Mechanistic Study on the Mechanism and Origins of Reactivity for the Metal–Organic Cage-Catalyzed Knoevenagel Condensation under Neutral Conditions in Water

Understanding how supramolecular confinement enhances carbon-carbon bond formation under neutral aqueous conditions remains a central challenge in cage-based catalysis. Herein, we present a density functional theory (DFT) study of the Knoevenagel condensation between naphthaldehyde and Meldrum's acid in bulk water and within a Pd₆L₄-based supramolecular cage, using an ONIOM (QM/SE) approach to achieve an efficient yet reliable description of this large catalytic system. Our calculations identify a feasible neutral, water-assisted reaction pathway in which Meldrum's acid reacts through its enol form, without requiring prior full deprotonation. In both solution and confined environments, the reaction involves water-assisted proton transfer, carbon-carbon bond formation, and subsequent dehydration, with dehydration identified as the rate-determining step. Comparison of the free-energy profiles reveals that confinement within the Pd-based cage uniformly lowers the activation barriers of the key transition states relative to bulk solution. Indeed, substantial stabilization is found for the dehydration transition state inside the cage, leading to a significant reduction of the overall rate-determining barrier. These findings show that the enhanced reactivity under confinement arises from transition-state stabilization rather than a change in the fundamental neutral reaction mechanism.