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The selective functionalization of remote C–H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis. This radical-mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways. As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C–H functionalization. This review outlines the history, recent advances, and mechanistic underpinnings of intramolecular HAT as a guide to addressing ongoing challenges in this arena. 1 Introduction 2 Nitrogen-Centered Radicals 2.1 sp3 N-Radical Initiation 2.2 sp2 N-Radical Initiation 3 Oxygen-Centered Radicals 3.1 Carbonyl Diradical Initiation 3.2 Alkoxy Radical Initiation 3.3 Non-alkoxy Radical Initiation 4 Carbon-Centered Radicals 4.1 sp2 C-Radical Initiation 4.2 sp3 C-Radical Initiation 5 Conclusion
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This content will become publicly available on October 16, 2026
Divergent Concerted Proton–Electron Transfer (CPET) and Hydrogen Atom Transfer (HAT) Pathways of Amidyl Radical Reactivity Enable Chemoselective Functionalization
Amidyl radicals mediate a diverse array of intermolecular aliphatic C(sp3)–H and decarboxylative functionalizations. Interestingly, we have observed that decarboxylative processes proceed with excellent chemoselectivity even with substrates containing weak C(sp3)–H bonds. Herein, we report a mechanistic basis for understanding this high chemoselectivity of amidyl radicals through divergent reaction pathways. A computational assessment of the transition state SOMOs and intrinsic bonding orbitals for amidyl radical hydrogen atom transfer (HAT) and concerted proton-electron transfer (CPET) processes support a shift in mechanism between aliphatic C(sp3)–H or carboxylic acid O–H abstraction, which is supported by experimental studies. These findings provide a rationale for the chemoselectivity of decarboxylative reactions mediated by amidyl radicals.
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- Award ID(s):
- 2304548
- PAR ID:
- 10643217
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- Organic Letters
- ISSN:
- 1523-7060
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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