A Model for Sequential Threading of α-Cyclodextrin onto a Guest: A Complete Thermodynamic and Kinetic Study in Water

The first variable-temperature and variable-pressure stopped-flow spectrophotometric study of the sequential threading of α-cyclodextrin (α-CD) onto the guest dye Mordant Orange 10, S, is reported.Complementary ¹H one-dimensional (1D) variable-temperature kinetic studies and two-dimensional (2D) rotating-frame nuclear Overhauser effect spectroscopy (ROESY) and EXSY NMR studies are also reported.In aqueous solution at 298.2 K, the first α-CD threads onto S to form a 1:1 complex S•α-CD* with a forward rate constant k_1,f = 15 200 ± 200 M^-1 s^-1 and dethreads with a reverse rate constant k_1,f = 4.4 ± 0.3 s^-1.Subsequently, S•α-CD* isomerizes to S•α-CD (k_3,f = 0.158 ± 0.006 s^-1, k_3,f = 0.148 ± 0.006 s^-1).This process can be viewed as a thermodynamically controlled molecular shuttle. A second α-CD threads onto S•α-CD* to form a 1:2 complex, S•(α-CD)₂*, with k_2,f = 98 ± 2 M^-1 s^-1 and k_2,r = 0.032 ± 0.002 s^-1.A second α-CD also threads onto S•(α-CD) to form another 1:2 complex, S•(α-CD)₂, characterized by k_4,f = 9640 ± 1800 M^-1 s^-1 and k_4,r = 61 ± 6 s^-1.Direct interconvertion between S•(α-CD)₂* and S��(α-CD)₂ was not detected; instead, they interconvert by dethreading the second α-CD and through the isomerization equilibrium between S•α-CD* and S•α-CD.The reaction volumes, ΔV⁰, were found to be negative for the first three equilibria and positive for the fourth equilibrium. For the first three forward and reverse reactions, the volumes of activation are substantially more negative, indicating a compression of the transition state in comparison with the ground states.These data were used in conjunction with ΔH^‡, ΔH°, ΔS^‡, and ΔS° data to deduce the dominant mechanistic threading processes, which appear to be largely controlled by changes in hydration andvan der Waals interactions, and possibly by conformational changes in both S and α-CD.The structure of the four complexes were deduced from ^-1H 2D ROESY NMR studies.