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Selective arylation of atypical C–F bonds in polyfluoroarenes with aryl chlorides

Nature Chemistry (2025)Cite this article

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Abstract

Selective activation of specific C–F bonds in polyfluoroarenes represents a challenge in transition metal catalysis. Here we report a photoexcited nickel-catalysed cross-electrophile coupling between polyfluoroarenes and aryl chlorides, achieving highly selective arylation at atypical C–F sites of fluoroarenes, facilitated by a synergistic lithium salt effect. A wide range of structurally diverse fluorine-containing biaryls are obtained in 33−94% yields with satisfying C–F regioselectivity. Notably, the observed regioselectivity is atypical and complements existing methodologies, such as palladium-catalysed and visible-light photoredox-catalysed defluorinative functionalization reactions. Our mechanistic studies and theoretical calculations suggest that the lithium salt could interact with both pentafluorobenzene and the Ni catalyst, effectively lowering the energy barrier and modulating the regioselectivity. The synthetic versatility of our approach is underscored by late-stage synthetic application and sequential functionalization of multiple C–F bonds, which further demonstrates its robust utility in concisely constructing partially fluorinated and biologically interesting compounds.

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Fig. 1: Functionalization of multifluoroarenes.
Fig. 2: Reaction development and mechanistic investigation.
Fig. 3: Computed free energy profiles for the insertion of Ni(dtbbpy) into C(1) and C(3) sites during the C–F bond cleavage of C6F5H in the absence and presence of LiI.
Fig. 4: Synthetic applications.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2231838 (13), 2231820 (14), 2231850 (16), 2231848 (17), 2231841 (20), 2231844 (25) and 2231843 (79). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures. All other data supporting the findings of this study are available within the Article and its Supplementary Information.

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Acknowledgements

We thank the National Key Research and Development Program of China (grant no. 2022YFA1503200), National Natural Science Foundation of China (grant nos. 22471121, 22471122 and 22271144) and Fundamental Research Funds for the Central Universities (grant no. 020514380327) for financial support. J. Huang, Y. Cheng and B. Ling are gratefully acknowledged for their reproduction of the experimental procedures for products 16, 32 and 45. All theoretical calculations were performed at the High Performance Computing Center of Nanjing University.

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Authors and Affiliations

  1. State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Zhi Liu, Chaoyu Du, Jie Han, Xiaoliang Yang, Siyu Xia, Kai Liu, Chengjian Zhu, Weipeng Li & Jin Xie

  2. Green Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou, China

    Chengjian Zhu

  3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China

    Jin Xie

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Contributions

J.X. and Z.L. conceived the work and designed the experiments. Z.L., K.L., S.X. and W.L. performed the experiments and analysed the experimental data. X.Y. performed the NMR measurements. C.D. and J.H. performed the DFT calculations and discussed the results with C.Z. and J.X. co-wrote the manuscript with input from all the other authors.

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Correspondence to Jie Han, Chengjian Zhu, Weipeng Li or Jin Xie.

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Supplementary Information

Supplementary Figs. 1−88, discussion and Tables 1−14.

Supplementary Data 1

Cartesian coordinates of all the optimized geometries.

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Liu, Z., Du, C., Han, J. et al. Selective arylation of atypical C–F bonds in polyfluoroarenes with aryl chlorides. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01962-1

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