The molecular host cucurbit[7]uril forms an extremely stable inclusion complex with the dicationic ferrocene derivative bis(trimethylammoniomethyl)ferrocene in aqueous solution. The equilibrium association constant for this host-guest pair is 3 × 10 ¹⁵ M ⁻¹ ( K _d = 3 × 10 ⁻¹⁶ M), equivalent to that exhibited by the avidin–biotin pair. Although purely synthetic systems with larger association constants have been reported, the present one is unique because it does not rely on polyvalency. Instead, it achieves its extreme affinity by overcoming the compensatory enthalpy–entropy relationship usually observed in supramolecular complexes. Its disproportionately low entropic cost is traced to extensive host desolvation and to the rigidity of both the host and the guest.

This Account focuses on stimuli responsive systems that function in aqueous solution using examples drawn from the work of the Isaacs group using cucurbit[n]uril (CB[n]) molecular containers as key recognition elements. Our entry into the area of stimuli responsive systems began with the preparation of glycoluril derived molecular clips that efficiently distinguish between self and nonself by H-bonds and π–π interactions even within complex mixtures and therefore undergo self-sorting. We concluded that the selectivity of a wide variety of H-bonded supramolecular assemblies was higher than previously appreciated and that self-sorting is not exceptional behavior. This lead us to examine self-sorting within the context of CB[n] host–guest chemistry in water. We discovered that CB[n] homologues (CB[7] and CB[8]) display remarkably high binding affinity (K_a up to 10¹⁷ M^–1) and selectivity (ΔΔG) toward their guests, which renders CB[n]s prime components for the construction of stimuli responsive host–guest systems. The CB[7]·adamantaneammonium ion complex, which is particularly privileged (K_a = 4.2 × 10¹² M^–1), was introduced by us as a stimulus to trigger constitutional changes in multicomponent self-sorting systems. For example, we describe how the free energy associated with the formation of host–guest complexes of CB[n]-type receptors can drive conformational changes of included guests like triazene–arylene foldamers and cationic calix[4]arenes, as well as induced conformational changes (e.g., ammonium guest size dependent homotropic allostery, metal ion triggered folding, and heterochiral dimerization) of the hosts themselves. Many guests display large pK_a shifts within their CB[n]–guest complexes, which we used to promote pH controlled guest swapping and thermal trans-to-cis isomerization of azobenzene derivatives. We also used the high affinity and selectivity of CB[7] toward its guests to outcompete an enzyme (bovine carbonic anhydrase) for a two-faced inhibitor, which allowed stimuli responsive regulation of enzymatic activity. These results prompted us to examine the use of CB[n]-type receptors in both in vitro and in vivo biological systems. We demonstrated that adamantaneammonium ion can be used to intracellularly sequester CB[7] from gold nanoparticles passivated with hexanediammonium ion·CB[7] complexes and thereby trigger cytotoxicity. CB[7] derivatives bearing a biotin targeting group enhance the cytotoxicity of encapsulated oxaliplatin toward L1210FR cells. Finally, acyclic CB[n]-type receptors function as solubilizing excipients for insoluble drugs for drug delivery purposes and as a broad spectrum reversal agent for the neuromuscular blocking agents rocuronium, vecuronium, and cis-atracurium in rats. The work highlights the great potential for integration of CB[n]-type receptors with biological systems.