INTRA-MOLECULAR GENERAL ACID CATALYSIS IN THE HYDROLYSIS OF ACETALS WITH ALIPHATIC ALCOHOL LEAVING GROUPS

The pH-rate constant profile for release of salicylic acid from phthalaldehydic acid methyl salicyl acetal at 15 °C in 50% dioxane-H2O (v/v) is bell shaped. The salicyl carboxyl group acts as an intramolecular general acid, but electrostatic catalysis by the second carboxyl group does not occur, indicating that the critical transition state is rcachcd before the carbonium ion intermediate is extensively developed. Benzaldehyde cis-2-carboxycyclohexyl methyl acetal hydrolyzes with hydronium ion catalysis at the same rate as the corresponding methyl ester and gives a plot of log kobsd vs. pH that shows only a very slight inflection at pH values close to the pKa of the carboxyl group. Intramolecular general acid catalysis is therefore not a favorable mechanism when the leaving group is an aliphatic alcohol. When there is strong electron withdrawal in the benzaldehyde portion of the molecule, as with the w-chloro and p-nitro derivatives, then ionization of the cyclohexyl carboxyl group produces large rate enhancements of 100-500-fold. The p value for hydronium ion catalyzed hydrolysis of substituted benzaldehyde cis-2-carboxycyclohexyl methyl acetal neutral species is -4.15, but in hydrolysis of the corresponding monoanions ρ is -0.95. Thus, the carboxyl group substituent is participating in the reaction but only to a significant extent when the carbonium ion intermediate is destabilized, thereby indicating electrostatic participation. Electrostatic stabilization effects become important only when there is a large amount of bond breaking in the transition state. The pH-rate constant profile for hydrolysis of benzaldehyde di(as-2-carboxycyclohexy[) acetal to benzaldehyde in 50% dioxane-H2O (v/v) shows hydronium ion catalysis at low pH, but in the pH range 3-7 the profile is bell shaped. The rate enhancement in comparison with the corresponding diethyl ester is 4 X 104. Intramolecular general acid catalysis must be occurring in this system even though the leaving group is an aliphatic alcohol. The requirement for the presence of a second cis-2-carboxycyclohexyl group before a large catalysis is observed indicates that the carbonium ion must be stabilized electrostatically before intramolecular general acid catalysis is possible when the leaving group is poor. The significance of these results for lysozyme catalysis is discussed. © 1979, American Chemical Society. All rights reserved.