As a fist and generally rate-limiting step, the amide hydrolysis reaction requires the nucleophilic attack of water (or of OH , if the reaction occurs as catalyzed in basic conditions) to the carbonyl carbon. While the cavity of cage 1 is markedly apolar, and the encapsulation of the guests in the cavity is essentially driven by hydrophobic effects, some accessibility by the solvent is therefore still required for the reaction to take place. We calculated the number of contacts between the solvent molecules and the carbonyl group of the 2 guest in the various case. In general, we can observe that the amide of 2 trans is slightly more accessible to the solvent compared to that of 2 cis when the guests are free in solution (dotted distributions), and a similar depletion is observed upon mono-guest confinement (dashed).