Thermodynamic selectivity and kinetic control in the encapsulation of spiropyran derivatives by cucurbit[8]uril

Spiropyrans (SPs) are promising building blocks for stimuli-responsive delivery because of their sensitivity to pH, light, and heat. However, their intrinsic hydrophobicity and limited stability in aqueous media severely restrict practical use under physiological conditions. Here, to overcome this aqueous-compatibility bottleneck, we propose a host-guest-guided design and screening strategy that integrates thermodynamic binding analysis with kinetic assessment, followed by experimental validation, to identify effective supramolecular complexes for controlled loading/release in water. Using cucurbit[8]uril (CB[8]) and three spiropyran derivatives (SP1-3) with their merocyanine isomers (MC1-3) as a model system, we first quantify host-guest recognition from a thermodynamic perspective by density functional theory. We then resolve stimulus-coupled loading/release kinetics by explicit-solvent umbrella sampling, yielding potential of mean force profiles that reveal a pronounced size-dependent kinetic-gating mechanism: MC1-2 display an entry-retention behavior consistent with efficient loading and high kinetic retention, while the bulkier SP3/MC3 is sterically restricted and favors a shallow capping mode with limited encapsulation and faster escape. ¹H NMR and time-resolved UV-vis measurements further verify the strong host-guest interactions and the host-modulated isomerization kinetics, in close agreement with the differentiated confinement regimes predicted by simulation. Beyond CB[8], comparative simulations indicate that γ-cyclodextrin provides a more accommodating cavity environment for SP2. Overall, this work demonstrates a generalizable theory-to-experiment workflow that couples thermodynamic and kinetic criteria to rationally select host-guest pairs, offering a transferable framework for designing low-leakage, multi-stimuli-responsive supramolecular delivery and controlled-release platforms.