In the wide area of supramolecular chemistry, cucurbit[n]urils (CBn) present themselves as a young family of molecular containers, able to form stable complexes with various guests, including drug molecules, amino acids and peptides, saccharides, dyes, hydrocarbons, perfluorinated hydrocarbons, and even high molecular weight guests such as proteins (e.g., human insulin). Since the discovery of the first CBn, CB6, the field has seen tremendous growth with respect to the synthesis of new homologues and derivatives, the discovery of record binding affinities of guest molecules in their hydrophobic cavity, and associated applications ranging from sensing to drug delivery. In this review, we discuss in detail the fundamental properties of CBn homologues and their cyclic derivatives with a focus on their synthesis and their applications in catalysis.

Cucurbit[n]urils (CBn) bind guest molecules through a combination of electrostatic interactions with the carbonyl rims and hydrophobic interactions with the inner cavity. Investigations with solvatochromic probes in CB7 reveal that the polarity of the cavity resembles that of alcohols (e.g., n‐octanol), while its polarizability (P=0.12) and apparent refractive index (nD=1.10±0.12) are extremely low, close to the gas phase. The calculated molecular quadrupole moments of CBs are extremely large (Θzz=−120 to −340 Buckingham). A survey of reported binding constants of neutral guests and hydrophobic residues that form 1 : 1 inclusion complexes with CB6, reveals a preferential inclusion of C3–C5 residues in its cavity. The largest guests which show non‐negligible binding contain 7 heavy atoms (excluding hydrogen). For CB7, the strongest binding is observed for guests with adamantyl (10 heavy atoms) and ferrocenyl groups (11 heavy atoms), while the largest guests known to be complexed are carborane and the adduct of two pyridine derivatives (12 heavy atoms). The evaluation of different volumes shows that the most meaningful cavity, namely that responsible for binding of hydrophobic residues, is confined by the planes through the oxygen carbonyls. The volume of this inner cavity follows the formula V/Å3=68+62(n−5)+12.5(n−5)2, affording representative cavity volumes of 68 Å3 for CB5, 142 Å3 for CB6, 242 Å3 for CB7, and 367 Å3 for CB8. The volume of the 2 bond dipole regions is comparably smaller, amounting, for example, to 2×35 Å3 for CB6. The analysis of packing coefficients for representative sets of known guests with clearly defined hydrophobic binding motifs reveals average values of 47 % for CB5, 58 % for CB6, 52 % for CB7, and 53 % for CB8, which are well in line with the preferred packing (“55 % solution”, see S. Mecozzi, J. Rebek, Chem. Eur. J. 1998, 4, 1016–1022) in related supramolecular host–guest assemblies. The driving force for binding of hydrophobic guests and residues by CBs is interpreted in terms of the unimportance of dispersion interactions (owing to the low polarizability of their cavity) and the dominance of classical and nonclassical hydrophobic effects related to the removal of very‐high‐energy water molecules (2 for CB5, 4 for CB6, 8 for CB7, and 12 for CB8) from the cavity.

Following up on scattered reports on interactions of conventional chaotropic ions (for example, I−, SCN−, ClO4 −) with macrocyclic host molecules, biomolecules, and hydrophobic neutral surfaces in aqueous solution, the chaotropic effect has recently emerged as a generic driving force for supramolecular assembly, orthogonal to the hydrophobic effect. The chaotropic effect becomes most effective for very large ions that extend beyond the classical Hofmeister scale and that can be referred to as superchaotropic ions (for example, borate clusters and polyoxometalates). In this Minireview, we present a continuous scale of water–solute interactions that includes the solvation of kosmotropic, chaotropic, and hydrophobic solutes, as well as the creation of void space (cavitation). Recent examples for the association of chaotropic anions to hydrophobic synthetic and biological binding sites, lipid bilayers, and surfaces are discussed.

Dodecaborate anions of the type B12X122− and B12X11Y2− (X=H, Cl, Br, I and Y=OH, SH, NH3+, NR3+) form strong (Ka up to 106 L mol−1, for B12Br122−) inclusion complexes with γ-cyclodextrin (γ-CD). The micromolar affinities reached are the highest known for this native CD. The complexation exhibits highly negative enthalpies (up to −25 kcal mol−1) and entropies (TΔS up to −18.4 kcal mol−1, both for B12I122−), which position these guests at the bottom end of the well-known enthalpy-entropy correlation for CDs. The high driving force can be traced back to a chaotropic effect, according to which chaotropic anions have an intrinsic affinity to hydrophobic cavities in aqueous solution. In line with this argument, salting-in effects revealed dodecaborates as superchaotropic dianions.

The supramolecular chemistry of cucurbit[n]urils (CBn) has been rapidly developing to encompass diverse medicinal applications, including drug formulation and delivery, controlled drug release, and sensing for bioanalytical purposes. This is made possible by their unique recognition properties and very low cytotoxicity. In this review, we summarize the host-guest complexation of biologically important molecules with CBn, and highlight their implementation in medicinal chemistry and chemical biology.

Inner-phase chemical reactions of guest molecules encapsulated in a macromolecular cavity give fundamental insight into the relative stabilization of transition states by the surrounding walls of the host, thereby modelling the situation of substrates in enzymatic binding pockets. Although in solution several examples of inner-phase reactions are known, the use of cucurbiturils as macrocyclic hosts and bicyclic azoalkanes as guests has now enabled a systematic mass spectrometric investigation of inner-phase reactions in the gas phase, where typically the supply of thermal energy results in dissociation of the supramolecular host-guest assembly. The results reveal a sensitive interplay in which attractive and repulsive van der Waals interactions between the differently sized hosts and guests need to be balanced with a constrictive binding to allow thermally activated chemical reactions to compete with dissociation. The results are important for the understanding of supramolecular reactivity and have implications for catalysis.

Cucurbit[n]urils (CBn, n = 7, 8) serve as artificial receptors for steroids (21 tested), including the hormones testosterone and estradiol as well as steroidal drugs. Fluorescence displacement titrations and isothermal titration calorimetry (ITC) provided up to nanomolar binding affinities in aqueous solution for these hydrophobic target molecules, exceeding the values of known synthetic receptors. Remarkable binding selectivities, even for homologous steroid pairs, were investigated in detail by NMR, X-ray crystal diffraction, ITC, and quantum chemical calculations. Notably, the CBn•steroid complexes are stable in water and buffers, in artificial gastric acid, and even in blood serum. Numerous applications have been demonstrated, which range from the solubility enhancement of the steroids in the presence of the macrocycles (up to 100 times, for drug delivery) and the principal component analysis of the fluorescence responses of different CBn•reporter dye combinations (for differential sensing of steroids) to the real-time monitoring of chemical conversions of steroids as substrates (for enzyme assays).

The host-guest complexation of hydrocarbons (22 guest molecules) with cucurbit[7]uril (CB7) was investigated in aqueous solution. Association constants were determined by using the indicator displacement strategy, which allows binding constant determinations also for poorly water-soluble (hydrophobic) guests. The binding constants (103–109 M−1) increased with the size of the hydrocarbon, pointing to the hydrophobic effect and dispersion interactions as driving forces. Besides potential applications for the sensing and separation of hydrocarbons, the measured affinities provide unique benchmark data for the binding of neutral guest molecules. Consequently, a computational blind challenge, the HYDROPHOBE challenge, was conducted in order to allow a comparison with state-of-the-art computational methods for predicting host-guest affinity constants. In total, 5 computational data sets were submitted, which allowed the comparison of experimental binding constants with those predicted by coupled-cluster theory (DLPNO-CCSD(T)), dispersion-corrected density functional theory (DFT), and explicit solvent molecular dynamics (MD) simulations parameterized with two different force field combinations from the AMBER simulation package. All submissions were capable of predicting the general binding trend, with a slightly better correlation for the MD compared to the quantum-chemical (QM) data sets (R2MD = 0.80 vs R2QM = 0.66, average values for the submitted data sets). On the other hand, QM calculations showed better predictions for the absolute values of the binding affinities as reflected by the mean signed errors (4.3 kcal mol−1 for MD vs 1.8 kcal mol−1 for QM). When searching for sources of uncertainty in predicting the host-guest affinities, the experimentally known hydration energies of the investigated hydrocarbons could be employed, which provided a distinct advantage of the HYDROPHOBE challenge. The comparison with the employed solvation models (explicit solvent for MD and COSMO-RS for QM) confirmed a good correlation for both methods, but revealed a rather constant offset of the COSMO data, by ca. +2 kcal mol−1, which was traced back to a required reference-state correction in the QM submissions (2.38 kcal mol−1). Introduction of the reference-state correction improved the predictive power of the QM methods, particularly for small hydrocarbons up to C5. The correlations of both QM and MD submissions also exposed specific outliers, which could be due to peculiarities of the investigated guests, for example, different degrees of conformational changes upon complexation, such as helical structures of the longer n-alkyl chains within the cavity. The latter was confirmed by 2D NMR experiments and both the MD as well as QM calculations.