Unveiling the Mechanism of Pd-Catalyzed γ-Methylene C(sp 3 )–H Arylation of Carboxylic Acids
Year: 2026
Type: article
Abstract: The γ-C(sp3)-H functionalization of carboxylic acids in the presence of β-C(sp3)-H bonds is a tremendous challenge due to the overwhelming formation of five-membered metallacycles over six-membered ones. In this study, the reaction mechanism of the Pd-catalyzed γ-methylene C(sp3)-H (hetero)arylation of cycloalkane carboxylic acids was investigated using density functional theory (DFT) method and the nature of the counter-cation effect was unveiled. Different from the previously proposed six-membered palladacyclic intermediate formed by the γ-C(sp3)-H activation, the calculated results indicate that in this reaction the β-C(sp3)-H bond will be favorably activated at first to form a five-membered palladacyclic intermediate instead of the γ-C(sp3)-H bond, and that the achieved β,γ-unsaturated acid after the β- and γ-C(sp3)-H activation is a key feasible transient intermediate for the following γ-C(sp3)-H arylation. The γ-arylation product is obtained by the C-C coupling of β,γ-unsaturated acid with aryl iodide, which could be realized by Pd-Ag catalytic model via a Pd(0)/Pd(II) mechanism instead of Pd-Ag-Cs catalytic model via a Pd(II)/Pd(IV) mechanism. The reaction mechanism not only reveals the origin of this unique reactivity, but also successfully explains the experimental phenomenon that the reaction is insensitive to bases, which is significantly different from the previous reports on the β-C(sp3)-H and γ-C(sp3)-H arylation of carboxylic acids.
Source: ACS Catalysis
Authors: Zhewei Li, Yanhui Tang, Ming Lei
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7127635620