Regiochemical inversion in Wacker-type catalysis: computational and kinetic insights into anti-Markovnikov and Markovnikov pathways

Abstract Controlling regioselectivity in palladium-catalyzed Wacker oxidations to synthesize anti-Markovnikov (AM) aldehydes remains challenging due to the intrinsic Markovnikov (M) bias of standard palladium complexes. Combining reaction kinetics, multinuclear NMR, ESI–MS, and Density Functional Theory (DFT) calculations, we investigated the mechanism governing regiochemical inversion during 1-decene oxidation. Conducting the reaction in anhydrous tertiary alcohols, specifically tert -butanol ( t -BuOH) and 2-methyl-2-butanol, allows the solvent to act directly as a steering nucleophile, achieving an AM-selectivity of 19.1 ± 0.8% (57:43 AM:M ratio). DFT energy profiles show that the reaction proceeds via an inner-sphere syn-nucleopalladation manifold. In this step, the steric bulk of t -BuOH or 2-methyl-2-butanol as nucleophiles and co-bound acetonitrile ligands physically shield the internal alkene carbon, forcing nucleophilic attack onto the terminal position. Deactivation kinetics and mass spectra reveal that AM selectivity loss over time is driven by chloride displacement of the labile nitrile ligands, which generates the thermodynamically preferred [PdCl 4 ] 2− sink ( ΔG = − 7.7 kcal mol −1 relative to PdCl 2 (MeCN) 2 . Additionally, trace water acts as an unhindered competitive nucleophile (ΔΔ G ‡ = 6.7 kcal mol −1 ) favoring M-products. Overcoming catalyst fatigue in AM-selective Wacker oxidations will therefore require non-labile spectator ligands and halide-free co-catalyst systems.