We conducted a first explorative WT-MetaD simulation, where the amide was biased to exchange in/out the cage cavity. Qualitatively, similar to what seen also in other hostguest and dynamic supramolecular systems, this simulation showed that the exchange of a guest from the cage cavity into the solvent is most likely a 2-steps process, where (i) the encapsulated guest is first expelled out of the cage cavity and it remains absorbed onto the cage surface (Figure ,b: in-to-out cavity transition), and then (ii), from such absorbed state, it jumps in solution. The same holds for the back (encapsulation) process, but in opposite direction. As explained in the main text, for the purposes of this specific work, the exchange step (i) is the key one. In fact, this transition relates the state where 2 is encapsulated within the cage cavity vs. the closest state in free-energy where 2 is out of the cavity of 1 -i.e., the most likely transition (accompanied by the lowest exchange barrier) having consequences in terms of stabilization of the reactive 2 cis conformers seen in Figure of the main paper). Indeed, as the crowding has a direct effect on the guest favored conformers and on their related reactivity, being out of the cage and adsorbed on the surface or in solution has negligible effects in terms of crowding for amide.