The reactivity of p-difluorobenzene/methanol cluster ions has been investigated by using triple quadrupole mass spectrometry and DFT calculations. The present study was performed in light of a recent investigation of p-difluorobenzene/methanol (P = F-C6H4-F and M = CH3OH) heterocluster ions where the solvent-catalyzed formation of p-fluoroanisole (A = CH3O-C6H4-F) was observed in P(M)(2)(+) clusters and not in PM+ clusters. The results of our mass selected cluster ion study and theoretical calculations confirm that a single extra molecule of methanol can lower the reaction activation energy barrier in agreement with previous work for smaller clusters (PM+ and P(M)(2)(+)). However, we also observe that P(M)(3)(+) and P(M)(4)(+) clusters undergo evaporative loss of neutral methanol to establish the P(M)(2)(+) cluster before reacting. P(M)(n>4)+ clusters are capable of reacting through multiple pathways, in some cases generating a 1,4-dimethoxybenzene (B = CH3O-C6H4-OCH3) product via two separate substitution reactions within the same cluster ion. DFT calculations were employed to model the structures of the parent cluster ions, and transition state calculations were used to evaluate the activation energy for the p-fluoroanisole-forming substitution reaction. The calculations suggest that the reaction proceeds through a transition state containing a six-member hydrogen-bonded ring involving a reacting methanol and a second methanol that significantly lowers the activation energy.