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Late-stage deuteration and tritiation through bioinspired cooperative hydrogenolysis

Nature Synthesis volume 4, pages 444–452 (2025)Cite this article

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Abstract

Hydrogenolysis, a fundamental chemical process with broad applications, has traditionally been performed using heterogeneous catalysis at high temperatures and pressures with limited selectivity. Recent advancements highlight the potential of homogeneous catalysis as a promising alternative, offering improved selectivity under milder conditions. However, the development of a general homogeneous catalysis approach capable of hydrogenolysing carbon–halogen bonds—one of the most fundamental, versatile and extensively studied functional groups—remains an unresolved challenge. Here we present a comprehensive rationale for the fundamental mechanistic prerequisites crucial to achieving general homogeneous carbon–halogen bond hydrogenolysis, with a particular focus on the tritiation of challenging yet abundant alkyl chlorides. We demonstrate how cooperative interplay of bioinspired carbon–halogen activation and hydrogenation can efficiently catalyse the selective hydrogenolysis of unactivated organohalides. The utility of this approach is demonstrated through its capability to enable deuteration and tritiation of pharmaceutically relevant organohalides with simultaneous control over reactivity and selectivity.

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Fig. 1: Biomimetic carbon–halide hydrogenolysis via cooperative catalysis.
Fig. 2: Reaction development.
Fig. 3: Substrate scope for reductive deuteration.
Fig. 4: Site-selective isotopic labelling enabled by cooperative catalysis.

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Data availability

All relevant data generated and analysed during this study, which include experimental and spectroscopic data, are included in this article and its Supplementary Information. Source data are provided with this paper.

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Acknowledgements

We thank V. Derdau and C. Loewe (Sanofi-Aventis Deutschland GmbH) for NMR spectroscopy analysis. We thank T. Ritter (Max-Planck-Institut für Kohlenforschung) and D. Muri (Roche Innovation Center Basel) for insightful discussions and suggestions. This project was supported by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (grant no. 22101278 to D.Z.), the Chinese Academy of Sciences, the Special Educating Project of the Talent for Carbon Peak and Carbon Neutrality of University of Chinese of Academy of Sciences, University of Chinese Academy of Sciences and the Project of Talent Cultivation for Carbon Peak and Carbon Neutrality of the University of Chinese of Academy of Sciences.

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Authors and Affiliations

  1. School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, P. R. China

    Beibei Zhang, Zhenyang Zhang, Yang Wang & Da Zhao

  2. Binzhou Institute of Technology, Weiqiao-UCAS Science and Technology Park, Binzhou, P. R. China

    Yang Wang & Da Zhao

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  1. Beibei Zhang
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  2. Zhenyang Zhang
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  4. Da Zhao
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Contributions

D.Z. conceived the project. B.B.Z. optimized the hydrogenolysis reaction and explored the substrate scope. B.B.Z. and Z.Y.Z. investigated the mechanism. D.Z. wrote the manuscript with input from all authors. Y.W. and D.Z. supervised the project.

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Correspondence to Da Zhao.

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Nature Synthesis thanks Aleš Marek and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Experimental Details, Supplementary Discussion, Figs. 1–108, Schemes 1–3 and Tables 1–14.

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Zhang, B., Zhang, Z., Wang, Y. et al. Late-stage deuteration and tritiation through bioinspired cooperative hydrogenolysis. Nat. Synth 4, 444–452 (2025). https://doi.org/10.1038/s44160-024-00716-0

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