Origins of Unconventional γ Site Selectivity in Palladium-Catalyzed C(sp3)–H Activation and Arylation of Aliphatic Alcohols

The mechanism of palladium-catalyzed γ-C(sp3)–H arylation of aliphatic alcohols has been explored with density functional theory. In contrast to the common “inner-sphere” C–H activation mode that favors five-membered over six-membered cyclopalladation, the computational results reveal that the “outer-sphere” C–H activation pathway assisted by added base (e.g., Li2CO3) is kinetically favorable and supports six-membered over five-membered cyclopalladation to yield the experimental γ-C(sp3)–H arylation product. Distortion/interaction analysis reveals the origins of the unconventional γ site selectivity.