In contrast to observations with carbohydrates, experiments with 4-alkoxy-substituted acetals indicate that an alkoxy group can accelerate acetal hydrolysis by up to 20-fold compared to substrates without an alkoxy group. The acceleration of ionization in more flexible acetals can be up to 200-fold when compensated for inductive effects.

The hydrolysis of 4-alkoxy-substituted acetals was accelerated by about 20-fold compared to that of sterically comparable substrates that do not have an alkoxy group. Rate accelerations are largest when the two functional groups are linked by a flexible cyclic tether. When controlled for the inductive destabilization, an alkoxy group can accelerate acetal hydrolysis by up to 200-fold. The difference in rates of acetal hydrolysis between a substrate where the alkoxy group was tethered to the acetal group by a five-membered ring compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly 10(6)-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom.

Nucleophilic substitution reactions of acetals with benzyloxy groups four carbon atoms away can be highly diastereoselective. The selectivity in several cases increased as the reactivity of the nucleophile increased, in violation of the reactivity-selectivity principle. The increase in selectivity with reactivity suggests that multiple conformational isomers of reactive intermediates can give rise to the products.

In contrast to observations with carbohydrates, experiments with 4‐alkoxy‐substituted acetals indicate that an alkoxy group can accelerate acetal hydrolysis by up to 20‐fold compared to substrates without an alkoxy group. The acceleration of ionization in more flexible acetals can be up to 200‐fold when compensated for inductive effects.

Nucleophilic substitution reactions of acetals having benzyloxy groups four carbon atoms away can be highly diastereoselective.T he selectivity in several cases increased as the reactivity of the nucleophile increased, in violation of the reactivity/selectivity principle.T he increase in selectivity with reactivity suggests that multiple conformational isomers of reactive intermediates can give rise to the products.