The cover picture shows in the center an electron‐density map of the molecular container compound cucurbit[7]uril. The polarizability inside the cavity of this host can be explored through solvatochromic effects on the absorption spectra (bottom right) when probed by the inclusion of an azo chromophore guest (top left). This novel method allows insight into the inner phase of supermolecules. More details about this process is described by Marquiz and Nau on pp. 4387 ff.

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.

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.

Rhodamines are arguably the most important fluorescent dyes as shown by their classical and contemporary applications, [1][2][3][4][5][6][7][8] for example, in dye lasers, as quantum counters, as photosensitizers, for spectral calibration in fluorometers, in single-molecule detection, as imaging agents for biomolecules, for scanning confocal microscopy, in fluorescence correlation spectroscopy (FCS), and in high-throughput screening assays. The various applications are made possible through the combination of their water solubility, close-tounity quantum yields, high extinction coefficients, and very high photostability. Rhodamine 6G (Rh6G) is the most prominent derivative and has become a prototype for many reasons, [3,4] including its photostability: the first continuouswave dye laser, for example, was based on an aqueous solution of Rh6G containing 1.5 % triton X as surfactant.[9]

Faster in cyclohexane than in acetonitrile is the fluorescence quenching of the azoalkane 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) by amines and sulfides. Although this photoreaction is induced by charge transfer (CT; see picture) and exciplexes are formed, the increase in the dipole moment of the exciplex is not large enough to offset the solvent stabilization of the excited reactants, and an "inverted" solvent effect results.

20 times more rapid is the complexation of the organic ammonium ion receptor cucurbit[6]uril (CB6) with cyclohexylmethylamine than with the cyclohexylmethylammonium species (see scheme). Within the narrow pH region around the pKa value of the amine, the complexation kinetics are accelerated but the binding constant remains essentially unaffected. In this region, the ammonium complex is formed through binding of the amine form followed by fast protonation and not through direct complexation of the ammonium form. Molecular dynamics calculations suggest that the amine form undergoes a direct inclusion into CB6 while the ingression of the ammonium form is retarded by the formation of an association complex, which reacts through a different, higher lying transition state to the inclusion complex.

There is rapidly developing interest in the potential of macrocyclic host molecules to modify the effective pK a values of included guests. Following early reports of small pK a shifts of included guests in cyclodextrins (DpK a % 1) [1,2] and cucurbit[6]uril [3] (DpK a % 1), we have used cucurbit [7]uril (CB7, DpK a % 2-3) [4,5] and sulfonatocalixarenes (DpK a % 2) as additional hosts and proposed structure-reactivity relationships.