Dissecting the Effects of Cage Structure in the Catalytic Activation of Imide Chlorenium-Ion Donors

Imide-based chlorinating reagents are mild and easy to use yet can lack the reactivity of charged chlorenium-ion donors. Here, we present a simple strategy for increasing the reactivity of these neutral chlorinating species by encapsulation inside a cationic coordination cage. Using this approach, we demonstrate that two different-sized Pd₂L₄ cages can catalyze chlorolactonization and chlorocycloetherification reactions of acid and alcohol functionalized α and β-substituted styrene substrates with either 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) or N-chlorosuccinimide (NCS) as the chlorenium sources. A kinetic study shows that the cages are proficient catalysts with a significant acceleration up to 10⁵. However, an unexpected dichotomy is revealed wherein the smaller cage, which is best preorganized to bind and nominally provide maximum activation of the imide reagent, shows an order of magnitude less acceleration than the larger cage that has apparently mismatched host–guest chemistry. When the scope of reactions is further extended to the chlorination of simple, unfunctionalized α-methylstyrene, the same pattern of cage reactivity is observed, suggesting that differences are not explained by coencapsulation. Computational studies indicate that the trend in reactivity is caused by the transition state being less fixed in the larger cage, allowing it to find optimal binding and thereby generate stronger interactions. This investigation highlights the importance of understanding the underlying mechanisms of cage reactivity to design new noncovalent catalysts for a greater range of transformations.