviewer(s) 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

Supplemental Tables 1–15, Discussion, Methods and compound characterization data.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bian, KJ., Lu, YC., Nemoto, D. et al. Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids. Nat. Chem. 15, 1683–1692 (2023). https://doi.org/10.1038/s41557-023-01365-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-023-01365-0

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