Proton-mediated catalysis in [Ga4L6]12−: Theoretical study of acetal-ketone hydrolysis

Abstract

Acetal hydrolysis to ketones is a crucial reaction in organic synthesis, typically requiring strongly acidic conditions. This study presents a theoretical investigation of proton-mediated catalysis in the metallocage [Ga₄L₆]¹²⁻. Quantum mechanical and molecular dynamics simulations demonstrate that [Ga₄L₆]¹²⁻ creates an acidic microenvironment within its cavity, enhancing hydrolysis through cationophilic behavior and stabilization of reactive intermediates via hydrogen bonding with cage ligands. The encapsulation of 2,2-dimethoxypropane (DMP) was found to be both kinetically and thermodynamically favorable, as shown by attach-pull-release (APR) simulations. The hydrolysis mechanism suggests that the catalytic efficiency of [Ga₄L₆]¹²⁻ approaches that of traditional acid catalysis, with similar Gibbs energy barriers for key proton transfer steps. Importantly, the optimal pathway involves cooperative interactions among H₃O⁺, water molecules, and the cage structure, lowering hydrolysis energy barriers and suggesting potential sustainable catalytic applications for [Ga₄L₆]¹²⁻.