The release of two organic guests from cucurbit[7]uril (CB7) was selectively monitored by the stopped‐flow method in aqueous solutions of inorganic salts to reveal the mechanistic picture in detail. Two contrasting mechanisms were identified: The symmetric dicationic 2,7‐dimethyldiazapyrenium shows a cation‐independent complex dissociation mechanism coupled to deceleration of the ingression in the presence of alkali and alkaline earth cations (Mⁿ⁺) due to competitive formation of CB7–Mⁿ⁺ complexes. A much richer, unprecedented kinetic behaviour was observed for the ingression and egression of the monocationic and non‐symmetric berberine (B⁺). The formation of ternary complex B⁺–CB7–Mⁿ⁺ was unambiguously revealed. A difference of more than two orders of magnitude was found in the equilibrium constants of Mⁿ⁺ binding to B⁺–CB7 inclusion complex. Large cations, such as K⁺ and Ba²⁺, also promoted B⁺ expulsion from the ternary complex in a bimolecular process. This study reveals a previously hidden mechanistic picture and motivates systematic kinetic investigations of other host–guest systems.

The inclusion of protonated (−)-tetrahydropalmatine (THP⁺) and dehydrocorydaline (DHC⁺), natural alkaloids, in the cavity of cucurbit[7]uril was monitored in real time by a spectrofluorimetric method in water at various temperatures. Both guests produced 1 : 1 complexes in enthalpy controlled processes without any detectable intermediates. The tight entrance of CB7 imposed substantial steric hindrance for encapsulation making the entry into the host several orders of magnitude slower than diffusion. Despite the ∼6 kJ mol⁻¹ lower activation enthalpy, the rate constant of THP⁺ ingression into CB7 was about 44-fold smaller at 298 K than that of DHC⁺ as a consequence of the considerably negative activation entropy of the former binding. The egression rates of the two studied alkaloids differed to a much lesser extent because the lower energy barrier of THP⁺ release was almost compensated by the unfavourable activation entropy. In comparison with the kinetics of the reversible confinement of the palmatine parent compound, the presence of the methyl substituent on the aromatic heterocyclic ring in DHC⁺ barely modified the rate constant of entry into CB7 but caused about 10-fold increase in the dissociation rate at 298 K.

The understanding of the relationship between molecular structure and the thermodynamics of host-guest binding is essential for the rational design of the applications of inclusion complexes. To obtain insight into the factors governing the driving force of complex formation in aqueous solutions, the encapsulation of five pharmaceutically important protoberberine alkaloids was studied in sulfobutylether-β-cyclodextrin having on average 6.4 degrees of substitution (SBE_6.4βCD). Spectrophotometric, fluorescence spectroscopic, and isothermal calorimetric measurements showed 1:1 complexation in dilute solutions. From 1.92 × 10⁴ M⁻¹, about an eight-fold decrease of the association constant was observed in the series of berberine ≈ coptisine >> palmatine > epiberberine > dehydrocorydaline. The embedment of these alkaloids in the SBE_6.4βCD cavity was entropy-controlled with mildly negative enthalpy contributions. These findings suggest that the stabilization of the examined complexes arises primarily from the hydrophobic interaction between the constituents. The more than three orders of magnitude smaller association constants of protoberberine alkaloids with SBE_6.4βCD than with cucurbit[7]uril, a host having similar cavity size, originates from the much smaller exothermicity of the confinement in the former macrocycle.

Due to the great potential of biocompatible cucurbit[7]uril (CB7) and 4-sulfonatocalix[4]arene (SCX4) macrocycles in drug delivery, the confinement of the pharmaceutically important metronidazole as an ionizable model drug has been systematically studied in these cavitands. Absorption and fluorescence spectroscopic measurements gave 1.9 × 10⁵ M⁻¹ and 1.0 × 10⁴ M⁻¹ as the association constants of the protonated metronidazole inclusion in CB7 and SCX4, whereas the unprotonated guests had values more than one order of magnitude lower, respectively. The preferential binding of the protonated metronidazole resulted in 1.91 pH unit pK_a diminution upon encapsulation in CB7, but the complexation with SCX4 led to a pK_a decrease of only 0.82 pH unit. The produced protonated metronidazole–SCX4 complex induced nanoparticle formation with protonated chitosan by supramolecular crosslinking of the polysaccharide chains. The properties of the aqueous nanoparticle solutions and the micron-sized solid composite produced therefrom by nano spray drying were unraveled. The results of the present work may find application in the rational design of tailor-made self-assembled drug carrier systems.

Competitive binding of an indicator dye and an optically silent guest was exploited to develop a powerful method for the accurate determination of the kinetic and thermodynamic parameters of host–guest complex formation.