Mechanism and Origin of Regioselectivity in Mn(I)-Catalyzed C–H Hydroarylation of 3-Substituted Aryloxazolines

The mechanism and origin of regioselectivity in the Mn(I)-catalyzed hydroarylation of 3-substituted aryloxazolines were computationally elucidated and experimentally validated. Density functional theory (DFT) calculations show that the reaction proceeds through an acetate-assisted concerted metalation–deprotonation (CMD) C–H activation, followed by migratory C–C insertion and a final proton transfer step leading to product formation. Across all systems examined, C–H activation consistently favors ortho -metalation, highlighting that the subsequent C–C bond-forming migratory insertion (MI) is both the turnover- and regioselectivity-determining event. This mechanistic picture accounts for the experimentally observed selectivity reversal between fluoro- and trifluoromethyl-substituted substrates, which preferentially afford ortho - and para -functionalized products, respectively. Energy decomposition analysis (EDA) reveals that ortho -selectivity in the fluorinated system arises from more stabilizing orbital interactions at the regioselectivity-determining transition states (TSs), whereas para -selectivity in the CF 3 -substituted substrate results from a combination of increased Pauli repulsion (Δ E Pauli ) and greater geometric distortion along the ortho -pathway. The resulting mechanistic model accurately predicted the regioselectivity across a series of 3-substituted-aryloxazolines, with excellent agreement between computed and experimental outcomes.