Mechanistic Studies of Pd-Catalyzed β- and γ-C(sp3)–H Arylations and the Computational Design of Bidentate Pyridone Ligands

This study outlines a detailed reaction mechanism for the Pd-catalyzed β-C(sp³)–H arylation of free carboxylic acids, which unfolds through three distinct stages: (i) ligand-driven β-C(sp³)–H activation, leading to the formation of the five-membered-ring intermediate IM2; (ii) oxidative addition of ArI to Pd of IM2, resulting in the Pd(IV) complex IM4; and (iii) reductive elimination, which produces the desired arylated product and regenerates the active species for the next catalytic cycle. Notably, the oxidative addition step, with a free energy barrier of 28.5 kcal/mol, is identified as the rate-determining step (RDS) of the entire catalysis. EDA-NOCV analysis revealed that the RDS is governed by a combination of intrinsic energy (ΔE_int) and preparation energy (ΔE_prep). Building on these mechanistic insights, we further explored a series of bidentate pyridone ligands (L2–L12) aimed at lowering the free energy barrier of the RDS. Among them, ligand L9 exhibits exceptional potential in promoting the overall reaction efficiency. Furthermore, L9 possesses computational potential in facilitating remote γ-C(sp³)–H arylations. These findings offer valuable mechanistic insights into both β- and γ-C(sp³)–H arylations, providing a theoretical guide for improving current catalytic systems and advancing the development of new arylation methodologies for free carboxylic acids.