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Chemical reactivity from the perspective of enthalpic coupling

Nature Synthesis volume 5, pages 321–329 (2026)Cite this article

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Abstract

The energy balance of an elementary step in a chemical transformation is fundamental to our understanding of reaction pathways. Here we evaluate the enthalpic coupling between bond cleavage and bond formation in diverse elementary steps in organic chemistry. To illustrate the relationship between specific bond-altering events, we use enthalpic maps. This analysis compares mechanistically distinct reactions and offers a framework for modifying the existing elementary steps with the objective of reaction discovery.

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Fig. 1: Representative transformations highlighting enthalpic coupling.
Fig. 2: Bond strengths and enthalpic coupling.
Fig. 3: Influence of strain and aromaticity on enthalpic coupling.
Fig. 4: Structural analogies and enthalpic map reconfiguration across various transformations.

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Acknowledgements

This work was supported by the Natural Sciences and Engineering Research Council of Canada and ACS Petroleum Research Fund (grant PRF#62221-ND1). A.K.Y. acknowledges the Alexander von Humboldt Foundation and P. Seeberger for hosting a six-month sabbatical stay at the Max Planck Institute (Potsdam) in 2022, during which parts of this paper were conceived. A.K.Y. thanks the Australian National University and Hokkaido University for hospitality during visiting professorships in 2023 and 2024, respectively. C.B. acknowledges support from the Natural Sciences and Engineering Research Council of Canada, Ontario Graduate Scholarship and Walter C. Sumner Memorial Fellowship.

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  1. Davenport Chemical Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario, Canada

    Chelsey Brien & Andrei K. Yudin

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  1. Chelsey Brien
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  2. Andrei K. Yudin
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Contributions

A.K.Y. created the concepts of enthalpic maps and enthalpic coupling for interpreting diverse reaction mechanisms. C.B. and A.K.Y. jointly analysed the mechanistic data and wrote the paper.

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Correspondence to Andrei K. Yudin.

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Brien, C., Yudin, A.K. Chemical reactivity from the perspective of enthalpic coupling. Nat. Synth 5, 321–329 (2026). https://doi.org/10.1038/s44160-025-00986-2

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