(208e) Theoretical Study of the Mechanism of Fructose Dehydration to Hydroxymethylfurfural in the Aqueous Phase

Hydroxymethylfurfural (HMF) and its furan derivatives can replace key, petroleum-based, building blocks. However, HMF is not yet a high-volume chemical, due to difficulties in cost-effective production. HMF synthesis by dehydration of D-fructose is a problem that illustrates the selectivity challenges involved in the processing of highly functionalized carbohydrates, because the reaction intermediates and HMF itself degrade through various processes. Effective process design is currently impeded by our limited knowledge of the reaction pathways. In this talk, we focus on fructose dehydration and employ theoretical methods in order to elucidate the multi-step mechanism and its energetics in aqueous solutions with acid (proton) catalyst. To that end, we propose a mechanism for the dehydration reaction of fructose to HMF and study the energetics of each elementary step by performing free energy calculations in the aqueous phase; we calculate reaction and activation free energies and thus obtain much needed kinetic constants. Our methodology involves hybrid QM/MM (Quantum Mechanics/Molecular Mechanics) Molecular Dynamics simulations in the canonical ensemble at 363 K, with explicit solvent molecules. To account for reactive events, namely, bond cleaving and forming, the fructose molecule and all reaction intermediates are treated quantum mechanically at the PM3 theory level. Explicit water molecules are treated at the Molecular Mechanics level using the SPC/E parameterization. Furthermore, to account for rare events in reaction steps involving high energy barriers, we employ umbrella sampling and the weighted-histogram analysis method. Entropic contributions to the calculated free energies are also obtained, revealing the importance of the solvent in the stabilization of the reaction intermediates. For example, we find that upon protonation of the anomeric carbon (C2) hydroxyl group, water removal leads to the formation of a cyclic species whose quantum mechanical energy is ~23 kcal/mol higher than that of the protonated fructose, whereas its free energy is of ~2.3 kcal/mol lower, revealing the importance of solvation in the stabilization of the reaction intermediates. We uncover similar phenomena in the subsequent elementary steps of the dehydration reaction.