Cucurbit[10]uril

Abstract

Melamine diamine 1 is able to displace CB[5] from the CB[10]•CB[5] complex resulting in CB[10]•1₂ and precipitated CB[5]•1. We were able to isolate free CB[10] by treatment of CB[10]•1 with acetic anhydride followed by washing with MeOH, DMSO, and water. The spacious cavity of CB[10] is able to complex large guests including a cationic calix[4]arene derivative in its 1,3-alternate form (CB[10]•1,3-alt-3). The addition of adamantane carboxylic acid (4) to CB[10]•3 triggers a conformational change during the formation of termolecular complex CB[10]•cone-3•4.

In 1981, Mock disclosed the structure of cucurbit[6]uril (CB[6]) and subsequently delineated its outstanding binding properties toward ammonium ions in a series of elegant papers.¹ Nearly 20 years later, the groups of Kim and Day reported the preparation and isolation of the CB[n] homologues CB[5], CB[7], CB[8] and CB[10] as its CB[10]•CB[5] inclusion complex.² With their enhanced cavity size, the new members of the CB[n] family³ display a range of novel properties and applications including gas encapsulation, polarizability enhancement, and supramolecular dendrimer chemistry.⁴ Most notable, however, is the ability of CB[8] to simultaneously bind two aromatic guests which function as molecular machines in response to external stimuli.^3b,5 In this paper we report the isolation of free CB[10] and disclose its unusual recognition properties. These results suggest that CB[10] will rival CB[8] for use as an advanced component for molecular machines and biomimetic systems.^3,6

We isolated CB[10]•CB[5] in good quantities using a modification of the procedure reported by Day.^2b,2c After much experimentation we discovered that treating a solution of CB[10]•CB[5] (Figure 1a) with a five equivalents of 1 results in the precipitation of the (CB[5]•1)_n exclusion complex and the formation of the CB[10]•1₂ inclusion complex (Figure 1b). ¹H NMR and x-ray crystallography indicates that 1 adopts a U-shape⁶ within the cavity of CB[10] (Figure 2); the two equivalents of 1 are arranged in a head-to-tail manner which results in a single set of resonances for H_b and H_c within CB[10]•1₂. The second equivalent of 1 is relatively weakly bound to CB[10] and can be removed by washing with MeOH to yield CB[10]•1 (Figure 1c). Once again, 1 adopts a U-shape within the CB[10]•1 complex; in this instance the top and bottom of CB[10] are differentiated and two sets of resonances are observed for H_b and H_c. Free CB[10] was obtained by heating CB[10]•1 in Ac₂O followed by washing with (CH₃)₂SO, MeOH, and H₂O (Figure 1d). CB[10] is quite stable in acidic solution (>1 month in 20% D₂O/DCl at room temperature) which enabled our investigations of its molecular recognition properties.

Figure 1.

¹H NMR spectra (400 MHz, D₂O, 298 K) for: a) CB[10]•CB[5], b) CB[10]•1₂, c) CB[10]•1, d) CB[10] (20% D₂O/DCl).

Figure 2.

Cross-eyed stereoview of the structure of CB[10]•1₂ in the crystal. Solvating water has been removed for clarity.

CB[10] is insoluble in D₂O (< 50 µM) but its inclusion complexes often are nicely soluble which allows their characterization by NMR. Alternatively, CB[10] can be dissolved in 20% DCl / D₂O for binding studies. An initial screen of many guests revealed that CB[10] – with its cavity volume of ≈ 870 ų – undergoes complexation with several chemically and biologically important substances (e.g. dyes, fluorophores, pharmaceuticals, and peptides) although some of these complexes occur as insoluble precipitates (Supporting Information). A soluble, kinetically stable complex was obtained with the more sizable and cationic guest (R)-2 which gave exclusively the termolecular complex CB[10]•(R)-2₂. Interestingly, when racemic (±)-2 was used, the racemic mixture of homochiral complexes (CB[10]•(R)-2₂ and CB[10]•(S)-2₂) was preferred relative to the heterochiral meso- complex (CB[10]•(R)-2•(S)-2) by a factor of three (Supporting Information). In combination, these results suggest that CB[10] may find application in drug delivery, for peptide sensing, and even to modulate the behavior of catalysts based on binaphthalene derived ligands.

Given the vast size of the CB[10] cavity we envisioned the encapsulation of smaller host molecules like cyclodextrins, calixarenes, or even CB[6] that would merge the advantageous features of these host families. In the event, only cationic calix[4]arene derivative 3 formed a soluble stable complex (CB[10]•3 Figure 3a). Based on the number and multiplicity of resonances observed for CB[10]•3, we conclude that 3 adopts a mixture of the D_2d-symmetric 1,3-alternate conformation and a rapidly equilibrating mixture of cone, 1,2-alternate and partial cone conformers within the CB[10] host. Intrigued by the possibility of using allosteric effects to control the conformation of the macromolecular complex⁷ we studied the binding of small molecule guests to CB[10]•3. We found that substituted adamantanes (4 – 8) – which do not bind to 3 alone – induce a dramatic change in the conformer distribution during the formation of CB[10]•cone-3•adamantane complexes (Figure 3b).⁸ Scheme 1 shows an MMFF minimized model of the CB[10]•cone-3•4 complex.⁹ One of the hallmarks of biological allostery is the reversible response of the system to activator concentration. For this purpose we added stoichiometric amounts of CB[7] which sequesters 4 as its CB[7]•4 complex^3b,6d and resets the system to its original CB[10]•3 state (Figure 3c).

Figure 3.

¹H NMR spectra recorded (400 MHz, D₂O / DCl, RT) for: a) CB[10]•3 (1,3-alt and dynamic equilibrium beween cone, 1,2-alt and partial cone), b) CB[10]•cone-3•4 with excess 4 (0.8 equiv.), and c) CB[10]•3 and CB[7]•4. Subscripts: 1,3 = 1,3-alt-3; dyn = dynamic equilibrium of 3.

Scheme 1.

Allosteric control of the conformations of CB[10]•3 (MMFF minimized) with 4 (purple) and CB[7].

Just like the smaller CB[n] homologs, CB[10] retains the ability to bind a variety of chemically and biologically important cationic substances within its cavity. We have further demonstrated that CB[10] readily forms termolecular complexes (e.g. CB[10]•2₂ and CB[10]•cone-3•4); the vast cavity volume of CB[10] (≈ 870 ų) suggests the potential formation of even higher molecularity complexes. The termolecular complexes already display a range of intriguing behavior including chiral recognition and efficient allosteric control of macromolecular geometry in response to a small molecule (e.g. 4). Overall, these results suggest that CB[10] will find broad application as an advanced component of molecular machines and biomimetic systems.

Supplementary Material

1si20050923_03. Supporting Information Available.

Synthetic procedures, characterization data for CB[10], and selected ¹H NMR spectra for CB[10]•guest complexes (.pdf), and details of the x-ray structure of CB[10]•1₂ (.cif). This material is available free of charge via the internet at http://pubs.acs.org.