Decarboxylation reactions are ubiquitous across chemical and biological disciplines, yet the exact origin of non-catalytic effects remain elusive. Specific effects of solvent on structure and energetics have not been well described, and in fact, may have been inappropriately extended from gas-phase observations. Within our study, Truhlar’s Minnesota functional, M062X, with the jul-cc-pvdz basis set was used for geometry optimizations, energy evaluation, and frequency analysis, supplemented with second-order Møller-Plesset (MP2) theory. Bulk-phase solvent effects have been approximated using Tomasi’s polarizable continuum model (PCM) for malonate embedded, in water cluster sizes of one- to fifteen-water molecules. Our first principal discovery is that in explicit solvent, malonate adopts a novel orthogonal conformation as the ground state (GS) over the gas-phase pseudo-chair conformation. When malonate is embedded in a ten-water cluster, the orthogonal conformation is preferred over the commonly assumed pseudo-chair conformer by ca. 5 kcal/mol. In our second finding, the computed uncatalyzed activation enthalpy (ΔH^‡) is consistent with the experimental observation of 30.0 kcal/mol for three cluster models investigated. Cluster sizes of three-, ten-, and fifteen-water molecules in the solution-phase computed an error of 0.6 kcal/mol, 0.0 kcal/mol and 0.2 kcal/mol, respectively. The fifteen-water cluster model was required to satisfy all donor/acceptor positions through a hydrogen bond network. Although the fifteen-water cluster is a representative model, the three-water cluster model delivers the differential solvation effects between the GS and transition structure (TS) to converge to experimental observation. The three-waters identified are referred to as the hydration buckle that selectively stabilizes the GS of malonate with four strong, direct hydrogen bonds. Breaking the strong hydrogen bond network to the TS computes the to experimental observation. 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.

Jeffrey Rohde

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