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.