Direct Bronsted Acid-Catalyzed Dehydration of Glucose to HMF in Methyl Isobutyl Ketone

We report the direct Bronsted acid-catalyzed glucose dehydration in methyl isobutyl ketone solvent doped with small fractions of water to a high yield of 5-hydroxymethylfurfural (HMF) (74%) at low temperatures without using a Lewis acid catalyst, but the mechanistic understanding remains unclear. We combine fast experimental reaction kinetics, quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) simulations, IR and C-13 NMR spectroscopy, and kinetic isotope effects to elucidate the solvent effects and infer the potential reaction mechanism for glucose dehydration. Our results indicate that the direct conversion of glucose to HMF proceeds via acyclic isomerization to fructose, initiated by protonation of the ring oxygen followed by the opening of the pyranose ring. We found that ketone-based organic solvents promote the selective dehydration of glucose by enhancing the catalyst-substrate interactions at the ring oxygen, which facilitates dehydration. In contrast, alcohol-based organic solvents promote protonation of secondary hydroxyl groups, leading to reversion products and humins. Our findings highlight the importance of solvent selection in facilitating the protonation of the target glucose oxygen while minimizing protonation of the hydroxyl groups, which leads to undesired byproducts.