AbstractA single acyloxy group at C‐2 can control the outcome of nucleophilic substitution reactions of pyran‐derived acetals, but the extent of the neighboring‐group participation depends on a number of factors. We show here that neighboring‐group participation does not necessarily control the stereochemical outcome of acetal substitution reactions with weak nucleophiles. The 1,2‐trans selectivity increased with increasing reactivity of the incoming nucleophile. This trend suggests the intermediacy of both cis‐fused dioxolenium ions and oxocarbenium ions in the stereochemistry‐determining step. In addition, as the electron‐donating ability of the neighboring group decreased, the preference for the 1,2‐trans products increased. Computational studies show how the barriers for the ring‐opening reaction on the dioxolenium ions and the transition states to provide the oxocarbenium ions change with the electron‐donating capacity of the C‐2‐acyloxy group and the reactivity of the nucleophile.