Theoretical study of HOCl-catalyzed keto-enol tautomerization of β-cyclopentanedione in an explicit water environment.

The mechanism of acid-catalyzed keto-enol tautomerization of β-cyclopentanedione (CPD) in solution is studied computationally. Reaction profiles are first calculated for a limited solvation environment using ab initio and density functional methods. Barrier heights for systems including up to one hydration shell of explicit water molecules depend strongly on the number of waters involved in proton transfer and to a lesser but significant extent on the number of waters forming hydrogen bonds with waters in the proton-transfer chain (each such water reduces the barrier by 4.4 kcal/mol on average). Barriers of 8-13 kcal/mol were obtained when a full or nearly full hydration shell was present, consistent with calculations for nonacid-catalyzed keto-enol tautomerization of related molecules. The presence of HOCl reduced the barrier by 4.5 kcal/mol in relation to the gas phase, consistent with the well-known principle that keto-enol tautomerization can be acid- or base-catalyzed. The reaction was also modeled beginning with snapshots of reactant conformations taken from a 300 K molecular dynamics simulation of CPD, HOCl, and 324 explicit waters. Reaction profiles were calculated at a QM/MM level with waters in the first hydration shell either fixed or energy-minimized at each step along the reaction coordinate. A substantial variation in barrier height was observed in both cases, depending primarily on electrostatic interactions (hydrogen bonding) with first-hydration-shell waters and, to a lesser extent, on electrostatic interactions with more distant waters and geometric distortion effects. For the lowest barriers, the extent of barrier reduction by waters involved in proton transfer is consistent with the limited solvation results, but further barrier reduction due to hydrogen bonding to waters involved in proton transfer is not observed. It is postulated that this is because highly flexible structures such as extensive hydrogen bonding networks optimal for reaction are entropically disfavored and so may not contribute significantly to the observed reaction rate.