Mechanistic Studies of Pd-Catalyzed β- and γ<i>-</i>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<b>-</b>ring intermediate <b>IM2</b>; (ii) oxidative addition of <b>ArI</b> to Pd of <b>IM2</b>, resulting in the Pd(IV) complex <b>IM4</b>; 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 (Δ<i>E</i>_int) and preparation energy (Δ<i>E</i>_prep). Building on these mechanistic insights, we further explored a series of bidentate pyridone ligands (<b>L2</b>-<b>L12</b>) aimed at lowering the free energy barrier of the RDS. Among them, ligand <b>L9</b> exhibits exceptional potential in promoting the overall reaction efficiency. Furthermore, <b>L9</b> 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.