文摘
Solvent effects on the rate of the Claisen rearrangement of chorismate to prephenate have beenexamined in water and methanol. The preequilibrium free-energy differences between diaxial and diequatorialconformers of chorismate, which had previously been implicated as the sole basis for the observed 100-fold rate increase in water over methanol, have been reframed using the near attack conformation (NAC)concept of Bruice and co-workers. Using a combined QM/MM Monte Carlo/free-energy perturbation (MC/FEP) method, 82%, 57%, and 1% of chorismate conformers were found to be NAC structures (NACs) inwater, methanol, and the gas phase, respectively. As a consequence, the conversion of non-NACs toNACs provides no free-energy contributions to the overall relative reaction rates in water versus methanol.Free-energy perturbation calculations yielded differences in free energies of activation for the two polarprotic solvents and the gas phase. The rate enhancement in water over the gas phase arises frompreferential hydration of the transition state (TS) relative to the reactants via increased hydrogen bondingand long-range electrostatic interactions, which accompany bringing the two negatively charged carboxylatesinto closer proximity. More specifically, there is an increase of 1.3 and 0.6 hydrogen bonds to the carboxylategroups and the ether oxygen, respectively, in going from the reactant to the TS in water. In methanol, thecorresponding changes in hydrogen bonding with first shell solvent molecules are small; the rateenhancement arises primarily from the enhanced long-range interactions with solvent molecules. Thus,the reaction occurs faster in water than in methanol due to greater stabilization of the TS in water byspecific interactions with first shell solvent molecules.
