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Photocatalytic C–F bond activation in small molecules and polyfluoroalkyl substances

Abstract

Organic halides are highly useful compounds in chemical synthesis, in which the halide serves as a versatile functional group for elimination, substitution and cross-coupling reactions with transition metals or photocatalysis1,2,3. However, the activation of carbon–fluorine (C–F) bonds—the most commercially abundant organohalide and found in polyfluoroalkyl substances (PFAS), or ‘forever chemicals’—is much rarer. Current approaches based on photoredox chemistry for the activation of small-molecule C–F bonds are limited by the substrates and transition metal catalysts needed4. A general method for the direct activation of organofluorines would have considerable value in organic and environmental chemistry. Here we report an organic photoredox catalyst system that can efficiently reduce C–F bonds to generate carbon-centred radicals, which can then be intercepted for hydrodefluorination (swapping F for H) and cross-coupling reactions. This system enables the general use of organofluorines as synthons under mild reaction conditions. We extend this method to the defluorination of PFAS and fluorinated polymers, a critical challenge in the breakdown of persistent and environmentally damaging forever chemicals.

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Fig. 1: Direct activation of organofluorines and fluorinated polymers.
Fig. 2: Mechanism and analysis for photoredox-catalysed C–F bond activation.
Fig. 3: Substrate scope for the hydrodefluorination of aryl and alkyl fluorides.
Fig. 4: Substrate scope for the hydrodefluorination of perfluoroalkyl substances, PFAS and fluorinated polymers.
Fig. 5: Intermolecular couplings from challenging aryl fluoride precursors.

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Data availability

Materials and methods, experimental procedures, useful information, mechanistic studies, 1H NMR spectra, 13C NMR spectra, 18F NMR, gel permeation chromatography, mass spectrometry data and DFT calculation results are available in the Supplementary Information.

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Acknowledgements

X.L., A.R.G., N.F.P., A.S., N.H.D. and G.M.M. acknowledge support from the National Science Foundation (2016557). Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM144356. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.S.P., M.V.P. and Y.L. acknowledge support from the NSF (CHE-1955876) and computational resources from the RMACC Summit supercomputer supported by the NSF (grant nos. ACI-1532235 and ACI-1532236), the University of Colorado Boulder and Colorado State University, and XSEDE through allocation no. TG-CHE180056.

Author information

Authors and Affiliations

Authors

Contributions

X.L. and G.M.M. conceived the idea. X.L., A.R.G. and Y.Z. executed the reaction methodology development. N.F.P., A.S., M.V.P., N.H.D., X.L. and A.R.G. conceived of and contributed to the mechanistic studies. M.V.P., Y.L. and R.S.P. performed the DFT calculations. X.L., N.F.P., A.S., R.S.P., N.H.D. and G.M.M. co-wrote the manuscript. All authors read and edited the manuscript.

Corresponding authors

Correspondence to Robert S. Paton, Niels H. Damrauer or Garret M. Miyake.

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Nature thanks Jinyong Liu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Formation of BPI-N-RO from BPI-N.

a, Using a more symmetric variant BPI-N for intermediate study. b, Comparing the UV–visible spectra of isolated BPI-N-RO (post basic alumina column with and without aqueous workup) with that of the crude BPI-N with nBu4NF mixture. Absorption spectrum of BPI-N is shown for reference. c, 1H-1H COSY of the isolated intermediate BPI-N-RO (acetone-d6, 300 MHz). d, 1H-13C HSQC of the isolated intermediate BPI-N-RO (acetone-d6, 300 MHz).

Extended Data Fig. 2 Cyclic voltammetry of BPI and BPI with nBu4NF.

a, Cyclic voltammogram of Fc+/Fc standard (1.0 mM in THF). b, Cyclic voltammogram of BPI (1.0 mM in THF) showing the first reduction event. c, Cyclic voltammogram of BPI (1.0 mM in THF) showing two reduction events. d, Cyclic voltammogram of BPI (1.0 mM in THF) with nBu4NF (200 equiv.) showing two reduction events.

Extended Data Fig. 3 Mechanistic studies.

a, Emission profiles for BPI and BPI-RO. b, Fluorescence spectra of BPI in a THF solution in the presence of a varying equivalence of nBu4NF. c, Monitoring BPI and nBu4NF interaction via UV–vis spectroscopy. d, Quenching experiments on BPI-RO2−• by Ph-F. e, Quenching experiments on BPI-RO-H2− by Ph-F. f, Quenching experiments on BPI-RO-H2− by methyl 4-flurobenzoate.

Extended Data Fig. 4 Computed reduction potentials for the proposed photocatalytic species.

Using the CAM-B3LYP-D3(BJ)/def2-SVP[C;H]def2-TZVPD[N;O;F]-SMD(THF) level of theory.

Extended Data Fig. 5 Computed hydrolysis mechanisms.

The model system C at the M06-2X-D3/def2-SVP[C;H]def2-TZVPD[N;O;F]-SMD(THF) was used.

Extended Data Fig. 6 Proposed structures of the ring-opened intermediate and closed shell species.

Original catalyst (left), isolated ring-opening intermediate (middle), suggested closed-shell species (right).

Supplementary information

Supplementary Information

Supplementary Information sections 1–15, Figs. 1–66, Tables 1–22 and references.

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Liu, X., Sau, A., Green, A.R. et al. Photocatalytic C–F bond activation in small molecules and polyfluoroalkyl substances. Nature 637, 601–607 (2025). https://doi.org/10.1038/s41586-024-08327-7

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