Theoretical insights into Pd-catalyzed dual γ-1,1-C(sp3)–H activation of aliphatic carboxylic acids: mechanistic pathways, substituent influence on product selectivity, diastereoselectivity, and additive effects

Abstract

Employing density functional theory (DFT) calculations, the study meticulously analyzes the mechanistic details of the Pd-catalyzed dual-γ-1,1-C(sp³)–H activation of aliphatic carboxylic acids. To explore the intrinsic nature of double C(sp³)–H in aliphatic carboxylic acids, we compared the reaction mechanisms of two coupling agents: allyl alcohol and methyl acrylate. The calculations indicated that allyl alcohol favors the second C(sp³)–H activation due to the absence of conjugation effects, which typically hinder C(sp³)–H activation. In contrast, methyl acrylate favors the Michael addition mechanism due to reduced steric hindrance and the formation of a stabilizing Na–O coordination interaction. We also computed the reaction mechanism of the coupling agent but-3-en-2-yl acetate and compared it with that of allyl alcohol to determine the reasons for the occurrence of β-H elimination. For allyl alcohol, β-H elimination is favored due to the lack of steric hindrance in the transition state, whereas for but-3-en-2-yl acetate, β-OAc elimination is preferred because of a stabilizing N–H⋯O hydrogen bond in the transition state. The study also highlights the significant role of Na₂HPO₄ base in enhancing the reaction's efficiency. Specifically, we found that the presence of Na₂HPO₄ base significantly facilitates the hydroxyl deprotonation process. To further explore the reaction's diastereoselectivity, we calculated the diastereoselectivity-determining steps for two substrates with significantly different d.r. ratios and analyzed the driving forces behind the high diastereoselectivity. Our analysis revealed that the diastereoselectivity of the reaction improves as the disparity in steric hindrance between the two substituents at the β-position of the carboxylic acid increases. Overall, the mechanistic insights gained in this study may prove valuable in the ongoing advancement and application of metal-catalyzed dual-1,1-C(sp³)–H activation.