Reaction pathways, solvent effects, and energy barriers have been determined for the base-catalyzed hydrolysis of two representative alkyl esters in aqueous solution, using a hybrid supermolecule-polarizable continuum approach. Four solvent water molecules were explicitly included in the supermolecular reaction coordinate calculations; the remaining solvent water was modeled as a polarizable dielectric continuum surrounding the supermolecular reaction system. Two competing reaction pathways were observed, sharing a common first step, i.e. the formation of the tetrahedral intermediate. One pathway involves a direct proton transfer in the second step, i.e. the decomposition of the tetrahedral intermediate. A second pathway involves a water-assisted proton transfer during the decomposition of the tetrahedral intermediate. The direct participation of the solvent water molecule in the proton-transfer process significantly drops the energy barrier for the decomposition of the tetrahedral intermediate. Thus, the energy barrier calculated for the decomposition of the tetrahedral intermediate through the water-assisted proton transfer becomes lower than the barrier for the formation of the tetrahedral intermediate, while that through the direct proton transfer is higher. The computations reveal the important effect of solvent hydrogen bonding on energy barriers; without explicit consideration of the hydrogen-bonding effects, the calculated energy barriers for the formation of the tetrahedral intermediate become ∼4−5 kcal/mol smaller. The favorable pathway involving water-assisted proton transfer and the energy barriers calculated using the hybrid supermolecule-polarizable continuum approach, including both the hydrogen-bonding effects and the remaining bulk solvent effects, are consistent with available experimental results. The energy barriers calculated for the first step of the hydrolysis in aqueous solution are in excellent agreement with the reported experimental data for methyl acetate and methyl formate.

An optimized potential function for base-stacking interactions is constructed. Stacking energies between the complementary pairs of a dimer are calculated as a function of the rotational angle and separation distance. Using several different sets of atomic charges, the electrostatic component in the monopole-monopole approximation (MMA) is compared to the more refined segmented multipole-multipole representation (SMMA); the general features of the stacking minima are found to be correctly reproduced with IEHT or CNDO atomic charges. The electrostatic component is observed to control the location of stacking minima.The MMA, in general, is not a reliable approximation of the SMMA in regions away from minima; however, the MMA is reliable in predicting the location and nature of stacking minima.The attractive part of the Lennard-Jones 6-12 potential is compared to and parameterized against the expressions for the second-order interaction terms composed of multipole-bond polarizability for the polarization energy and transition-dipole bond polariz abilities for approximation of the dispersion energy. The repulsive part of the Lennard-Jones potential is compared to a Kitaygorodski-type repulsive function; changing the exponent from its usual value of 12 to 11.7 gives significantly better agreement with the more refined repulsive function.Stacking minima calculated with the optimized potential method are compared with various perturbation-type treatments. The optimized potential method yields results that compare as well with melting data as do any of the more recent and expensive perturbation methods.

The hydrolysis of six representative alkyl esters in aqueous solution were evaluated by performing ab initio molecular orbital calculations using five different self-consistent reaction field (SCRF) procedures. Energy barriers were obtained for hydrolysis by bimolecular base-catalyzed acyl-oxygen cleavage (B AC 2) and bimolecular base-catalyzed alkyl-oxygen cleavage (B AL 2). Despite strong solute-solvent hydrogen bonding, the calculated solvent shifts of the energy barriers are dominated by electrostatic interactions between solute and solvent, and nonelectrostatic interactions largely cancel out. SCRF calculations that ignore volume polarization or use a charge renormalization scheme usually overestimate the solvent shifts of the energy barriers. A recently developed surface and volume polarization for electrostatic interaction (SVPE) procedure yields results comparable to experimental data when the solute cavity surface is defined as the 0.002 au electron charge isodensity contour. The differences between values from the SVPE calculations with this contour and the corresponding average experimental values for the examined esters are smaller than the range of experimental values reported by different laboratories. The SVPE calculations for the B AC 2 hydrolysis predicted the lowest energy barrier for methyl formate and the highest for tert-butyl acetate, and the remaining four esters grouped closely. These results are consistent with the substituent shifts of the experimental activation energies. The energy barriers predicted for B AL 2 hydrolysis are always considerably higher than those predicted for the B AC 2, consistent with the observation that in aqueous solution B AL 2 hydrolysis is negligible compared to B AC 2 for alkyl esters.