Abstract
Frustrated Lewis pairs (FLPs) are well documented for the activation of small molecules such as dihydrogen and carbon dioxide1,2,3,4. Although canonical FLP chemistry is heterolytic in nature, recent work has shown that certain FLPs can undergo single-electron transfer to afford radical pairs5. Owing to steric encumbrance and/or weak bonding association, these radicals do not annihilate one another, and they have thus been named frustrated radical pairs (FRPs). Notable preliminary results suggest that FRPs may be useful reagents in chemical synthesis6,7,8, although their applications remain limited. Here we demonstrate that the functionalization of C(sp3)–H bonds can be accomplished using a class of FRPs generated from disilazide donors and an N-oxoammonium acceptor. Together, these species undergo single-electron transfer to generate a transient and persistent radical pair capable of cleaving unactivated C–H bonds to furnish aminoxylated products. By tuning the structure of the donor, it is possible to control regioselectivity and tailor reactivity towards tertiary, secondary or primary C–H bonds. Mechanistic studies lend strong support for the formation and involvement of radical pairs in the target reaction.
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Data availability
The data supporting the findings of this study are available within the paper and its Supplementary Information. Should any raw data files be needed in another format they are available from the corresponding author upon reasonable request.
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Acknowledgements
Financial support was provided by the National Institutes of Health (R01GM134088 to S.L. and F32GM142264 to M.J.) and Genentech. We thank R. Mandel for assisting in setting up reactions with high-pressure ethane; I. Keresztes for his help in structural elucidation of complex products; J. H. Freed and A. L. Lai for their help in EPR experiments; D. B. Collum, Y. Ma and R. Woltornist for suggestions on synthesis of lithium disilazides; P. Yu for reproducing experiments; and D. Stephan for discussion. We thank the Advanced Electron-Spin Resonance Spectroscopy (ACERT) centre (NIH grant number 1R24GM146107) for providing EPR facilities.
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S.L. supervised the project. Z.L., M.J. and S.L. conceived the work. Z.L. and M.J. designed the experiments. Z.L., M.J., J.M.M. and J.I.M.A. conducted synthetic experiments and mechanistic studies. Y.W. conducted DFT calculations. E.V. and J.A.T. provided guidance on the project. Z.L., M.J. and S.L. wrote the paper. J.M.M., J.I.M.A., Y.W., E.V. and J.A.T. assisted in writing and editing the paper.
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A US provisional patent (no. 63/369,353) was filed on the reaction method.
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Lu, Z., Ju, M., Wang, Y. et al. Regioselective aliphatic C–H functionalization using frustrated radical pairs. Nature 619, 514–520 (2023). https://doi.org/10.1038/s41586-023-06131-3
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DOI: https://doi.org/10.1038/s41586-023-06131-3
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