Rigid, biconical hydrogen-bonded dimers that strongly encapsulate cationic guests in solution and the solid state
The octol of a new rigid, tetraarylene-bridged cavitand was investigated for self-assembly behaviour in solution. 1 H and DOSY NMR spectroscopic experiments show that the cavitand readily dimerizes through an unusual seam of interdigitated hydrogen-bonds that is resistant to disruption by polar co-solvents.The well-defined cavity encapsulates small cationic guests, but not their neutral counterparts, restricting the conformation of sequestered tetraethylammonium in solution and the solid state.
Introduction<!>Results and discussion<!>+<!>Conclusions
<p>Conned spaces within self-assembled capsules are distinct from the bulk solvent, sequestering complementary guests 1 or catalysing chemical reactions. [2][3][4] The volume and morphology of the cavity depends upon the size and shape of the monomers: Rebek's highlycurved arcs homo-dimerize into the spherical tennis balls 5 and soballs 6 (Fig. 1a), whereas the shallow and exible bowls resorcin [4]arenes and pyrogallol [4]arenes form hexamers [7][8][9][10][11][12][13][14] or dimers [15][16][17][18][19][20][21][22] (Fig. 1b) depending on the solvent and added guests. While hydrogen-bonded assemblies of other molecular bowls are known (trioximes 23 tribenzo-triquinacenes, 24 calix [4]arenes, 25 cyclotriveratrylenes 26 and cyclotricatechylenes 27 ), the majority of reported capsules are built upon the readily available resorcin [4]arene scaffold, the intrinsic concave surface and an exoannular array of hydroxyl groups providing the elements for capsular self-assembly. Importantly, the solubility of the macrocycle in polar and non-polar solvents is modulated through the length of the alkyl "feet". 28 The upper-rim of resorcin [4]arenes is readily functionalized, with additional hydrogen-bond donors and acceptors increasing the cavity size and/or strengthening the interaction. [29][30][31][32][33] For example, Rebek's diimide 34 and de Mendoza's benzimidazolone 35 cavitands interact through a seam of 16 bifurcated N-H/O bonds to generate large, cylindrical dimers around complementary guests (Fig. 1c).</p><p>We recently reported the synthesis of the novel resorcin [4]  arene-derived octamethoxy tetraarylene-bridged cavitand 1a (Scheme 1), with an enforced, conical cavity that is not subject to the conformational uxionality experienced by many resorcin [4]arene bowls. 36 As part of further studies into this new class of cavitand, we were interested as to whether its octol, 2a, would self-assemble into multicomponent aggregates through the four catechol units at the upper-rim (Fig. 1d). The unusual rigidity of the cavitand, combined with the preorganized and inexible array of exoannular hydroxyl groups, was predicted to give hydrogen-bonded constructs of distinct geometry and high stability. Herein we report the ndings of this study, in which 2a and its undecyl-footed analogue 2b homo-dimerize through a remarkable circular seam of hydrogen-bonds to give a rigid, biconical capsule with a well-dened cavity (Fig. 1d).</p><!><p>Cleavage of the eight exoannular methyl ethers of 1a with BBr 3 in CH 2 Cl 2 was facile; however, the product 2a was insoluble in the non-polar solvents CHCl 3 or CH 2 Cl 2 (Scheme 1). To improve the solubility in non-polar solvents, we used our recent synthesis of C 2v -symmetric resorcin [4]arene derivatives 37 to prepare the undecyl analogue 1b in eight steps (see ESI †).</p><p>Eightfold methyl ether cleavage afforded 2b in 93% yield, and the macrocycle was found to be soluble in CHCl 3 , CH 2 Cl 2 and acetone. The 1 H NMR spectrum of a freshly prepared solution of 2b in CDCl 3 showed three cavitand species in slow exchange on the NMR timescale. Within ca. 60 minutes, equilibrium was established showing only a single species of C 4vsymmetry, with no further change over days. The nature of the stable species formed from 2b was investigated by DOSY NMR spectroscopy. Self-assembled aggregates are predicted to diffuse more slowly than their monomers, as shown by the Stokes-Einstein equation in which the diffusion coefficient (D) is inversely proportional to the spherical hydrodynamic radius 38 (see ESI †). Experiments in CDCl 3 (Table 1) showed 2b diffuses more slowly than octamethoxy 1b-which cannot form multicomponent adducts through intermolecular hydrogen-bonding and is an appropriate surrogate for the monomer-but faster than the related resorcin [4]arene hexamers reported by Cohen (2.8 Â 10 À6 cm 2 s À1 ; R ¼ C 11 H 23 ). 11,38 The estimated diffusion volume of octol 2b is 1.7 times that of "monomer" 1b (see ESI †), consistent with homo-dimerization to 2b$2b driven by mutual hydrogen-bonding interactions at the cavitands' wide rims. An energy-optimised model of the dimer 2 0 $2 0 supports this analysis (the prime symbol in 2 0 $2 0 denotes calculated structures throughout this text), showing a unidirectional, cyclic seam of eight intermolecular and eight intramolecular hydrogen bonds (Fig. 2). In the 1 H NMR spectrum of 2b (CDCl 3 , 298 K) a single OH resonance appears at ca. 6.89 ppm, its shi largely independent of 2b concentration across the range 1-14 mM (Dd ¼ 0.05 ppm; see ESI †). This lone OH signal is consistent with the rapid interconversion between the two equivalent arrangements of hydrogen-bonds on the NMR timescale (Fig. 2).</p><p>Further 1 H NMR experiments in 20-50% v/v CHCl 3 /CDCl 3 mixtures show solvent is encapsulated by the host, as evidenced by the appearance of CHCl 3 resonance at 3.03 ppm (Dd ¼ À4.23 ppm; see ESI †). Similarly, in 50% v/v C 6 D 6 /CDCl 3 two species are present in a 6 : 1 ratio at equilibrium, corresponding to the complexes 2b$2b3CDCl 3 or 2b$2b3C 6 D 6 . The absence of a third species likely excludes the co-capture of two guest molecules.</p><p>To probe the stability of the dimer in protic, polar solvents, the diffusion coefficient of 2b$2b in CDCl 3 with increasing proportions of CD 3 OD (0-800 equiv. per 2b) was measured by DOSY NMR spectroscopy (see ESI †). 14 D remained consistent with a dimer across the series (3.4-3.5 Â 10 À6 cm 2 s À1 ), in mixtures of up to 15% CD 3 OD (v/v). This high stability of the complex contrasts with the resorcin [4]arene and pyrogallol [4]  arene hexamers studied by Cohen, 14 which show rapid increases in diffusion coefficient upon the addition of small amounts of MeOH. At the limit of solubility (1600 equiv. CD 3 OD), a second species appears in slow exchange with the dimer; however, its diffusion coefficient could not be differentiated. Unfortunately, the dimerization constant, K dimer , for 2b in CDCl  dimerization constants for direct comparison; however, on the basis of the 1 H and DOSY NMR and UV-vis data presented herein, and the high stability of the complex in protic, polar solvents, K dimer for 2b is likely >10 6 M À1 and may exceed >10 9 M À1 . Similar values were reported for a dimeric capsule stabilised by eight hydrogen-bonds. 39 To assess the guest-binding properties of the cavitand to non-solvent guests, 2b was combined with NEt 4 Br in 1 : 1, 2 : 1 and 4 : 1 ratios in CDCl 3 at 298 K and the 1 H NMR spectra examined for evidence of encapsulation (Fig. 3). The 1 : 1 mixture showed slow exchange between 2b$2b and 2b$2b3NEt 4 + species, reaching quantitative encapsulation within 60 minutes (Fig. 3b). The free and bound NEt + is observed (Fig. 3c). DOSY NMR spectroscopy conrmed equal diffusion rates of the host and encapsulated guest at 3.35 Â 10 À6 cm 2 s À1 (Table 1, entry 3), a rate similar to that of the free host 2b$2b. Increasing the hostguest ratio to 4 : 1 shows complete encapsulation of the guest, with an equimolar amount of residual free dimer host 2b$2b (Fig. 3d). These data support both the apparent exclusive formation of the homodimer 2b$2b and quantitative uptake of NEt 4 + to give 2b$2b3NEt 4</p><!><p>, with both species in slow exchange in CDCl 3 . The association constant, K a , for the binding of NEt 4 + by 2b$2b is 4.6 AE 0.3 Â 10 5 M À1 (DG ¼ À31.9 AE 1.6 kJ mol À1 in CHCl 3 , 293 K), as determined by UV-vis titrations 40 of the host with the guest, and assuming a 1 : 1 host : guest binding model on the assumption K dimer [ K a (see ESI †).</p><p>The coordination of catechol units with halide anions is well known, 41 and similar interactions have been shown to template the formation of resorcin [4]arene and pyrogallol [4]arene capsules. 42 Homo-dimeric resorcin [4]arene-derived capsules formed through intermolecular hydrogen-bonding alone are rare; solvent molecules or the halide counterions of cationic guests are typically incorporated into the hydrogen-bonded network to template the dimerization processes, usually observed only in the solid state. 22 Here, dimerization readily occurs in solution in the absence of templating molecules or anions, and moreover, is unaffected by their presence. Presumably, the low concentration of bromide counterions relative to the complex, combined with the competitive solvent, appear to limit interactions to the periphery of the dimer, causing only a moderate downeld shi in the OH proton resonance that increases with bromide concentration (Fig. 3). The limited role of the bromide ion in bonding at the seam is supported by crystallography (vide infra). While beyond the scope of the present study, it is noted that coordinating halide anions at higher concentrations may template different/larger multicomponent adducts and is an interesting avenue for further investigation.</p><p>In the bulk polar aprotic solvent d 6 -acetone, 2b failed to dimerize, as shown by the similar diffusion coefficients for 1b and 2b (Table 1, entries 4 and 5; Scheme 1; Fig. 4). The addition of excess NEt 4 Br to the monomer solution of 2b saw quantitative formation of the complex 2b$2b3NEt 4 + , as evidenced by the shi in OH proton resonance (Dd ¼ +1.29 ppm) consistent with  increased hydrogen-bonding and the reduced diffusion coefficient (Table 1, entry 6). From these data it is clear interactions with the cationic guest play a role in the enthalpic-stabilisation of the dimer in bulk polar media.</p><p>The ethyl-footed analogue 2a and NEt 4 + (2 : 1) failed to form a soluble 2a$2a3NEt 4 + complex in neat CDCl 3 ; however, following the addition of 20% CD 3 OD, the suspension dissolved within 12 hours. 1 H NMR analysis again showed complete formation of a 2 : 1 complex in this competitive media (see ESI †). The charged complexes 2a$2a3NEt 4 + and 2b$2b3NEt 4 + observed in solution were similarly detected in the gas phase by ESI-MS (see ESI †). Pleasingly, X-ray quality crystals of the complex adduct could be grown, an analysis conrming that the solid-state behaviour mirrors that of the solution-phase experiments (Fig. 5). ‡ The cavitands interact via a cyclic seam of hydrogen bonds to give a pseudo-octagonal bipyramidal capsule with a volume of ca. 1500 Å3 and dimensions of ca. 10.7 Â 14.4 Å (excluding the alkyl feet, Fig. 5a and b). The internal cavity is 235 Å3 of which 65% is occupied by the guest (152 Å3 ), notably higher than the optimal 55% (ref. 43) (see ESI † for details of cavity and guest volume calculations). [44][45][46] This tight t, combined with the rigid biconical topology of the cavity (Fig. 5d and e) forces the ethyl groups of the guest into magnetically anisotropic environments-axial (along the long axis of the capsule) and equatorial (in the plane of the cavitand rims)-resulting in the breaking of the guest's symmetry observed by NMR. The methyl groups of the axiallyorientated substituents are buried deeply within the cavitand and localised over four aromatic rings, consistent with the large upeld shis observed in the 1 H NMR spectrum. The phenolic protons of the host were well dened in the Fourier difference map and are positionally restrained only by their O/H distance (0.84 Å; Fig. 5c). The cavitands interact through seven intermolecular hydrogen-bonds (O/O distance 2.73-2.81 Å), six of which follow a head-to-tail arrangement around the capsule. Those groups not involved in cavitand-cavitand stabilization are free to form intramolecular hydrogen-bonds within the catechol subunit (i.e. O1/O2), or interact with MeOH solvent or the bromide counterion (Fig. 5c). In solution, these non-intermolecular hydrogen-bonds likely offer redundancy to the cavitand-cavitand interactions and may act to defend the dimer against interference by competitive media or bromide counterions.</p><p>The hydrogen-bonding motif is unprecedented for resorcin [4]arene-derived cavitands due to the coplanar arrangement of exoannuar hydroxyl groups, and may be thought of as an extension of the intercalated cyclotricatechylene (CTC)  "clamshell" dimers reported by Abrahams. 27 Here, the four catechol units of the interacting cavitands are rotationally offset by ca. 45 relative to the cavitand partner (compared to 60 for CTC dimers), the resulting greater cavity volume able to encapsulate larger guests with retention of the full hydrogenbonding array.</p><p>An energy-optimised model of 2 0 $2 0 3CHCl Neutral guests of a size and geometry complementary to the host cavity including adamantane (147 Å3 ), SiEt 4 (176 Å3 ) and terephthalonitrile (116 Å3 ) showed no interaction, nor did the electron-poor aromatic C 6 F 6 (113 Å3 ). Calculated binding energies for the complexes 2 0 $2 0 3CHCl 3 and 2 0 $2 0 3SiEt 4 are indistinguishable within the range of error, whilst the cationic complexes 2 0 $2 0 3NEt 4 + and 2 0 $2 0 3choline + enjoy signicant stabilisation (Table 2; B3LYP-D3/6-311G++(2d,2p), in vacuo, see ESI † for full details). Electronic surface potential maps show the curvature of the host imparts a substantial electronegative bias to the internal surface of the cavity (Fig. 5f; see ESI †); it is likely that a favourable enthalpic contribution from p-basic/cation interactions drives the exchange of CDCl reconcile based on the volume of the guests alone, it seems likely that the OH group of choline + interferes with the hydrogen-bonding motif between cavitands, destabilizing the complex. It should be noted that this geometry is not reected in the calculated structure of the 2 0 $2 0 3choline + complexpossibly due to bias in the starting geometry-likely resulting in an overestimation of the binding energy.</p><!><p>We have presented our observations into highly stable, selfassembled capsules stabilised by a cyclic seam of eight hydrogen bonds. The rigid cavity selectively sequesters and restricts the conformation of cationic guests, behaviour observed in both bulk solutions and the solid state, and analytically in the gas phase by ESI-MS. The hydrogen-bond array acts to articulate the interface between the rigid cavitands, allowing for some exibility in the cavity volume and dimensions.</p>