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Binding affinities of cucurbit[n]urils with cations
浏览: 发布日期:2019-11-08

Abstract

High binding constants of 19 inorganic cations with the cucurbit[n]uril homologues (CBnn = 5, 6, 7, 8) in water were determined and the far-reaching consequences and interferences of the high affinities (millimolar to micromolar) are discussed.

Graphical abstract: Binding affinities of cucurbit[n]urils with cations

 

The design of artificial receptors for inorganic cations has underpinned the development of supramolecular chemistry.1,2 Through advances in the understanding of non-covalent interactions,3 carefully designed supramolecular receptors for (earth) alkaline cations emerged in the 1980's such as Cram's spherands4,5displaying high selectivity for Li+. Conversely, Lehn's cryptands6,7 and the more recently introduced orthoester cryptands by von Delius8,9 can strongly and selectively bind (earth) alkali cations. In contrast to these designer hosts, other classes of macrocyclic receptors were originally tailored for organic guests but later also found to be interesting metal ion binders, for example, p-sulfonatocalix[4]arene (CX4). For supramolecular applications, this behavior is often undesirable because alkali ion binding competes for the binding of the target guests (e.g., choline) in biologically relevant, aqueous saline media.10,11 Likewise, cucurbit[n]uril (CBnFig. 1) macrocycles were long known to interact with (earth) alkaline cations, leading to an increase in their aqueous solubility but a decrease in their organic–guest binding affinities.12–17 CBn have found widespread use as solubility enhancers,18for materials applications,19,20 and for assay development,17,21 which often take place in buffered aqueous media.12,16,22,23 The influence of metal cation binding to CBn macrocycles is therefore a critical factor. However, while the interaction of CB6 with Ca2+ was inferred already a century ago,24 and while absolute affinity values for some ions such as Na+ have been reported,23,25–29 (see also Table S1 in the ESI) binding affinities for metal cations to CBn in water have not been systematically studied across the homologous series and associated structure-affinity relationships are unknown.

Fig. 1 (a) Chemical structures and their 3D representation (space filling model) of CBn and (b) of the metal cations investigated in this study, with sizes drawn to scale with respect to CBn; the portal diameters are 2.4 Å for CB5, 3.9 Å for CB6, 5.4 Å for CB7, and 6.9 Å for CB8.

We now provide a comprehensive data set for the complexation of 19 inorganic cations with CB5, CB6, CB7, and CB8 in water. The determination of cation–CBn binding is challenging because their interaction does not provide a diagnostic signal change in conventional NMR or UV-vis absorption spectra and phase-extraction protocols30are inapplicable for water-soluble hosts such as CX4 or CBn. As alternatives, fluorescence displacement titrations and isothermal titration calorimetry (ITC) experiments came to mind for the determination of macrocycle-cation binding constants (Ka).10,31,32 The experimental details are shown in the ESI and the aggregated log Ka values are shown in Table 1, along with the ionic radii and their hydration free energies in order to correlate with size fitting and desolvation effects. Additional reference data for classical cation–receptor macrocycles such as 18-crown-6,2,33,34p-sulfonatocalix[4]arene (CX4),10,32,35,36 and Cryptand [2.2.2]6,31,37,38 are also shown. Monovalent alkali metal ions, Ag+, NH4+, and H3O+, divalent earth alkaline ions, transition metal ions, and trivalent cations were investigated. It transpires from Table 1 and from the comparison to the data for the established hosts that CBn are highly competitive inorganic cation receptors, although they are much better known for their tight binding of organic guests. Correlations of the log Ka values with ionic cation radius are shown in Fig. 2; the interconnected lines for the alkali and alkaline earth ions reveal a general trend in favour of a stronger binding for the larger and less strongly hydrated metal ions; only for the smallest CB5 a bell-shaped curve for the alkaline metal ions is obtained, which points to an ideal size matching as an additional determinant (see Fig. 1 for size comparison). Within a homologous series, the most rigid macrocycle, CB5 in our series, is in general known to display a pronounced peak selectivity.6,31 Rb+ and Cs+ appear to be too large to penetrate into the carbonyl portal region of CB5, where the dipolar interaction with the oxygen lone pairs is most effective. Ag+ follows the trend for the alkaline metal ions, but NH4+ and H3O+ fall binding-wise below the correlation for (similarly sized) monovalent ions (Fig. 2), presumably because they engage as potent hydrogen bond donors in bulk water. This demonstrates that the formation of hydrogen bonds to the cucurbituril portals presents no significant driving force for organic guest complexation. Instead, the enhanced binding of organic guests upon introduction of cationic groups can be satisfactorily explained by ion–dipole interactions with the portals. Cationic centers that do not act as hydrogen-bond donors and that are less strongly hydrated, such as quaternary ammonium groups, present accordingly the better choice if optimized binding to CBn is desired.43 Hydrogen-bond proximity patterns, that are frequently observed in crystal structures of CBn,14,44,45 do not reflect on the driving force of host–guest binding in aqueous solution.