Ultrafast Two-Dimensional Infrared Spectroscopy and Molecular Dynamics Simulations Reveal Slow Water Dynamics in...

Despite the central role of cyclodextrins in supramolecular chemistry and biomedical formulations, their internal hydration dynamics have remained inaccessible to ultrafast vibrational spectroscopy due to the absence of a suitable vibrational reporter. Here, we present the first application of two-dimensional infrared (2DIR) spectroscopy to probe water dynamics inside a cyclodextrin cavity under thermal equilibrium. By employing azidoadamantane (AdN₃)─an intelligently designed vibrational reporter that combines strong binding affinity for a cyclodextrin cavity with a spectrally isolated azide stretch─we investigate the host-guest complex of AdN₃ and sulfobutylether-β-cyclodextrin (SBE-β-CD). The 2DIR spectra reveal minimal spectral diffusion, strong vibrational frequency correlation, and extended water residence times, indicative of a rigid, nanoconfined hydration environment. Frequency-frequency correlation function (FFCF) analysis and complementary molecular dynamics simulations show that restricted translational mobility governs these slow dynamics. This combined experimental-computational approach underscores the unique hydration dynamics within cyclodextrin cavities and highlights the potential of 2DIR spectroscopy for probing ultrafast hydration in nanoscale cavities and provides critical mechanistic insights with broad implications for drug delivery, molecular recognition, and confined water systems. Unlike previous reports attributing interfacial water slowdown to polar or ionic binding, we identify steric confinement by a host cavity as a distinct cause of retarded water dynamics.