Hydrogen Atom Transfer-Based C(sp³)–H Bond Oxygenation of Lactams and Cycloalkenes: The Influence of Ring Size on Reactivity and Site Selectivity

Kinetic and product studies on the reactions of the cumyloxyl (CumO^•) and <i>tert</i>-butoxyl (<i>t</i>BuO^•) radicals with secondary and tertiary <i>N</i>-methyl and <i>N</i>-benzyl lactams and with cycloalkenes, accompanied by BDE calculations of the substrate C-H bonds involved in these reactions, are reported. Within the lactams, the rate constants for HAT (<i>k</i>_H) from the C-H bonds to CumO^• decrease by a factor ∼4 going from the 5- and 6-membered derivatives to the 8-membered ones. Product distributions obtained through oxygenation initiated by <i>t</i>BuO^• show that HAT preferentially occurs from the most electron-rich α-C-H bonds, with site selectivity that, within the <i>N</i>-methyl and <i>N</i>-benzyl series, progressively shifts from the endocyclic to the exocyclic α-C-H bonds with increasing ring size, indicative of deactivation of the former bonds that, for the 8-membered derivatives, translates into competitive oxygenation at different sites. Similar trends have been observed for the corresponding reactions of the cycloalkenes, with <i>k</i>_H values that decrease by a factor of ∼4 together with site selectivity for HAT from the activated allylic C-H bonds, going from cyclopentene to cyclooctene. It is proposed that the greater flexibility of the medium-sized rings decreases the extent of hyperconjugative overlap between the α-C-H bonds and the amide or C═C π-systems, increasing the kinetic barrier for HAT from these sites, with decreases in reactivity that approach factors of 83 and 18, for the endocyclic α-C-H bonds of tertiary <i>N</i>-methyl lactams and the allylic C-H bonds of cycloalkenes, respectively.