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Cucurbituril-Based Molecular Recognition.

This review highlights the past six year advances in the blossoming field of cucurbit[n]uril chemistry. Because of their exceptional recognition properties in aqueous medium, these pumpkin-shaped macrocycles have been generating some tremendous interest in the supramolecular community. They have also become key units in various self-organizing and stimulus-controlled assemblies, as well as in advanced materials and drug carriers. The scope of this review is limited to the main family of cucurbit[n]urils (n = 5, 6, 7, 8, 10). The reader will find an overview of their preparation, their physicochemical and biological properties, as well as their recognition abilities towards various organic and inorganic guests. Detailed thermodynamic and kinetic considerations, as well as multiple applications including supramolecular catalysis are also discussed.

Cucurbituril chemistry: a tale of supramolecular success

In this paper we review cucurbit[n]urils (CB[n]), a relatively new family of macrocycles that has shown potential in improving drug delivery. Encapsulation of drugs within the homologues CB[6], CB[7], or CB[8] can impart enhanced chemical and physical stability, improve drug solubility, and control drug release. The formulation of CB[n] into a dosage form suitable for clinical use is a non-trivial task, because the free macrocycle and its host-drug complex generally exhibit pseudo-polymorphism in the solid state. Despite this, cucurbiturils have been included in tablets for oral delivery and inserts for nasal delivery. Here we examine the potential use of cucurbiturils in drug delivery in the context of getting a new drug into clinical trials and discuss what further research is needed in this area.

The potential of cucurbit[n]urils in drug delivery

Structural determination of crystalline powders, especially those of complex materials, is not a trivial task. For non-stoichiometric guest−host materials, the difficulty lies in how to determine dynamical disorder and partial cage occupancies of the guest molecules without other supporting information or constraints. Here, we show how direct space methods combined with Rietveld analysis can be applied to a class of host−guest materials, in this case the clathrate hydrates. We report crystal structures in the three important hydrate crystal classes, sI, sII, and sH, for the guests CO2, C2H6, C3H8, and methylcyclohexane + CH4. The results obtained for powder samples are found to be in good agreement with the experimental data from single crystal X-ray diffraction and 13C solid-state NMR spectroscopy. This method is also used to determine the guest disorder and cage occupancies of neohexane and tert-butyl methyl ether binary hydrates with CH4 in the structure H clathrate hydrates. The results are found to b...

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Direct space methods for powder X-ray diffraction for guest-host materials: applications to cage occupancies and guest distributions in clathrate hydrates.

Cucurbit[n]urils (CB[n], n = 5–8) have been prepared, separated, and purified, and the structure of their solid state assemblies has been addressed. A number of general features were identified which are of interest to understand some peculiar properties of cucurbiturils (solubility, aggregation, assembly, transformation to porous crystals, influence of air humidity). CB[5], CB[6], and CB[8] were isolated as hydrate crystals whose structures were found to show a strong tendency of the macrocycles to interpenetrate. A self-closing effect was rationalized in terms of multiple weak CH···O interactions between the macrocycles, the degree of which is discussed in detail. Solid state cross polarization magic angle spinning (CP-MAS) 13C NMR spectra obtained at 900 MHz were correlated with the crystal structures. An odd–even effect in the crystallinity of thermally treated CB samples (CB[5] and CB[7] amorphous, CB[6] and CB[8] crystalline) was observed, which is reflected in differences in water solubility (CB[5]...

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Cucurbit[n]urils (n = 5–8): A Comprehensive Solid State Study

Nitroxide free radicals are demonstrated to be useful guests for probing cucurbit[n]uril (CB[n]) assemblies in water by EPR spectroscopy. CB[7] and CB[8] significantly aggregate either in solution or in the solid state (as evidenced by a single-crystal X-ray structure in which CB[8] forms supramolecular triangles with 4-methoxy-TEMPO). The included nitroxides show a striking resistance to biologically relevant reduction, benefiting from the carcerand effect of CB[7] and CB[8] solutions.

Probing cucurbituril assemblies in water with TEMPO-like nitroxides: a trinitroxide supraradical with spin-spin interactions.

Coumarin was found to form stable inclusion complexes with cucurbiturils. In the presence of cucurbit[7]uril (CB[7]), 1 : 1 inclusion complexes were observed in aqueous solution, as monitored by 1H NMR and UV-visible absorption spectroscopies, and further supported by ab initio calculations, whereas with cucurbit[8]uril (CB[8]) a solid phase 1 : 2 host : guest complex was found in a single crystal X-ray diffraction structure determination.

Mélanie Waite

Papers

Probing cucurbituril assemblies in water with TEMPO-like nitroxides: a trinitroxide supraradical with spin-spin interactions.

Inclusion complexes of coumarin in cucurbiturils.