The encapsulation of amide 2 within cage 1 was shown to enhance amide hydrolysis in considerable way in mildy basic conditions (experimental results of Figure have been obtained at [NaOH] = 100 mM 10 ). To obtain information on the effect of confinement on the hydrolysis reaction (slow-down, inhibition, acceleration, etc.), here we modeled the hydrolysis reaction when the amide is free in solution vs. when this is encapsulated the the cavity of cage 1. In moderate pH conditions (6 < pH < 13), and in the absence of other catalysts, the hydrolysis of amides occurs via hydroxide attack, forming a tetrahedral intermediate (TI), followed by a second step consisting in the C-N bond rupture. The first step of the reaction is typically considered the rate determining step of the process (although in some cases the subsequent bond rupture can contribute to, and also control, the rate of hydrolysis). For this reason, for the study of the hydrolysis of amide 2, here we focused our investigation only on the formation of the TI via nucleophilic attack by a solvated hydroxide (Figure ).