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Water-mediated inclusion of benzoates and tosylates inside the bambusuril macrocycle† Vaclav Havel,ab Vladimir Sindelar,*ab Marek Necasbc and Angel E. Kaiferd

Received 11th October 2013, Accepted 26th November 2013 DOI: 10.1039/c3cc47828a www.rsc.org/chemcomm

A supramolecular complex between benzoates and a bambusuril crystallizes out immediately after mixing in chloroform but only in the presence of residual water molecules. In this complex each of the two portals of the macrocycle is occupied by one benzoate. Carboxylate groups are connected through hydrogen bonding interactions with one molecule of water positioned between them in the center of the bambusuril cavity. Similar water assisted host–guest behavior was also observed when tosylates instead of benzoates were used.

Supramolecular interactions mediated by water molecules play important roles in both natural and artificial self-assembly. Specific waterassisted interactions are expected to significantly influence the thermodynamics as well as the kinetics of protein association and protein folding.1–6 Water acts as a glue also in the formation of molecular capsules from resorcinarenes and pyrogallolarenes in the solid state and in nonpolar wet solvent systems.7–12 Bambus[n]urils are a family of macrocyclic molecules formed by n glycoluril units connected by n methylene bridges (Fig. 1).13–18 The ability of six-membered bambusurils to bind inorganic anions with high affinity and selectivity was described recently. Here, we report the formation of stable supramolecular complexes of dodecabenzylbambus[6]uril (BU6) with tetrabutylammonium benzoates (A1 and A2 ) and a tosylate (A3 ) in the solid state and in a wet chloroform solution. The formation of these complexes is unexpectedly mediated by water molecules. Initial experiments showed that mixing of BU6 and A1 solutions in regular chloroform results in the immediate formation of a microcrystalline polydisperse solid (ESI,† Fig. S1).

Fig. 1

Structural formulas of hosts and guests used in the study.

We dissolved this solid in d6-DMSO and used 1H NMR spectroscopy to determine that the solid contains BU6 and A1 in 1 : 2 ratio, with solvent molecules also present (ESI,† Fig. S2). We were also able to obtain single crystals suitable for X-ray diffraction analysis. The crystal structure revealed that each molecule of the benzoate anion occupies opposite sides of the macrocycle (Fig. 2). While the phenyl moieties of the guest molecules are located on the BU6 portal, the carboxylate groups point towards the center of the cavity. Interestingly, one water molecule is located inside BU6,

a

RECETOX, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. E-mail: [email protected] b Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic c Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic d Center for Supramolecular Science and Department of Chemistry, University of Miami, Coral Gables, FL 33124-0431, USA † Electronic supplementary information (ESI) available: 1H NMR spectra, ESITOF MS spectra, and crystallographic data. CCDC 953267 and 965535. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c3cc47828a

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Fig. 2 Side view of the crystal structure of the BU6–2(A1 ) complex. Molecules of the solvent and TBA counterions were removed for clarity.

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between the two benzoate ions. Due to the crystallographic inversion symmetry, the water molecules are observed at two positions inside the macrocycle, each position having a 50% occupancy. The distances between the water oxygen and the nearest oxygen atoms in each of the carboxylates are 2.749 and 2.786 Å, respectively. They form an angle of 122.791. This special arrangement corresponds to the O–H  O hydrogen bonding between the water oxygen and the nearest oxygen atoms in each of the carboxylates. The complex is further stabilized by C–H  O hydrogen bonding interactions between the methine hydrogen atoms of the macrocycle and oxygen atoms of both carboxylates, 14 of them having distances ranging from 2.259 to 2.859 Å. Also the oxygen atom of water interacts with 6 methine hydrogen atoms by C–H  O hydrogen bonding interactions with distances ranging from 2.526 to 2.881 Å. It was previously described that the BU6 cavity with positive electrostatic potential attracts anions, which are bound in the center forming 1 : 1 complexes.14,15 Thus, the main driving force for the inclusion of benzoate anions inside the BU6 cavity is ion–dipole interactions. However, the aromatic ring of the benzoate is probably too big to be included inside BU6. This forces benzoate anions to rest on the portals with the carboxylate groups directed towards the center of the BU6 cavity. Thus, the water molecule not only functions as a bridge between the two carboxylate groups, but also fills the interior of the cavity, giving optimal packing to the complex. The experimental data obtained from the crystal structure show the importance of water for the complexation in the solid state. Therefore, we decided to investigate the role of water in more detail. First, we mixed the BU6 solution (5.0 mM) with 2.5 equiv. of A1 . In contrast to the initial experiment we used water saturated CDCl3 (wet CDCl3) to ensure sufficient amount of water for the complex formation. After mixing we observed immediate formation of crystals in which the ratio of BU6 : A1 was 1 : 2. In total 71% of BU6 crystallized out as the complex. Second, the same experiment was conducted in carefully dried CDCl3. Only 3% of BU6 crystallized out as the 1 : 2 complex with A1 , which also contained water molecules in the center of the cavity as determined by the X-ray analysis. Further deposition of the crystals as the 1 : 2 complex was observed more than 25 h after mixing. We assumed that deposition of small amounts of crystals in dried CDCl3 was caused by the presence of residual water. We hypothesized that subsequent formation of the crystals from dried CDCl3 was caused by diffusion of moisture from air to the solution. To confirm our assumption, we performed additional experiments. We filled the NMR tube with dried CDCl3, sealed it with a plastic cap and left it in air. Water diffusion into the NMR tube was monitored by the appearance of the signal at 1.56 ppm in the 1H NMR spectra, which is known to correspond to free water molecules dissolved in CDCl3.19 In contrast to this, when the same experiment was performed in the presence of the host–guest system, gradual crystallization of the complex took place. Crystal formation was proportional to the amount of water diffused in CDCl3. Moreover, all of the diffused water was consumed by the complexation as we did not observe the signal corresponding to free water molecules in the 1H NMR spectra even after 2 days. These experiments clearly show that water mediates the formation of the 1 : 2 complex between BU6 and A1 in chloroform solutions. The NMR spectra of the solutions obtained after the crystallization of the BU6–2(A1 ) complex in wet CDCl3 (ESI,† Fig. S3) indicate that

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residual BU6 and A1 form at least two types of complexes. However, the low solubility of this system precludes further supramolecular study in the solution. This was the main reason to prepare the model anion A2 , which does not precipitate out when mixed with BU6 even in wet chloroform.20,21 The binding mode of BU6 with A1 and A2 should be similar, as both guests contain the benzoate binding site. The binding interactions between BU6 and A2 was readily followed by measuring the chemical shifts of the host signals a, b and c in the 1 H NMR spectra (see Fig. 1 for proton labels). In wet chloroform, addition of 0.9 equiv. of A2 to the BU6 solution was accompanied by the appearance of two new sets of signals for the host (Fig. 3). The first set of BU6 signals (as, bs, and cs) increased in intensity with subsequent addition of A2 while the signals remained in the same position. This corresponds to a complex with slow exchange between the free and bound host molecules on the NMR time scale. In contrast, the BU6 signals of the second set (af, bf, and cf) experienced subsequent chemical shifts with increased addition of A2 showing fast exchange on the NMR time scale. The intensity of signals af, bf, and cf decreased with increasing amounts of A2 . When 7.4 equiv. of A2 were added (Fig. 3D), the second set of signals is no longer present and only signals as, bs, and cs were observed in the spectrum. The complexation-induced shift pattern of both sets of signals is consistent with anion inclusion inside the BU6 cavity.15 Thus, two types of supramolecular complexes between BU6 and A2 co-exist in the solution. Signals as, bs, and cs probably correspond to the 1 : 2 complex between BU6 and A2 as they persist even in the presence of a large excess of A2 . The second set of BU6 signals (af, bf, and cf) could be assigned to a 1 : 1 complex. The presence of the 1 : 1 complex was further confirmed by ESI MS through the observation of a signal at m/z 2338.9795 (ESI,† Fig. S6). The situation is quite different when the titration is performed in dry CDCl3 (Fig. 3E). Addition of 2.5 equiv. of A2 into the BU6 solution resulted only in a small shift of the original host signals and appearance of new signals indicating the formation of the 1 : 2 complex. Integral intensities of cs and cf signals revealed that only 15% of BU6 is in the form of the 1 : 2 complex. This is in contrast with 51% of the macrocycle which was detected to participate in the 1 : 2 complex in wet chloroform after addition of 2.0 equivalents of

Fig. 3 1H NMR spectra (300 MHz, CDCl3) of BU6 in the absence (A) and in the presence of 0.9 equiv. (B), 2.0 equiv. (C), 7.4 equiv. (D) of A2 in water saturated CDCl3 and the spectrum of BU6 with 2.5 equiv. of A2 (E) in dried CDCl3. *Signal of the guest.

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A2 (Fig. 3C). Also the chemical shift signal cf is much less pronounced in dry than in wet chloroform. These experiments provide further evidence that water plays an important role in the interaction of BU6 with benzoates and its derivatives in chloroform. Two different supramolecular complexes BU6–A2 and BU6–2(A2 ) are formed in wet chloroform. In contrast to this, the formation of both complexes is significantly suppressed in the absence of water. We also attempted to monitor signals corresponding to water encapsulated inside the macrocycle in the 1H NMR spectra. The benzyltrimethylammonium counterion was used instead of TBA because it does not interfere with water signals. However, we did not observe any signals for the protons of encapsulated water even when the experiment was carried out at 30 1C. The reason for this is probably related to the fast rotation of the encapsulated water molecule22 or to the formation of a large number of non-equivalent low energy complexes. Results obtained with the A2 derivative helped us to better understand the interaction between A1 and BU6. The complexationinduced shift patterns for BU6 after addition of A1 and A2 are similar. Two sets of signals recorded for the BU6–A2 system (Fig. 3) resemble those observed in the spectrum of the BU6–A1 solution (Fig. S3, ESI†). Thus, the formation of both 1 : 1 and 1 : 2 complexes between A1 and BU6 takes place in the solution. The 1 : 1 complex was confirmed by ESI MS by observation of a signal at m/z 2126.8902 (ESI,† Fig. S7). Although the ESI MS spectrum did not show the signal for the 1 : 2 complex, its presence in the solution is essential for its fast crystallization. The 1 : 1 and 1 : 2 complexes must be in equilibrium in the solution. This is the reason why the BU6–2(A1 ) complex with significantly lower solubility in chloroform, compared to the BU6–A1 complex, solely crystallizes out from the solution. We envisioned that the described crystallization phenomena should apply not only for benzoate but also for aromatic compounds bearing other anionic groups. To test this idea we selected the TBA

Fig. 4 Side view of the crystal structure of the BU6–2(A3 ) complex. Molecules of the solvent and TBA counterions were removed for clarity. Hydrogen atoms of water are not shown as their positions could not be determined with sufficient level of certainty.

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salt of p-toluenesulfonate (A3 ) and studied its interaction with BU6 in dry and wet chloroform. Mixing 0.5 M solution of BU6 with 2.5 equiv. of A3 in wet chloroform resulted in immediate deposition of microcrystals of the BU6–2(A3 ) complex. More than 90% of the macrocycle immediately separated out from the solution within several seconds after mixing. The same experiment in dry chloroform resulted only in deposition of 1% of the BU6–2(A3 ) complex. These experiments showed that the host–guest interaction behavior of BU6 and A3 in chloroform and their dependence on the presence of water resemble those between carboxylates and the macrocycle. Moreover, single crystal X-ray analysis of the crystals deposited from the solution revealed inclusion of two molecules of A3 in the macrocycle (Fig. 4). Similarly to BU6–2(A2 ) in the BU6–2(A3 ) complex also water is located at the center of the macrocycle acting as a bridge between the two sulfonate functions. In conclusion, we have reported novel supramolecular complexes in which two benzoates are bound to the bambusuril macrocycle. The 1 : 2 complex between BU6 and A1 crystallizes in wet chloroform immediately after mixing both components. Remarkably this complex is stabilized by one molecule of water incorporated between the benzoate anions. We also demonstrated that tosylates resemble benzoates in their interaction with BU6 including the formation of the 1 : 2 complex in the solid state. Further studies showed that BU6 and benzoates form not only 1 : 2 but also 1 : 1 complexes in wet chloroform. Water plays a key role in this process as the formation of these complexes is significantly suppressed in the absence of water molecules. Support for this work was provided by the project CETOCOEN (no. CZ.1.05/2.1.00/01.0001) from the European Regional Development Fund, the Czech Science Foundation (13-15576S), AMVIS/ KONTAKT II (LH11012) and the Brno PhD Talent Scholarship program sponsored by Brno City Municipality.

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Water-mediated inclusion of benzoates and tosylates inside the bambusuril macrocycle.

A supramolecular complex between benzoates and a bambusuril crystallizes out immediately after mixing in chloroform but only in the presence of residu...
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