Mechanisms and Origins of Regioselectivity in Rare-Earth-Catalyzed C–H Functionalization of Anisoles and Thioanisoles

The direct catalytic C-H functionalization of aromatic compounds such as anisoles and thioanisoles is of great interest and significance. However, achieving precise regioselectivity remains a major challenge. In this study, we conducted comprehensive density functional theory calculations to explore the mechanisms of rare-earth-catalyzed regioselective C-H alkylation, borylation, and silylation of anisole and thioanisole. The results reveal that in cationic C-H alkylation systems, the alkene insertion step follows a substrate-assisted mechanism, in which an additional substrate molecule acts as a ligand to facilitate the transformation. In neutral C-H borylation and silylation systems, although mononuclear hydride species readily dimerize into binuclear hydride species due to thermodynamic stability, the catalytic process predominantly proceeds via a mononuclear pathway. Furthermore, the origins of regioselectivity were thoroughly elucidated. A detailed analysis of electronic and steric effects in related transition states reveals that, for anisole, regioselectivity is primarily governed by ring strain. Since α-C(sp³)-H activation involves the formation of a highly strained three-membered ring, the reaction preferentially occurs at the <i>ortho</i>-C(sp²)-H site, forming a less strained four-membered ring. In contrast, for thioanisole, electronic effects play a decisive role, driving C-H activation at the more negatively charged α-C(sp³) site due to stronger metal-carbon interactions.