Activation and Deactivation of Benzylic C?H Bonds Guided by Stereoelectronic Effects in Hydrogen Atom Transfer from Amides and Amines to Alkoxyl Radicals

Kinetic and product studies on the reactions of tert-alkoxyl radicals with secondary and tertiary alkanamides bearing benzylic α-C?H bonds, isoindoline, tetrahydroisoquinoline and the corresponding N-acetyl derivatives were carried out. Product studies on the reactions with the tert-butoxyl radical (tBuO?) point toward exclusive HAT from the benzylic α-C?H bonds. Comparison of the k_H values measured for reaction with the cumyloxyl radical (CumO?) with those obtained previously for the corresponding reactions of N-alkyl- and N,N-dialkylalkanamides, are indicative of a lack of benzylic activation and the operation of steric and stereoelectronic effects. Compared to N-methyl and N-ethyl groups, the presence of N-benzyl groups increases the barrier required to reach the optimal conformation for HAT, where the α-C?H bond to be cleaved is perpendicular to the plane of the amide, precluding concurrent overlap with the phenyl π-system. When the benzylic α-C?H bonds are in a conformation that allows for optimal overlap with both the phenyl π-system and the amide π-system or amine nitrogen lone pair, as in the isoindoline and tetrahydroisoquinoline derivatives, increases in k_H that exceed 2-orders of magnitude were observed, highlighting the strong contribution provided by stereoelectronic activation to these HAT processes.