Revisiting the Origins of Reactivity and Selectivity in the Pd₆L₄-Cage-Catalyzed Diels–Alder Reactions: A Combined Computational and Experimental Study

Supramolecular metal-organic cages (MOCs) have gained attention as versatile catalytic platforms due to their self-assembled architectures and well-defined cavities, which mimic enzyme active sites and enable spatial confinement. This confinement modulates the reaction pathways and enhances the catalytic performance. Recent studies highlight their catalytic potential in various organic transformations, but the factors governing the MOC-catalyzed reactions remain incompletely understood. This work builds on prior computational studies of Diels-Alder reactions catalyzed by palladium-based MOCs, showing that the common view of transition-state stabilization via π-π interactions is not valid. Instead, we find that π-π interactions between the substrate and the ligands destabilize the transition state. Additionally, theoretical studies of regioselectivity, validated experimentally, suggest that substrate encapsulation efficiency is key to determining reaction selectivity. These findings provide new insights into the mechanisms of MOC-catalyzed reactions.