Curtin-Hammett and steric effects in HOBt acylation regiochemistry

While hydroxybenzotriazole is commonly used in a variety of bond-forming reactions, its acylation has been shown to produce a regiochemical (O vs N) mixture with complex kinetic behavior. Increased steric bulk on the electrophile favors formation of the oxygen-acylated product. Upon standing as a solid, the mixture can isomerize completely to the nitrogen adduct. An equilibrium ratio of regioisomers can be re-established in solution by adding either nucleophilic or electrophilic reagents, suggesting that the composition of the mixture is not significant to subsequent reactivity. Solvents can affect this regiochemical equilibrium through a Curtin-Hammett effect, where the shift in the tautomeric equilibrium of HOBt in polar solvents biases the reaction toward the oxygen adduct.