Computational study on hydroxybenzotriazoles as reagents for ester hydrolysis

Abstract

1-Hydroxybenzotriazole (1) and several of its derivatives (2-5) demonstrate potent esterolytic activity toward activated esters such as p-nitrophenyl diphenyl phosphate (PNPDPP) and p-nitrophenyl hexanoate (PNPH) in cationic micelles at pH 8.2 and 25 °C. The deprotonated anionic forms of such reagents act as reactive species in the hydrolysis of ester. To rationalize the origin of their nucleophilic character, a detailed ab initio/DFT computational study has been performed on 1-5 along with additional hydroxybenzotriazole derivatives (6-13). The geometries of 1-hydroxybenzotriazoles (1-13) and their corresponding bases are discussed in detail. All calculations were carried out using different methods, i.e., restricted Hartree-Fock (RHF) and hybrid ab initio/DFT (B3LYP) using 6-31G∗ and 6-31+G∗ basis sets. Free energy of protonation ('fep') of the 1-hydroxybenzotriazoles (1-13), free energy of solvation ΔG_aq, and the corresponding pK_a values have been calculated. Solvation-free energies were calculated using density functional theory and the polarizable continuum model. In addition, to examine the reliability of calculated fep, benzaldehyde oxime (14) and 2-methyl propionaldehyde oxime (15) have been computed as reference systems using different methods and basis sets, the experimental feps of which are known. Our experimental finding shows that the compound 4 is the most effective catalyst for the hydrolytic cleavages of PNPDPP and PNPH. This has been predicted from our calculated fep, pK_a, and natural charge analysis results as well. In general, the introduction of electron-withdrawing substituents on 1-hydroxybenzotriazoles facilitates the lowering of pK_a and fep. As the pK_a values are lowered, a greater percentage of such hydroxybenzotriazoles remain in their deprotonated, anionic forms at pH 8.2. Since the anionic forms are nucleophilic, pK_a lowering should enhance their ester cleaving capacity. However, such substitution also decreases the charge density on the catalytically active oxido atom (O₇). Taking these two factors together, the derivatives are only modestly better nucleophiles in comparison to the parent 1-hydroxybenzotriazole. Interestingly, the introduction of electron-donating groups does not significantly enhance the charge accumulation on the oxido atom (O₇) of 1-hydroxybenzotriazoles.