Ab initio quantum mechanical gas phase (MP2/6-31 + G*//HF/6-31G*), continuum solvation model (IPCM-HF/6-31G*), and molecular dynamical potential of mean force calculations were used to study the intermolecular anhydride formation reaction between acetate and acetate phenyl ester (1), and the corresponding intramolecular reaction of glutarate (2), succinate (3)1 and 3,6-endoxo-Delta(4)-tetrahydrophthalate monoester (4); Energies were calculated for the two sequential:steps of the reaction: (1) the formation of a reactive bimolecular ion-molecule complex from the separated reactants (1) or intramolecular ion-molecule complex from a pool of extended conformations (2-4) and (2) the formation of transition state from the ion-molecule complex. The calculated reaction activation energies in aqueous solution correlated very well with the experimental values. The differences in the gas-phase energies, solvation energies, and the-free energy cost to bring the separated reactants together in a bimolecular ion-molecule complex (for intermolecular reaction) were all found to be important in explaining the reactivity differences of the molecules studied. In addition, both steps contributed to the reactivity differences.