Recognition of 1,4-Xylylene Binding Sites in Polyimidazolium Cations

J. Phys. Chem. B 2009, 113, 9493–9498

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Recognition of 1,4-Xylylene Binding Sites in Polyimidazolium Cations by Cucurbit[7]uril: Toward Pseudorotaxane Assembly Salim Samsam, Loı¨c Leclercq, and Andreea R. Schmitzer* Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128 Succursale Centre-Ville, Montre´al, Que´bec H3C 3J7, Canada ReceiVed: April 14, 2009; ReVised Manuscript ReceiVed: May 26, 2009

The binding interactions between cucurbit[7]uril (CB[7]) and different polyimidazolium cations containing aromatic binding sites (1,4-xylylene units) were studied experimentally by 1D and 2D NMR, high-resolution mass spectrometry (HRMS), and fluorimetry, and, theoretically, by computed geometries and enthalpy changes. CB[7] was found to form [2]- and [3]-pseudorotaxanes with these cations by the inclusion of the internal 1,4-xylylene units. Introduction With its focus on intermolecular interactions and bonds, supramolecular chemistry sees a move away from more traditional chemistry. In place of the covalent bond, supramolecular chemistry relies on molecular recognition between groups that are both electronically and geometrically complementary to drive the formation of supramolecular assemblies. The goal of supramolecular chemistry is to increase the organization and complexity of matter.1 The formation of self-organized structures able to carry out functions at the molecular level, such as molecular switches, are a clear demonstration of the successes in this field to date.2 The formation of a host-guest complex involves molecular recognition between the host, a large molecule that contains a cavity, and the guest, a smaller molecule which is designed to reside in the cavity. To form the complex, the host molecule must possess converging binding sites while the guest must possess diverging binding sites.3 In 1905, Robert Behrend and co-workers were the first to report the synthesis of cucurbituril (CB) via an acid-catalyzed condensation reaction between glycoluril and formaldehyde.4 More than 75 years later, Freeman et al. published the first crystal structure of cucurbituril.5 The popularity of CBs has grown substantially in recent years. The host properties of CBs are immediately obvious. The hydrophobic cavity is capable of holding guests of varying sizes, and, because of the relative rigidity of this receptor molecule, it generally forms very stable host-guest complexes. Because CB possesses an electronegative portal and an electropositive cavity, a CB host demonstrates a high specificity for those guest molecules with complementary charge distributions. It is noteworthy that the sizes of CBs vary according the number of the glycoluril repeat units. The conventional abbreviation used in this publication is CB[n], where n is the number of glycoluril units. The best documented group of guest molecules for CB[6] are the diaminoalkanes and their ammonium mono- and dications. Diaminoalkanes thread themselves through the cavity of the CB so that their amino groups lie level with the oxygen-ringed portals. Their amino and ammonium groups engage in both electrostatic and hydrogen bonding with the portal oxygens, and Mock and Shih have shown that 1,6-diaminohexane is of the * To whom correspondence should be addressed. E-mail: ar.schmitzer@ umontreal.ca.

Figure 1. Structure and schematic representation of CB[7].

Figure 2. Diimidazolium cations used in this work and their schematic representation.

optimal length for these types of interactions.6 Because the inner CB cavity is hydrophobic, displacing water molecules in favor of an alkane chain is thought to stabilize the complex.7 Despite the growing interest in host-guest complexation processes involving cucurbiturils in water and their applications, relatively little is known about the use of CB[7] (Figure 1) in the construction of pseudo-, poly(pseudorotaxanes),8 and supramolecular switches.9 Previously, we reported the synthesis and the formation of binary complexes of 1,1′-dibenzyl-3,3′-methylenediimidazolium bis(bromide) (1) with CB[7] (Figure 2).10 We observed that the CB[7] recognizes the external aromatic unit of the salt to form inclusion complexes. However, the central diimidazolium unit can also be a binding site for CB[7], but only in ternary complexes with cyclodextrins.11 Moreover, Macartney et al. have shown that R,R′-bis(3-(1-methylimidazolium))-p-xylylene dications can form inclusion complexes with CB[7] with association constants of 10-9 M-1.12 As an extension of our previous study, we have reversed the recognition pattern of these

10.1021/jp9034369 CCC: $40.75  2009 American Chemical Society Published on Web 06/19/2009

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SCHEME 1: Synthesis of the Diimidazolium Salts

diimidazolium salts (Figure 2) by placing the benzyl unit between the diimidazolium cations and increasing the number of the recognition sites in order to promote binding of more than one CB[7] molecule and assemble higher order complexes. In the case of CB[7] and our guest molecules the noncovalent electrostatic bonding (present in all cases) and hydrophobic effects may also be important. The hydrophobic effects pertain to the fact that the host-guest complexes are formed in aqueous solution and their formation involves the displacement of strained water molecules from the CB[7] cavity.13 Results and Discussion Very recently we studied the binding interactions between CB[7] and a series of symmetric diimidazolium cations having different aromatic substituents.10 We showed that the predominant binding site for CB[7] inclusion is the external one, where CB[7] engulfs the aromatic unit. Here, we investigate host-guest interactions between CB[7] and a series of guests that contain 1,4-xylylene and diimidazolium subunits. All molecules shown in Scheme 1 were newly synthesized and obtained with a reasonable yield, except for the methylene-bridged bis-imidazole (MBI) which was obtained by modifying the method of In and Kang.14 R,R′-Dibromo-p-xylene was used as a limiting or an excess reactant, in the presence of MBI in the appropriate solvent, to obtain 2 and 2′, respectively, as dication salts. The reaction between 2 and MBI in excess gave compound 3 as a tetracation salt (see Supporting Information for further details). We previously reported that, in aqueous solution, the aromatic protons of 1 are shifted upfield, consistent with the formation of an inclusion complex into the electron-rich inner cavity of the CB[7].10,11 The effect of the complexation on the imidazolium ring protons was weaker, consistent with CB[7], including the external benzyl unit inside its cavity, while the positively charged nitrogen interacts with the carbonyl oxygens on the host’s portal. We assumed that steric hindrance could play a

key role determining the main binding site for CB[7] to this dication. In other words, the shape of this dication with two methylene binding points could play an important role in the binding process and in the choice of the binding site. To address this issue, we synthesized compounds 2 and 3, in which the diimidazolium units are linked to a central phenylene spacer via methylene units. We reasoned that as CB[7] slides along the structure of this dication, it should find a similar level of steric hindrance to reach the central binding site such as that experienced when 1 binds to CB[7] in the presence of a cyclodextrin. NMR Spectroscopy. The binding interaction between CB[7] and 2 and 3 was monitored by 1H NMR spectroscopy (Figure 3). Each peak of the NMR spectra was assigned unequivocally by coupling connectivity in 2D COSY and ROESY experiments. The cavity of the CB[7] molecule is a magnetic shielding region, so the signals from species encapsulated in CB[7] undergo an upfield shift. This property can be used to determine not only whether a guest but also what part of the guest molecule has been encapsulated by the CB[7] cavity. Upon addition of 0.5 equiv of CB[7] to a solution of 2 in D2O (Figure 3), the singlet corresponding to the aromatic protons (H8) of the phenylene unit exhibits a pronounced upfield shift of 0.94 ppm, while the benzylic CH2 protons (H7) shift upfield by 0.46 ppm. At the same time, the methylene bridge protons (H5) between the imidazolium and the imidazole rings shift 0.29 ppm downfield. The significant upfield shift of the phenylene and benzylic protons reveals that CB[7] engulfs the central 1,4-xylylene unit, forming an internal inclusion complex with 2. As H4 protons are shifted upfield, it is reasonable to think that the imidazolium cations close to the benzyl group are partially included in the CB[7] cavity. Even at high ratios of CB[7], the central location of CB[7] remains the same, suggesting that the driving force of the internal complexation is the strong binding of the imidazolium-1,4-xylylene unit inside the hydrophobic cavity

CB[7] and Polyimidazolinium Binding Interactions

Figure 3. Partial 1H NMR (300 MHz) spectra of 2 and 3 protons in the presence of different CB[7] molar ratios in D2O: (a) 1:0.5; (b) 1:1; (c) 1:2; (d) 1:4. ([2] ) 1 mM; [3] ) 0.5 mM.)

of the host. The resulting [2]-pseudorotaxane is stabilized by the interaction between the positively charged imidazolium nitrogens and the carbonyl portals of the host. The exchange between free and bound CB[7] is slow on the NMR time scale, as signals corresponding to both the bound and the free guest can be observed at 2:CB[7] ratios inferior to 1. The signals of the free guest disappear upon the addition of 1.0 equiv of CB[7]. It is important to note that the addition of even small amounts of CB[7] entails the disappearance of the external imidazole’s H6 proton, probably due to its protonation by the residual acids contained by CB[7]. This imidazole protonated state can also be observed at high CB[7] ratios, where chemical shifts can be observed only for the H1, H2, H3, H4, and H5 protons (Figure 3, spectra c and d). At 2:CB[7] ratios superior to 1 no significant chemical shifts can be observed for H7 and H8 protons, indicating the formation of the [2]-pseudorotaxane once the xylylene binding site is reached. The same binding equilibrium was observed for 3, where threading of 2 equiv of CB[7] with 3 gives a [3]-pseudorotaxane, in which CB[7] appears to reside again at the aromatic units, according to the NMR data. It is important to note that in this case, after the 1:2 stoichiometry is reached, no more changes can be observed in the NMR spectra. Again, the most noticeable NMR changes observed in the [3]-pseudorotaxane are the upfield shifts of H7 and H8 aromatic protons and the downfield displacements of the H5 protons. As in the case of 2, the protonation of the terminal imidazole units can be observed when CB[7] is added.

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Figure 4. Partial 2D ROESY spectra (500 MHz) in D2O at 298 K corresponding to a mixture of: (a) 2 and CB[7] in a 1:2 molar ratio, (b) 3 and CB[7] in 1:4 molar ratio. Presence of cross-peaks is highlighted by red circles and absence of cross-peaks is shown in blue.

To provide additional evidence of pseudorotaxane formation and to gain further insights into the geometry of these complexes, we performed 2D ROESY studies (Figure 4). For the 2 · CB[7] mixture (Figure 4a), intense cross-peaks were observed between the protons H7 and H8 of the benzyl residues and the protons Hb (those in parallel to the CdO portal) of CB[7]. As in our previous studies,10,11 correlation peaks between the Hc protons of CB[7] with the aromatic protons of 2 can be observed, suggesting that the spatial distance between these protons is less than 5 Å. This observation confirms the inclusion of the 1,4-xylylene unit into the CB[7] cavity. The same behavior occurred in the case of the 3 · CB[7] mixture (Figure 4b). Mass Spectrometry. Mass spectrometry has been used to a lesser extent to detect the existence of host-guest complexes. Day et al. used this technique, in conjunction with NMR, to identify CB complexes, and their structures were later confirmed by crystallography.15 Similarly, MS was used by Buschmann et al. to detect the formation of pseudorotaxanes,16 while Zhang et al. have shown that the complex 1,4-butanediamine/CB[6] can survive the electrospray process used in sustained offresonance irradiation collision induced dissociation.17 An electrospray ionization-high-resolution mass spectrometry (ESIHRMS; positive ionization mode) study was carried out to demonstrate the formation of 2 and 3 complexes with an excess of CB[7]. This technique revealed the [2]-pseudorotaxane as the unique complex formed for 2. For 3 the major complex detected by MS is the [3]-pseudorotaxane, but traces of the [4]-pseudorotaxane can be observed at high ratios of CB[7] (see Table 1).

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TABLE 1: Comparison between the Observed m/z Values (m/zobs.) and the Calculated m/z (m/zcalc) for 2 · CB[7]x and 3 · CB[7]x (Obtained by ESI-HRMS) attributed species [(2 · CB[7] - 2Br) + H] [2 · CB[7] - 2Br]2+ 3 · CB[7] 2 · CB[7]2 [(3 · CB[7]2 - 4Br) + H]4+ 2 · CB[7]3 [(3 · CB[7]3 - 4Br) + 2H]4+ 3+

m/zcalc

m/zobs

intensa

521.1849 781.2774

521.1899 781.2795

744.5087

744.5120

1035.3445

1035.3500

+ ndb ndb + ndb -

a The observed intensity is reported according to the following relative convention: -, species with a relative intensity 0.98 (Figure 7). From this analysis we obtained the association constants along with the fluorescence enhancement of inclusion complexes. The estimated values of K11 and K12 for both molecules 2 and 3 in CB[7] are presented in Table 3. It is important to note that K11 values are similar for both guests, an observation that can be correlated with the hydrophobic nature of the 1,4-xylylene unit. K12 obtained for guest 3

stoichiometry

K11 (M-1)

SDa

K12 (M-1)

SDa

1:1 1:2

5.8 × 10 3.5 × 103

(0.40 (0.36

4.2 × 104

(0.80

2 · CB[7] 3 · CB[7]

3

a

SD is the standard deviation (reported values are the mean of three different measurements).

was 10 times greater than K11. This result shows that by multiplying the binding sites number the association constant can be increased and higher ordered stable supramolecular complexes can be obtained. The estimated values for the association constants are inferior to those previously reported by Macartney et al. for this type of imidazolium cations. This can be due to the different geometry of these guests, where the external imidazole groups hinder the access of the macrocycle on the binding site. However, this opens the way to the assembly of polyrotaxanes with this new recognition motif. Conclusion In summary, we have demonstrated that the formation of inclusion complexes between polyimidazolium cations and CB[7] results in a [2]- or [3]-pseudorotaxane, depending on the number of p-xylylene units. CB[7]slides along the dicationic molecule in order to reach the p-xylylene units. The presence of the imidazolium cations close to the p-xylylene unit results in the formation of stable pseudorotaxanes (even in the gas phase), with association constants similar to those obtained for p-xylylene diamine derivatives and CB[7]. In the [3]-pseudorotaxane from 3 and CB[7], K12 is superior in stability to K11, an observation that could provide an opportunity to study the complexation of CB[7] with oligo- and polyimidazolium cations. We are currently working along this line, by studying the assembly of poly(pseudorotaxanes) with CB[7]. Experimental Section

Figure 6. Job’s plot of 2 · CB[7] and 3 · CB[7] complexes. (a) Symmetric plot with maximum at 0.5 mol fraction indicating a 1:1 inclusion complex. (b) Asymmetric plot with maximum at 0.67 mol fraction indicating a 1:2 inclusion complex.

Materials. All experiments were performed with analytical reagent grade chemicals, pure solvents, and Milli-Q water. Imidazole, R,R′-dibromo-p-xylene, and CB[7] were purchased from Aldrich and used as received.

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Fluorescence Spectroscopy. Fluorescence measurements were performed on solutions in a microfluorimeter cell (10 mm), at 20 ( 0.1 °C. Fluorescence spectra were measured on a Cary Eclipse fluorescence spectrophotometer, with excitation and emission monochromator band passes set at 10 nm. Data acquisition and analysis were performed by the use of Cary Eclipse Scan software. Solutions were excited at 260 nm. The fluorescence enhancement F/F0 was determined at each CB[7] concentration as the ratio of the integrated fluorescence spectrum (intensity vs wavenumber) in the presence of CB[7] to that in its absence. Solution Preparation. A stock solution of CB[7], 1 mM in water, was prepared and dilutions were made from this stock solution to obtain different desired concentrations. Stock solutions of 2 and 3, 0.18 and 0.1 mM, respectively, were prepared in water, and 0.5 mL aliquots of these stock solutions were added to 0.5 mL of cucurbituril solutions of different concentrations to obtain 1 mL of fresh sample solutions, yielding final 2 and 3 concentrations of 0.09 and 0.05 mM, respectively. The concentration of CB[7] ranged from 9 × 10-6 to 3.6 × 10-4 M (in the case of 2) and from 1.5 × 10-5 to 2.5 × 10-4 M (in the case of 3). The sample solutions were mixed and then immediately transferred to a fluorescence cell for spectroscopic measurements. NMR Spectroscopy. The 1H, 13C, COSY, and ROESY NMR spectra were recorded at 300, 75.45, and 500 MHz on Bruker Advance instruments, respectively. Chemical shifts are given in parts per million (δ) and measured relative to residual solvent, for 1H and 13C NMR. ESI-HRMS and Elemental Analysis. ESI mass spectra were recorded with a TSQ Quantum Ultra (Thermo Scientific) mass spectrometer with accurate mass options (Universite´ de Montre´al Mass Spectrometry Facility). Elemental analyses were obtained at the Universite´ de Montre´al facility. Molecular Modeling. All calculations were performed on Windows Vista platform. The initial configurations were obtained from UFF calculations under ArgusLab 4.0.1 software (Mark Thompson and Planaria Sofware LLC).25 To assess the energy content for various molecules designed and minimized above, semiempirical quantum calculations were undertaken using the PM3 method with COSMO water solvation parameters as implemented in MOPAC2009 (Stewart Computational Chemistry). The COSMO method (conductor-like screening model) is useful for determining the stability of various species in a solvent environment, and particularly in water. Theoretical calculations were carried out at the restricted Hartree-Fock level (RHF) using the PM3 semiempirical SCF-MO methods. For water simulation, a relative permissivity of 78.4 was applied with up to 92 surface segments per atom for the COSMO model being used to construct a solvent accessible surface area based on van der Waals radii. All structures were optimized to a gradient inferior to 0.1 using the eigenvector method. Note that the MOPAC Cartesian coordinates were generated with OpenBabel 2.2.0 graphical interface (Chris Morley) from the geometries obtained with ArgusLab UFF. After MOPAC geometry optimization, the out files were opened with Molda 6.5 and final images are obtained with WebLab ViewerLite 3.7 (Molecular Simulations Inc.). Acknowledgment. We are grateful to the Natural Sciences and Engineering Research Council of Canada, the Fonds

Samsam et al. Quebe´cois de la Recherche sur la Nature et les Technologies, the Canada Foundation for Innovation, and Universite´ de Montre´al for financial support. We thank Dr. Alexandra Furtos and Marie-Christine Tang for mass spectrometry analysis and Sylvie Bilodeau for NMR spectra. We also thank colleagues for careful reading and discussion of this manuscript. Supporting Information Available: Synthesis and characterization of 2 and 3 (1H NMR, 13C NMR) and ROESY and ESI-HRMS spectra for 2 and 3 with various CB[7] molar ratios. This material is available free of charge via the Internet at http:// pubs.acs.org. References and Notes (1) Lehn, J.-M. Supramolecular Chemistry: Concepts and PerspectiVes; VCH: Weinheim, Germany, 1995. (2) (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, F. J. Angew. Chem., Int. Ed. 2000, 39, 3348–3391. (b) Dominguez, Z.; Dang, H.; Strouse, M. J.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2002, 124, 2398–2399. (3) Cram, D. J.; Cram, J. M. Container Molecules and Their Guests. Monographs in Supramolecular Chemistry; Stoddart, J. F., Ed.; The Royal Society of Chemistry: Cambridge, U.K., 1994. (4) Behrend, R.; Meyer, E.; Rusche, F. Liebigs Ann. Chem. 1905, 339, 1–37. (5) Freeman, W. A.; Mock, W. L.; Shih, N. Y. J. Am. Chem. Soc. 1981, 103, 7367–7368. (6) Mock, W. L.; Shih, N. Y. J. Org. Chem. 1986, 51, 4440–4446. (7) Mock, W. L.; Shih, N. Y. J. Am. Chem. Soc. 1988, 110, 4706– 4710. (8) (a) Tuncel, D.; Steinke, J. H. G. Chem. Commun. (Cambridge) 1999, 1509–1510. (b) Tuncel, D.; Steinke, J. H. G. Chem. Commun. (Cambridge) 2001, 253–254. (c) Lee, E.; Heo, J.; Kim, K. Angew. Chem., Int. Ed. 2000, 39, 2699–2701. (d) Park, K.-M.; Whang, D.; Lee, E.; Heo, J.; Kim, K. Chem.sEur. J. 2002, 8, 498–508. (9) (a) Roh, S.-G.; Park, K.-M.; Park, G.-J.; Sakamoto, S.; Yamaguchi, K.; Kim, K. Angew. Chem., Int. Ed. 1999, 38, 637–641. (b) Ong, W.; Go´mez-Kaifer, M.; Kaifer, A. E. Org. Lett. 2002, 4, 1791–1794. (c) Kim, H.-J.; Jeon, W. S.; Ko, Y. H.; Kim, K. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5007–5011. (d) Moon, K.; Kaifer, A. E. Org. Lett. 2004, 6, 185–188. (10) Noujeim, N.; Leclercq, L.; Schmitzer, A. R. J. Org. Chem. 2008, 73, 3784–3790. (11) Leclercq, L.; Noujeim, N.; Sanon, S. H.; Schmitzer, A. R. J. Phys. Chem. B 2008, 112, 14176–14184. (12) Wang, R.; Yuan, L.; Macartney, D. H. Chem. Commun. (Cambridge) 2006, 2908–2910. (13) Buschmann, H.-J.; Jansen, K.; Schollmeyer, E. Acta Chim. SloV. 1999, 46, 405–411. (14) In, S.; Kang, G. J. Incl. Phenom. Macrocycl. Chem. 2006, 54, 129– 132. (15) Day, A. I.; Blanch, R. J.; Arnold, A. P.; Lorenzo, S.; Lewis, G. R.; Dance, I. Angew. Chem., Int. Ed. 2002, 41, 275–277. (16) Buschmann, H. J.; Wego, A.; Schollmeyer, E.; Dopp, D. Supramol. Chem. 2000, 11, 225–231. (17) Zhang, H.; Paulsen, E. S.; Walker, K. A.; Krakowiak, K. E.; Dearden, D. V. J. Am. Chem. Soc. 2003, 125, 9284–9285. (18) Stewart, J. J. P. Stewart Computational Chemistry, Version 8.331W, http://openmopac.net/. (19) Poupaert, J. H.; Couvreur, P. J. Controlled Release 2003, 92, 19– 26. (20) Smith, M. B.; March, J. Mechanisms and Methods of Determining Them in March’s AdVanced Organic Chemistry 6th ed.; John Wiley & Sons: New York, 2007. (21) Job, P. Ann. Chim. 1928, 9, 113–134. (22) Wagner, B. D.; Boland, B. G.; Lagona, J.; Isaacs, L. J. Phys. Chem. B 2005, 109, 7686–7691. (23) Nigam, S.; Durocher, G. J. Phys. Chem. 1996, 100, 7135–7142. (24) GraphPad Prism, Version 5.0; GraphPad Software, Inc.: La Jolla, USA., http://www.graphpad.com/prism/Prism.htm. (25) Thompson, M. A. ArgusLab 4.0.1; Planaria Software LLC, http://www.arguslab.com.

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