C2 Hydroxyl Group Governs the Difference in Hydrolysis Rates of Methyl-α-d-glycero-d-guloseptanoside and Methyl-β-d-glycero-d-guloseptanoside

Abstract

A computational investigation into the hydrolysis of two methyl septanosides, methyl-α-D-glycero-D-guloseptanoside and methyl-β-D-glycero-D-guloseptanoside was undertaken. These septanosides were chosen as model compounds for comparison to methyl pyranosides and allowed direct comparison of α versus β hydrolysis rates for a specific septanoside isomer. Results suggest that hydrolysis takes place without proceeding through a transition state, an observation that was suggested in previous computational studies on exocyclic bond cleavage of carbohydrates. A conformational analysis of α- and β-anomers 1 and 2 and their corresponding oxocarbenium 3, coupled with relaxed potential energy surface (PES) scans (M06-2X/6-311+G**, implicit methanol), indicated that hydrolysis of the α-anomer is favored by 1-2 kcal/mol over the β-anomer, consistent with experiment. Model systems revealed that the lowest energy conformations of the septanoside ring system destabilize the β-anomer by 2-3 kcal/mol relative to the α-anomer, and the addition of a single hydroxyl group at the C2-position on a minimal oxepane acetal can reproduce the PES for the septanoside 1. These results suggest that the C2 hydroxyl plays a unique role in the hydrolysis mechanism, destabilizing the septanoside via its proximity to the anomeric carbon and also through its interaction with the departing methanol from the α-anomer via hydrogen-bonding interactions.

The Electronic Nature of the 1,4‐β‐Glycosidic Bond and Its Chemical Environment: DFT Insights into Cellulose Chemistry

“…[30,54] The acid hydrolysis of guloseptanosides in methanol was investigated by relaxed potential energy scans (M06-2X/6-311 + G**, with methanol represented by a polarizable continuum model). [36] This study showed that the hydroxyl group on the C(2) atom affects the hydrolysis mechanism because of its proximity to the anomeric carbon atom. The calculations predicted that the reaction should be also affected by the hydrogen-bond interaction of the hydroxyl group with the departing methanol from the a anomer.…”

“…[1] Substituents at the glycoside and the reaction solvent exert a decisive influence on the reaction pathway. [36,37] A mechanism involving an acyclic carbocation is often proposed for the hydroly-sis of glycosides confronted with ring strain issues or containing a poor leaving group, [38,39] whereas a mechanism through a cyclic carbocation is often assumed for cellulose. [40][41][42][43] Both acyclic and cyclic carbocations should have a short life time in solution.…”

“…[40][41][42][43] Both acyclic and cyclic carbocations should have a short life time in solution. [44] Computational studies applying ab initio, [45][46][47][48][49] density functional theory (DFT), [36,37] and molecular dynamics (MD) methods [37,[50][51][52][53] have been performed in order to uncover some mechanistic aspects of the hydrolysis of cellulose. Although cellobiose is an excellent model for cellulose, smaller molecules, such as dimethoxymethane, [45] 2-methoxytetrahydropyran, [46] 2-oxanol, [48] and 2-methoxyoxane [49] were chosen in the earlier computational studies because of limited computing power.…”

“…Two mechanisms are commonly considered for the hydrolysis of glycosides, as depicted in Scheme 1. Substituents at the glycoside and the reaction solvent exert a decisive influence on the reaction pathway 36. 37 A mechanism involving an acyclic carbocation is often proposed for the hydrolysis of glycosides confronted with ring strain issues or containing a poor leaving group,38, 39 whereas a mechanism through a cyclic carbocation is often assumed for cellulose 40–43.…”

“…The acid hydrolysis of guloseptanosides in methanol was investigated by relaxed potential energy scans (M06‐2X/6‐311+G**, with methanol represented by a polarizable continuum model) 36. This study showed that the hydroxyl group on the C(2) atom affects the hydrolysis mechanism because of its proximity to the anomeric carbon atom.…”