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The interplay of polar effects in controlling the selectivity of radical reactions

Nature Synthesis volume 1, pages 682–695 (2022)Cite this article

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Abstract

Radical reactivity is a powerful tool for molecular construction that often provides bond-forming strategies and retrosynthetic disconnections complementary to those available through ionic and metal-mediated approaches. Understanding reactivity and selectivity patterns in radical chemistry is crucial to harness and develop the full potential of open-shell species in synthetic settings. Polar effects operate at the transition-state level of all radical reactions and have important implications in controlling their outcomes. The recognition of the key factors that respond to polar effects can be used to understand reactivity trends and also to rationally enhance (or mute) the intrinsic reactivity of specific molecular sites over others. These features render radical reactivity easy to predict and, therefore, programmable. In this Review we highlight some of the key underlining mechanistic features associated with polar effects and we accompany our discussion with representative synthetic examples.

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Fig. 1: Polar effects control the outcome of radical reactions.
Fig. 2: Synthetic examples of site-selective C(sp3)–H functionalization by HAT.
Fig. 3: Synthetic examples of selective late-stage C(sp3)–H functionalizations of complex and bioactive materials.
Fig. 4: Difference in HAT reactivity upon amine protonation.
Fig. 5: Strategies to increase the reactivity of C(sp3)–H bonds in HAT processes.
Fig. 6: Example of polar effects in strategies for XAT.
Fig. 7: Site selectivity controlled by polar effects in homolytic aromatic substitutions with electrophilic radicals and electron-rich arenes.
Fig. 8: Site selectivity in Minisci reactions.

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Acknowledgements

D.L. would like to thank the EPSRC for a Fellowship (EP/P004997/1), the European Research Council for a research grant (758427) and the Leverhulme Trust for additional support (Philip Leverhulme Prize). R.M. would like to thank the EPSRC for a Doctoral Prize Fellowship (EP/T517823/1).

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Authors and Affiliations

  1. Department of Chemistry, University of Manchester, Manchester, UK

    Alessandro Ruffoni, Rory C. Mykura & Daniele Leonori

  2. Dipartimento di Scienze e Tecnologie Chimiche, Università ‘Tor Vergata’, Via della Ricerca Scientifica, Rome, Italy

    Massimo Bietti

  3. Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany

    Daniele Leonori

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Ruffoni, A., Mykura, R.C., Bietti, M. et al. The interplay of polar effects in controlling the selectivity of radical reactions. Nat. Synth 1, 682–695 (2022). https://doi.org/10.1038/s44160-022-00108-2

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