Abstract
Direct and selective functionalization of ubiquitous pyridine scaffold is of paramount importance across numerous fields, yet remains challenging due to the inherent inertness of pyridines and the presence of competing reactive sites. Here, using an undivided cell equipped with a zinc cathode, a graphite anode, and a TEMPO mediator, we report a room-temperature electrochemical strategy that enables the direct hydroxyalkylation of diverse pyridines with readily available carbonyl compounds. This method features a broad substrate scope, operational simplicity, metal-free conditions, and high step/atom economy. It overcomes the limitations of conventional approaches requiring pre-functionalized substrates or stoichiometric activators, establishing a practical platform for direct access to C4- or C2-hydroxyalkyl pyridines, depending on the substitution pattern of the pyridine substrates. Mechanistic studies reveal that acetic acid activates both reactants, and the products are formed via cross-coupling of cathodic reduction-induced pyridyl radicals and hydroxy α-radicals followed by protonation and anodic oxidative aromatization.
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All NMR spectra, mass spectrometry data, and experimental procedures generated in this study are provided in the Supplementary Information. The computational coordinate data generated in this study are provided in the Source Data, The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers of CCDC 2416007 (C21). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. All data are available from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
The authors are grateful for the financial support of the National Natural Science Foundation of China (22471080), Natural Science Foundation of Guangdong Province (2025A1515012079), Guangdong Basic and Applied Basic Research Foundation (2024B1515040027), and the Postdoctoral Fellowship Program of CPSF (GZB20250265).
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M.Z. conceived the idea, analyzed the data, directed the project, and wrote the manuscript. C.-Q.Z. and M.-R.W. carried out all the catalytic experiments. C.-Q.Z. drew the structures of all the obtained compounds, analyzed the single crystal structures, synthesized the raw materials and carried out NMR tests. M.-R. W. performed the DFT calculations. P.H.D. discussed the mechanistic aspects and revised the manuscript. All the authors have read the manuscript and agree with its content. All the authors contributed to the discussion during the whole project.
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Zhang, C., Wang, M., Dixneuf, P.H. et al. Room-temperature electrochemical hydroxyalkylation of pyridines. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71858-2
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DOI: https://doi.org/10.1038/s41467-026-71858-2
