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Decoding the redox behaviour of copper in Ullmann-type coupling reactions

Nature volume 646, pages 1105–1113 (2025)Cite this article

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Abstract

The copper-catalysed functionalization of aryl halides is one of the most preferred methods for forming carbon–carbon and carbon–heteroatom bonds1. Yet the redox behaviour of the copper species in the catalytic cycle remains poorly understood and a subject of debate2. We report experimental and theoretical mechanistic investigations into the reaction of a well-defined Cu(I) complex with an electron-poor aryl iodide, which leads to the formation of an isolable Cu(III)−aryl complex that subsequently reductively eliminates to form a C(sp2)−CF3 bond. Our integrated experimental and theoretical findings indicate that the process proceeds through a Cu(I)/Cu(III)/Cu(II)/Cu(III)/Cu(I) redox sequence. By controlling the temperature, we managed to interrupt this sequence and capture the reactivity of the copper species through various spectroscopic methods, enabling in-depth mechanistic analysis. These findings shed light on the intricate behaviour of copper species and challenge the traditional mechanistic proposal for the reaction of Cu(I) with aryl iodide, thus providing fresh perspectives into the mechanistic aspect of the copper-catalysed coupling reactions.

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Fig. 1: Mechanistic investigations into Ullmann-type reaction.
Fig. 2: Oxidative addition of p-CF3C6F4I (2-I) to [(bpy)CuI(CF3)] (1a) to form Cu(III)−aryl products via Cu(II) intermediates.
Fig. 3: Mechanistic studies on the reaction of [(bpy)CuI(CF3)] (1a) with p-CF3C6F4I (2-I) at −20 °C.
Fig. 4: Mechanistic studies on disproportionation between [(bpy)CuII(CF3)(I)] (Int-a-CuII) and [(bpy)CuII(CF3)(Ar)] (Int-b-CuII) at −10 °C.
Fig. 5: Density functional theory calculations on the reaction of [(bpy)CuI(CF3)] (1a) with p-CF3C6F4I (2-I).

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All data supporting the findings of this study are available in the main text and the Supplementary Information.

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Acknowledgements

We thank S. Ye at Sun Yat-sen University for UV-visible absorption spectroscopy and electron paramagnetic resonance experiments. We gratefully acknowledge the financial support from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0590000) and the National Natural Science Foundation of China (grant no. 22531010). We acknowledge the Beijing Super Cloud Center (BSCC) (http://www.blsc.cn/) for providing the high-performance computing resources that contributed to the research results reported within this paper.

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Author notes

  1. These authors contributed equally: Yongrui Luo, Yuli Li, Botao Wu

Authors and Affiliations

  1. State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Science, Chinese Academy of Sciences, Shanghai, People’s Republic of China

    Yongrui Luo, Botao Wu, Guangyu Wang, Jian Wu & Qilong Shen

  2. Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, CA, USA

    Yuli Li & K. N. Houk

  3. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Yuli Li

  4. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, People’s Republic of China

    Sheng-Ye Zhang

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Contributions

Q.S. and Y. Luo conceived the concept. Y. Luo performed the experiments and analysed experimental data. Y. Li, B.W. and S.Z. performed the DFT calculations. B.W. performed the EPR experiments and calculations and UV–vis spectroscopic investigations. G.W. contributed to the preliminary explorations. J.W. assisted in the kinetic studies. Q.S. and K.N.H. supervised the research. Y. Luo, B.W., K.N.H. and Q.S. wrote the manuscript. All authors discussed the results.

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Correspondence to K. N. Houk or Qilong Shen.

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Extended data figures and tables

Extended Data Fig. 1 19F NMR monitoring experiments for other Cu-mediated C − C coupling reactions.

a, The time-course plot for the reaction between [(bpy)CuI(CF3)] (1a) and pentafluoroiodobenzene. b, The time-course plot for the reaction between [(bpy)CuI(CF3)] (1a) and 3,5-difluoro-4-iodobenzonitrile. c, The time-course plot for the reaction between [(bpy)CuI(CF3)] (1a) and 3-fluoro-2-iodobenzonitrile. d, The time-course plot for the reaction between [(bpy)CuI(CF3)] (1a) and methyl 4-iodobenzoate. e, The time-course plot for the reaction between [(bpy)CuI(CF3)] (1a) and iodobenzene. f, The time-course plot for the reaction between [(bpy)CuI(CF3)] (1a) and 1-bromo-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene (2-Br). g, The time-course plot for the reaction between [(bpy)CuI(C6F4-p-CF3)] (1c) and aryl iodide 2-I. Purple line, sum of observed fluorine signals, calculated as [CF3]total = [(bpy)Cu(CF3)] + 2 × [(bpy)Cu(CF3)2(Ar)] + [ArCF3] + 3 × [(bpy)Cu(CF3)3] + 4 × [Cu(CF3)4]− (for trifluoromethylation), or [CF3]total = [(bpy)Cu(ArF)] + [ArF − ArF] (for biaryl synthesis). N.D. = not detected.

Extended Data Fig. 2 Kinetic studies of the reaction of complex 1a at millimolar concentrations.

a, Kinetics of the reaction between [(bpy)Cu(CF3)] (1a, 1.0 mM) and aryl iodide (100 mM) at −20 °C, monitored by in situ UV-visible absorption spectroscopy. The decay curve was fit to the expression ct = Ae−k1obst + B. b, Eyring analysis of the reaction of 1a (1.0 mM) with 2-I (100 mM) at several temperatures varying from 248 K to 257 K. c, EPR spectrum of the reaction between 1a (1.0 mM) and 2-I (100 mM) in CH3CN after UV-vis absorption spectral measurement (black line); EPR spectrum of the aliquot (10-fold diluted with dichloromethane) of the reaction between 1a (20 mM) and 2-I (200 mM) in CH3CN (black line) (blue line). All X-band EPR spectra were recorded at 100.1 K.

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Supplementary Information

Supplementary Sections 1–11, including Supplementary Figs. 1–63, Tables 1–23, references and NMR Spectra data – see Contents for details.

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Luo, Y., Li, Y., Wu, B. et al. Decoding the redox behaviour of copper in Ullmann-type coupling reactions. Nature 646, 1105–1113 (2025). https://doi.org/10.1038/s41586-025-09627-2

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