Interplay between Slow Chirality Inversion and Slow Guest Uptake in a Triple-Helical Closed-Cage Metallocryptand

Intelligent responsive materials are important components for molecular machines and memory devices. However, the mechanism of guest-induced chirality inversion remains elusive because guest binding is typically too fast to resolve the process. To address this challenge, it is necessary to develop a system in which chirality inversion and guest uptake occur on comparable, slow time scales. Here, we report a triple-helical closed-cage cobalt(III) metallocryptand incorporating three bridging 1,7-heptanediamine (hpda) ligands, which creates a closed-cage architecture that significantly slows guest uptake/release. X-ray crystallography revealed the formation of a (P,R₆) diastereomer with a right-handed triple-helical structure. In solution, a dynamic equilibrium between the (P,R₆) and (M,R₆) diastereomers was observed with slow interconversion (t_1/2(app) = 20 min). Upon addition of CsCl, the P/M chirality was gradually inverted from a P-abundant state to an M-abundant state over several hours, associated with slow Cs⁺ uptake. The closed-cage design with bridging hpda ligands significantly slowed both Cs⁺ uptake and P/M interconversion, allowing the two processes to proceed on comparable, slow time scales. Kinetic analysis based on a four-species reversible model revealed that Cs⁺ is preferentially taken up in the less abundant M form, whereas P form does not directly bind Cs⁺ but instead contributes to uptake after P→M isomerization. The M form binds Cs⁺ more strongly than the P form, thus driving the P→M chirality inversion through this M-form-mediated pathway. In contrast, addition of Cl^- shifted the equilibrium toward the more P-favored mixture by interacting with Cl^- at the peripheral binding pocket, highlighting its opposite stereodynamic effect relative to Cs⁺. These findings demonstrate that cage closure modulates both the timing and sequence of events during the pathway of guest-induced chirality inversion, and provide a kinetic platform for probing guest effects on stereodynamic equilibria. We also anticipate that the strategies used here can be applied to the rational design of other smart molecular architectures.