Intramolecular general-acid and electrostatic catalysis in acetal hydrolysis. Hydrolysis of 2-(substituted phenoxy)-6-carboxytetrahydropyrans and 2-alkoxy-6-carboxytetrahydropyrans

Article abstract of DOI:10.1021/ja00020a028

Rate constants have been determined for hydrolysis of a series of trans-2-(substituted phenoxy)-6-carboxytetrahydropyrans (e,a) in H₂O and 50% dioxane-H₂O. The second-order rate constant (k₂) for the apparent hydronium ion catalyzed reaction of the anionic species of the p-nitro derivative in 50% dioxane-H₂O (50 °C) is 620-fold larger than the second-order rate constant for hydrolysis of 2-(p-nitrophenoxy)tetrahydropyran. The slope (p) of the Hammett plot of log k₂ vs σ is approximately 0, which supports a mechanism involving intramolecular general-acid catalysis by the un-ionized carboxyl group with proton transfer to the leaving group oxygen. Sizable catalytic effects can therefore be obtained in an intramolecular general-acid-catalyzed reaction when the leaving group is sufficiently good, even though the steric fit is poor and proton transfer may necessarily occur via an intervening water molecule. Intramolecular general-acid-catalyzed ring opening is not a favorable in the hydrolysis of tetrahydropyranyl acetals; such a mechanism does not occur in the hydrolysis of 2-alkoxy-6-carboxytetrahydropyrans. In the pH-independent decomposition of 2-(p-nitrophenoxy)-6-carboxytetrahydropyran at pH >6, the neighboring carboxylate anion participates electrostatically in 50% dioxane-H₂O and gives a 10-fold rate enhancement. The plot of log k_obed vs pH for hydrolysis of 2-(o-carboxyphenoxy)-6-carboxytetrahydropyran is bell shaped, which indicates that the monoanionic species is maximally reactive. The rate enhancement in that reaction in comparison with the hydrolysis of 2-(p-carboxyphenoxy)-6-carboxytetrahydropyran or 2-(p-carboxyphenoxy)tetrahydropyran is a factor of (2-4) × 10³ in H₂O but is 10₄-10₅ in 50% dioxane-H₂O. The o-carboxyl group acts as an intramolecular general acid. However, bifunctional catalysis does not take place in this system. The lack of efficient electrostatic facilitation of these reactions by a neighboring carboxylate anion is most likely due to the energy expenditure for the 6-carboxylate group to approach the developing oxocarbonium ion closely. There is no chemical support for proposed mechanisms of lysozyme-catalyzed reactions that involve intracomplex general-acid-catalyzed opening of an unstrained hexose ring or large electrostatic stabilization effects by Asp-52.