DFT Investigation of the Mechanism of Pd‐Catalyzed Alkoxy‐Carbonylation of C─H Bonds

Abstract

The functionalization of unactivated methyl (sp3)C─H bond remains a formidable challenge in organic synthesis due to their high bond dissociation energies and poor site selectivity. Palladium‐catalyzed carbonylation using carbon monoxide (CO) is a well‐established method for ester synthesis. Recently, researchers claim that alkyl chloroformates are replacing toxic carbon monoxide as a safer, more effective means of overcoming the difficulty of activating inert (sp3)C─H bonds for ester synthesis. In this study, we present a Density Functional Theory (DFT) investigation of the detailed mechanism of palladium‐catalyzed direct alkoxycarbonylation of methyl (sp3)–hybridized C─H bonds. This Pd‐catalyzed reaction pathway, involving an 8‐aminoquinoline‐directed molecule, identifies several transition states and intermediates, highlighting main steps such as coordination and C─H activation, followed by oxidative addition of methyl chloroformate. However, the interesting fact is that, possibly due to the presence of Ag+, precipitation of AgCl occurs, and Cl− does not coordinate to Pd(IV). Thus, the important role of Ag+ has been justified. This work aims to provide fundamental mechanistic insights into the replacement of gaseous CO with chloroformate esters, offering a refined theoretical framework for the design of more efficient and sustainable C(sp3)–H functionalization protocols.