Three Water Molecules Mediate Ring Opening of d‑Glucose in Aqueous Solutions

The mechanism of d-glucose ring opening has long been debated, particularly with regard to whether proton transfer occurs through a concerted or stepwise pathway and how many water molecules participate in the process. Here, we employ ab initio molecular dynamics combined with metadynamics to investigate both possibilities. Our results identify a lower-energy concerted pathway in which proton transfer is mediated by a three-water hydrogen-bond network. Indeed, the transition state features a cyclic hydrogen-bonded water bridge linking OH₁ and O₅. This bridge promotes proton transfer from OH₁ to O₅, thereby initiating ring opening via an asynchronous yet concerted mechanism. This study provides the first direct dynamical evidence for the involvement of a three-water cyclic network in d-glucose ring opening, in support of earlier mechanistic proposals. The computed activation barrier of 15-18 kcal mol^-1 agrees closely with experimental estimates.