Tailoring cascade hydrolysis and cyclization efficiency in confined spaces via spatial and electrostatic regulation

Intramolecular end-to-end reactions of long-chain linear precursors remain challenging due to their inherent tendency to undergo intermolecular reactions. Herein, we investigated the cascade hydrolysis and intramolecular cyclization reactions of three guests with varying lengths within the well-defined nanocavities of cavitands in aqueous solution. Driven by hydrophobic effect, these guests were encapsulated within the dimeric capsules, adopting distinct conformations and orientations due to spatial constraints. Specifically, the shorter guest maintained an extended linear geometry, whereas the longer guests adopted a folded binding mode. Upon initiating the reaction, the terminal residue of the shorter guest displayed lower reactivity, while the longer guests, preorganized within the cavity, underwent efficient cyclization, resulting in significant differences in reaction kinetics. Furthermore, electrostatic potential fields played a critical role in modulating reaction rates, with the positively charged cavitand accelerating the reaction more efficiently compared to its negatively charged counterpart, likely due to stabilization of the anionic transition state. This study provides an effective strategy for designing enzyme-mimetic nanoreactors through the utilization of well-defined nanospaces.