In these systems, where the reactivity is observed to increase with the crowding inside the cage cavity, the a is also clearly related to the host-guest interaction (namely, to obtain a stable complexation, a strong host-guest affinity is necessary to compensate the crowding penalty associated to the binding). A similar trend can be observed also when looking at the weighted number of contacts between the host and the guest (Figure , evaluated from the distributions of Figure , i.e. a proxy for the host-guest interaction energy). If we consider the interaction between 2 and cage 1 to be consistent among all the investigated systems, we can trace the trend back to the interaction between guest and co-guest (or the absence thereof in the 2 ⇢ 1 case), with 3 showing a greater stabilizing effect for 2 cis within the cage cavity compared to another 2 co-guest. Noteworthy, as revealed by the obtained trends of Figures , such favorable affinity can stabilize the reactive conformer of amide 2 to a higher extent, which results in a remarkable increase in the reaction acceleration a.