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 have not been well described and may have been inappropriately extended from gas-phase observations. Within our study, ONIOM/PCM-X calculations were employed on three water clusters with malonate that 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 for the decarboxylation of mono-anionic malonate. Bulk phase solvation effects have been approximated using Tomasi’s polarizable continuum model (PCM) for all three clusters. Our principle discovery is that the bulk solvation parameters for the TIP3P definition of the water molecules fail at reproducing the QM and experimental ΔH‡. Whereas polarization of the water molecules with the CHarges from ELectrostatic Potentials using a Grid-based method (CHELPG) scheme converged to QM and experimental ΔH‡ for the three water clusters of 3, 10, and 15 water molecules. We have found that the ΔH‡ can only be reproduced when monoanionic malonate is in a novel orthogonal conformation as a ground state (GS) leading to the transition state (TS). The polarization of the water molecules suggest that they are part of the quantum system as opposed to the bulk solvation as typically modeled with the TIP3P model. Preliminary data for the dianion 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.

Polarization of three water clusters in quantum mechanical/molecular mechanical (QM/MM) calculations reveal a novel reaction mechanism for malonate decarboxylation

ACS Fall 2021

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