Recognition of Guests by Water-Stabilized Cavitand Hosts

Resorcinarenes are versatile modules for modern studies of molecular recognition.1 The monomeric resorcinarene (e.g., 1, Figure 1) and its simple derivatives show recognition properties, but their shallow curvatures cannot provide sufficient surface contacts for selecting between targets. Nonetheless, they bind ammonium ions, choline, acetylcholine, and carnitine in protic solvents.2 Ideally, a synthetic receptor should provide a congruent surface and chemical complementarity to the target molecule: a large fraction of the target should be surrounded, but how much? Deepened cavitands are prepared by fusing four aromatic “walls” to the resorcinarene.3 This increases the curvature of the cavitand's space. Cavitands with only three walls have been known since 1992,4 but their recognition properties were discovered by Ballester only in 2006.5 We describe here additional resorcinarene-derived cavitands with three walls and characterize their behavior in aqueous and organic media. Figure 1 Synthesis of cavitands 3 and 4 and representation of 3 in the vase conformation. Deep cavitands with benzimidazoles on their upper rims allow the study of molecular recognition events in protic solvents.6 Their vase-like conformations are stabilized (rather than disrupted) by water or alcohols because hydroxyl functions complete the hydrogen bond seam that helps maintain the shape of the receptor. The synthesis of two- and three-walled cavitands is low-yielding but has led to a number of intriguing applications.7 We used the known hexanitroderivative8 2 to prepare the cavitand 3. Reduction with tin(II) chloride then condensation with 5 gave the cavitand with 3 benzimidazole walls, each bearing an ester function. In addition, synthesis of the ethyl-footed analog 3a and subsequent saponification gave a water-soluble cavitand 4. Although 3a dissolves well in CDCl3, its 1H NMR spectrum shows broad and unassignable signals that sharpen upon addition of MeOH-d4 (Figure 2).9 The two methine resonances at 5.69 (Ha) and 5.62 (Hb) ppm indicate a vase conformation10 that is occupied by solvent. The fourth methine proton at the site of the missing wall appears at 4.20 ppm.11 Folding is less pronounced when using D2O-saturated chloroform, but the presence of a suitable guest again brings well-resolved signals. Cavitand 3b is only partially soluble in CD2Cl2/CD3OD. It dissolves and forms a folded structure in THF-d8/D2O, but the organic solvent outcompetes potential guests in binding. Figure 2 1H NMR spectra (600 MHz) of (a) 3a in CDCl3/5% CD3OD, (b) 3a in CDCl3/D2O saturated, and (c) 3a + 6a in CDCl3/D2O saturated. The large π-surfaces of the cavity are known to bind ammonium cations through cation-π and CH-π interactions.3,5 Accordingly, we examined various amines, ammonium cations and adamantanes (6−13, Figure 3) as potential guests. Typically, the anisotropy imparted by eight aromatic walls induces upfield shifts of up to 5 ppm in the NMR signals of guests. Alkanes, for example, appear in the region 0 to −4 ppm. We found that both an amine/ammonium group and a bulky aliphatic region which properly fills the inner space appear necessary for binding (Table 1). Figure 3 Structures of guests 6−13. Table 1 Binding Constants for Guests 6-11, Determined by 1H NMRa An additional feature of 3a is its selectivity in binding naturally occurring ammonium cations.12 Both choline and carnitine, which are poorly soluble in water-saturated chloroform, were taken up, but acetylcholine was not. The NMR signatures13 of the encapsulated guests in the upfield region and molecular modeling studies14 reveal that different binding modes operate depending on the guest (Figure 4). Primary ammonium cations or amines are positioned appropriately to hydrogen bond with the groups on the cavitand's rim. Bulkier groups such as a trimethylammonium or a pyridinium can maintain an electrostatic interaction with the ester groups on the rim only if they protrude from the cavity. Figure 4 Upfield region in the 1H NMR spectra of 6a, 8, and 13 and their assignments. Trimethylammonium guests with small hydrophobic regions such as choline or carnitine are accommodated with the trimethylammonium group positioned deep inside the cavity. For these guests, the hydroxyl and carboxylate functions can provide hydrogen bonding interactions with the groups at the rim. The ester group of acetylcholine appears unable to reach such binding sites. The water-soluble cavitand 4 displays different host behavior. Saponification of 3b gave 4, as shown by ESI-HRMS (see Supporting Information), but when 4 was dissolved in D2O, only broad signals were observed in the 1H NMR spectrum. Four-walled cavitands of this type display broad signals in the presence of salts; most likely, the cavitands exist as velcrand dimers6c,15 or larger, kinetically unstable aggregates (Figure 5). Figure 5 Side views of a simplified model for the complex 3·2H2O and 6a (left) and 8 (right) showing different orientations of the adamantyl group. Upon addition of excess 1-adamantanol 6f, the 1H NMR spectrum sharpened and peaks for folded cavitand binding 1-adamantanol were seen. The presence of a guest that correctly fills the hydrophobic cavity stabilizes the folded conformation of 4, breaking up the aggregates and providing a sharp spectrum of a 1:1 complex. Attempts to extend the range of guests were unsuccessful; cavitand 4 is not a sufficiently strong host to extract hydrophobics such as hexane, cyclohexane, isooctane, or adamantane into solution, as its four-walled counterpart can.6c Other adamantane-based guests such as 6b, 6d, and 6e did not fold the cavitand, presumably due to their higher water-solubility. Choline and acetylcholine also failed to break up the aggregates, although broad guest peaks were observed at δ −1 ppm, indicating some dynamic association of the guest and a folded host. In conclusion, new water-stabilized, deep cavitand recognizes various amines and ammonium guests of different shapes. The synthesis of a water-soluble derivative was also achieved and shown to bind suitably-sized hydrophobic molecules in aqueous medium. The absence of a fourth wall allows the binding of bulky ammonium groups and appears as a promising template for more flexible receptors with improved selectivity for biologically relevant ammonium guests. These and the cavitands reported earlier5 provide a bridge between more open-sided receptors16 and the capsules that more or less completely surround their guests.17