Decarboxylation of β-keto acids is essential across chemical and biological disciplines, yet the origins of non-catalytic effects remain elusive. Specific effects of solvent on structure and energetics are not well described and may have been inappropriately transferred from existing gas-phase observations. Within our study, ONIOM/PCM-X calculations were employed on four various sized water clusters with monoanionic malonate to converge to the experimental enthalpy of activation (ΔH^‡) of 30.0 kcal/mol. Truhlar’s Minnesota functional, M06-2X, with the jul-cc-pVDZ basis set was used for the quantum mechanical (QM) region while different charge schemes were employed for the partial charge assignment within the AMBER force field (MM) for the QM/MM calculations. Bulk phase solvation effects were approximated using Tomasi’s polarizable continuum model (PCM) for all four cluster systems. Our principal discovery is that the experimental ΔH^‡can be reproduced within 2 kcal/mol via QM when monoanionic malonate is in a novel “orthogonal” ground state conformation, which requires the complexation of malonate with three explicit and hydrogen bonded water molecules. This “hydration buckle” complex is a motif within the water clusters of 3, 7, 10, and 15 water molecules, yet the agreement with experiment can be refined to be within 1 kcal/mol with the addition of four explicit water molecules beyond the hydration buckle, as found in the 7-water cluster system. For QM/MM, we have found that the bulk solvation parameters for the TIP3P definition of the water molecules fail to reproduce the target QM ΔH^‡ and experimental ΔH^‡. However, we propose that polarization of the water molecules with the CHarges from ELectrostatic Potentials using a Grid-based method (CHELPG) scheme will allow for convergence to QM and experimental ΔH^‡for water clusters sizes 7, 10, and 15, such that the water molecules become part of the quantum system as opposed to the bulk solvation as typically modeled with the TIP3P model. Preliminary data for the dianionic malonate suggests a similar trend for the conformational preference of the GS for malonate. The dianion will be hydrated and the mechanism will be investigated in an analogous method to that of the monoanion. Fundamentally, this study has implications to other β-keto acids and may explain the conformation adopted by these acids prior to entry into enzymatic processes.

Inoka Pathiraja

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