DFT Study of Boric Acid-Promoted Thioester Hydrolysis via a Concerted Bond-Breaking Mechanism

Thioesters make up a versatile class of compounds, and their hydrolysis represents a fundamental reaction across diverse fields. Boric acid has been proposed as a potential catalyst for thioester hydrolysis; however, the underlying reaction mechanisms remain unclear, hindering the rational design of more effective catalytic systems. In this study, boric acid-catalyzed hydrolysis mechanisms of α-hydroxy thioester (1) and β-hydroxy thioester (2) substrates were investigated using density functional theory calculations. The computed free energy profiles show that hydrolysis of both substrates proceeds via a two-step process, yielding butanethiol and a carboxylate. Our results indicate a concerted mechanism in which the rate-determining step involves B-O bond cleavage, OH migration, and C-S bond breaking. Notably, substrate 1 forms a five-membered transition state involving boron, a hydroxyl group, and a carbonyl group, whereas substrate 2 forms a six-membered transition state. These geometrical differences affect the energy barriers for the hydrolysis. These mechanistic insights can facilitate the rational design of more efficient catalysts for thioester hydrolysis.