A Theoretical Analysis of the Free-Energy Profile of the Different Pathways in the Alkaline Hydrolysis of Methyl Formate In Aqueous Solution

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Abstract
The free‐energy profile for the different reaction pathways available to the hydroxide ion and methyl formate in aqueous solution is reported for the first time. The theoretical analysis was carried out by using the cluster‐continuum method recently proposed by us for calculating the free energy of solvation of ions. Unlike the gas‐phase reaction, our results are consistent with the fact that the reaction occurs mainly by nucleophilic attack of the hydroxide on the carbonyl carbon to yield a tetrahedral intermediate (BAC2 mechanism). However, an additional pathway, in which the hydroxide ion acts as a general base and a water molecule coordinated to this ion acts as the nucleophile, is also predicted to be important. The relative importance of these pathways is calculated to be 87 % and 13 %, respectively. The tetrahedral intermediate of the hydrolysis reaction has an estimated lifetime of 10 nanoseconds, and its conjugate acid has a pKa of 8.8. This tetrahedral intermediate is predicted to proceed to products by two pathways: elimination of methoxide ion (84 %) and by water catalyzed elimination of methanol (16 %). The less common reaction pathway, which involves attack of the hydroxide ion on the formyl hydrogen (decarbonylation mechanism) and leads to water, carbon monoxide, and methanol, is calculated to be only 3 kcal mol−1 less favorable than the BAC2 mechanism. By comparison, direct attack of the hydroxide ion on the methyl group (BAL2 or SN2 mechanism) leading to an acyl‐oxygen bond cleavage has a very high free energy of activation and is not expected to be important. The theoretically observed activation free energy at 298.15 K is calculated to be 15.5 kcal mol−1, in excellent agreement with the experimentally measured value of 15.3 kcal mol−1. This present model allows for a clear distinction between contributions due to solvation and those due to intrinsic (gas‐phase) effects and proves to yield results in very good agreement with available experimental data.