Abstract
Efficient C–H functionalization requires selectivity for specific C–H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C–H functionalization has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a simple theoretical tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the basis for the development of new, highly selective C–H functionalization reactions.
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Acknowledgements
The authors thank the National Institute of General Medical Sciences (GM088237), the National Institute of Biomedical Imaging and Bioengineering (EB013042), UCB Pharma and Kwanjeong Educational Foundation for funding. The authors further thank J. McClean (Harvard University) for helpful discussions.
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G.B.B., W.S.H. and A.R.M. designed and performed the experiments and analysed the data. G.B.B. discovered the Ar–TEDA formation reaction and conceived the mechanistic proposal and explanation for the positional selectivity. A.R.M. discovered the reduction of Ar–TEDA compounds to aryl piperazines. G.B.B. and T.R. prepared the manuscript with input from W.S.H. and A.R.M.
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Boursalian, G., Ham, W., Mazzotti, A. et al. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nature Chem 8, 810–815 (2016). https://doi.org/10.1038/nchem.2529
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DOI: https://doi.org/10.1038/nchem.2529
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