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C-H Amination Reactions via Radical Pathway; Repurposing Hofmann- Löfller-Freytag Reaction

Modern synthetic approaches try to incorporate already known chemical entities and then modify them using late-stage functionalization (LSF) procedures. Hofmann–Löffler–Freytag (HLF) reaction was originally discovered by Hofmann [1–3] in synthetic studies of unconventional N- halo amines. This reaction has the ability to functionalize inactivated C-H bonds and thus belongs in the LSF toolbox. Recently, Del Castillo and Muñiz [4] have modified the HLF reaction for stereoselective nicotine synthesis. Their modification implies an experimental trial and error approach. On the other hand, the quantum chemical approach provides the means for the theoretical determination of parameters that guide the intramolecular HAT step which constitutes the essence of the HLF reaction as well as evaluating the role of the substituents. Therefore, emphasis is set on these parameters, which include the stability of N- and C-centered radicals and the activation barrier. In pursuit after them, N-H bond dissociation energies and related stability values of N-centered radicals, as well as stability values of C-centred radical and corresponding C-H bond dissociation energies are calculated, and with the implementation of the Bell-Evans- Pollany principle, the corresponding activation barriers for the crucial HAT step is obtained. Finally, particular attention is given to prevalent organic solvents that may have an effect on the stability of radicals besides themselves participating in rearrangement steps. Establishing a clear picture of the underlying parameters and the role that substituents have on the crucial step may streamline HLF reaction in accordance with green chemistry principles.

Hofmann-Löffler-Freytag reaction, green chemistry, 1, 5-HAT, 1, 6-HAT, regioselectivity, mechanistic switch

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