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Langmuir 2008, 24, 11902-11910
Nonstoichiometric Gelation of Cyclodextrins and Included Planar Guests Dan Rizkov,† Shaul Mizrahi,† Jenny Gun,† Roy Hoffman,‡ Artem Melman,§ and Ovadia Lev*,† The Casali Institute and the NMR Laboratory, Institute of Chemistry, The Hebrew UniVersity of Jerusalem, Edmond E. Safra GiVat Ram Campus, Jerusalem, 91904 Israel, and The Department of Chemistry & Biomolecular Science, Clarkson UniVersity, Potsdam, New York 13699-5810 ReceiVed May 23, 2008. ReVised Manuscript ReceiVed July 28, 2008 A generic family of low molecular weight binary gels comprising β-cyclodextrin (β-CD) and one of a large variety of polyaromatic hydrocarbons (PAHs) in dimethylformamide (DMF), pyridine, and other polar solvents is described. The system is rather general and robust. It tolerates large changes in each of the major ingredients without losing gelation ability. R- and γ-CD, and negatively or positively modified β-CD (e.g., sulfate-, phosphate-, or amine-tethered β-CD) as well as methylated β-CD are all effective gelators. The cogelators encompass a similarly large variety of compounds characterized by the ability to form an ovular inclusion complex with the CD molecules and a capability to stack outside the CD cap to give long-range order far from the CD cap. Despite the low ratio between the CD and the cogelators, we show that most of the CD molecules are retained in the liquid phase and do not participate directly in the actual construction of the gel network. In fact, most of the sulfated and phosphated β-CDs can be cleaned off the gel structure by electrophoresis, leaving an intact gel porous structure. The nonstoichiometric nature of the gel is underscored by the fact that one molecule of β-CD can combine with as few as three molecules of chrysene or as many as 450 molecules of chrysene to gelate an additional 35 000-40 000 molecules of the solvent.
Introduction Low molecular weight gels, LMOGs, gels that are supported solely by noncovalent bonding of the small monomer building blocks, are an intriguing field of activity borrowing features from supramolecular chemistry and soft materials. A minute quantity of organic gelator can form a mesh of one-dimensional wirelike structures that entrap the solvent by surface tension forces and restrict its fluidity with minimal effect on local viscosity or diffusion in the porous network. LMOG supramolecular structures are still at the exponential phase of the learning curve, whereas similar polymeric constructions are now rather well understood and find many practical applications. Over the past decade, the field has undergone a revolution, where serendipity is gradually giving way to methodical design based on predictive concepts. At least partly, this careful design is necessary due to the fact that the vocabulary of gel monomers is now increasing rather slowly and the known (large) families of gelators are chemically modified to support additional morphologies and applications. New gel variants require more elaborate synthesis and chemical design, since the simpler building blocks have already been exploited. There is a need for additional building blocks that will increase the variety of available gelators. A facile way to diversify LMOGs is by designing two component gelators. Of particular interest within this subclass are the binary gels that are formed only in the presence of both components. Transition metal coordination by organic moieties,1,2 carbon dioxide reversible anchoring of amine functionalities,3 and hydrogen bond bridging4 are all examples of this general approach. Donor-acceptor * Corresponding author. † The Casali Institute, The Hebrew University of Jerusalem. ‡ NMR Laboratory, The Hebrew University of Jerusalem. § Clarkson University.
(1) Liu, Q. T.; Wang, Y. L.; Li, W.; Wu, L. Langmuir 2007, 23, 8217–8223. (2) Shirakawa, M.; Fujita, N.; Tani, T.; Kaneko, K.; Ojima, M.; Fujii, A.; Ozaki, M.; Shinkai, S. Chem.sEur. J. 2007, 13, 4155–4162. (3) (a) Xu, H.; Rudkevich, D. M. J. Org. Chem. 2004, 69, 8609–8617. (b) Xu, H.; Rudkevich, D. M. Chem.sEur. J. 2004, 10, 5432–5442.
interactions, such as those between anionic surface active agents and phenolic hydrogen donors,5 between bile acid bound pyrene or guaiazulene and trinitrofluorenone,6 or between polyaromatic hydrocarbons and nitroaromatics, have been well studied. 7 One particular intriguing class of gelators is the “nonstoichiometric” gels, where both components are essential for gel formation but the ratio between the two components is not constant and gel stoichiometry can vary over a wide range. Along this line, we have demonstrated that donor-acceptor interactions between cholesteryl 3,5-dinitrobenzoate, ester or alkyl 3,5dinitrobenzoate and different polyaromaric compound donors can gelate up to an additional 15 molecules of the latter in different solvents.7 Here, we extend this line of research to nonstoichiometric gels based on cyclodextrin host-guest inclusion interactions. Over four generations after their first discovery, cyclodextrins continue to be an endless source of surprises. Crystalline and soluble adducts of cylodextrins are of great scientific and practical interest, and different classes of adducts continue to emerge.8-15 In recent years, several researchers constructed low molecular (4) Bao, C. Y.; Lu, R.; Jin, M.; Xue, P. C.; Tan, C. H.; Liu, G. F.; Zhao, Y. Y. Org. Biomol. Chem. 2005, 3, 2508–2512. (5) (a) Singh, M.; Tan, G.; Agarwal, V.; Fritz, G.; Maskos, K.; Bose, A.; John, V.; McPherson, G. Langmuir 2004, 20, 7392–7398. (b) Xu, X. D.; Ayyagari, M.; Tata, M.; John, V. T.; McPherson, G. L. J. Phys. Chem. 1993, 97, 11350–11353. (6) Babu, P.; Sangeetha, N. M.; Vijaykumar, P.; Maitra, U.; Rissanen, K.; Raju, A. R. Chem.sEur. J. 2003, 9, 1922–1932. (7) Rizkov, D.; Gun, J.; Lev, O.; Sicsic, R.; Melman, A. Langmuir 2005, 21, 12130–12138. (8) Kano, K. Colloid Polym. Sci. 2008, 286, 79–84. (9) Venturini, C. D. G.; Nicolini, J.; Machado, C.; Machado, V. G. Quim. NoVa 2008, 31, 360–368. (10) Bhosale, S. V.; Bhosale, S. V. Mini-ReV. Org. Chem. 2007, 4, 231–242. (11) Frampton, M. J.; Anderson, H. L. Angew. Chem., Int. Ed. 2007, 46, 1028– 1064. (12) Fakayode, S. O.; Lowry, M.; Fletcher, K. A.; Huang, X. D.; Powe, A. M.; Warner, I. M. Curr. Anal. Chem. 2007, 3, 171–181. (13) Tian, H.; Wang, Q. C. Chem. Soc. ReV. 2006, 35, 361–374. (14) Haider, J. M.; Pikramenou, Z. Chem. Soc. ReV. 2005, 2, 120–132. (15) Drechsler, U.; Erdogan, B.; Rotello, V. M. Chem.sEur. J. 2004, 10, 5570–5579.
10.1021/la801592n CCC: $40.75 2008 American Chemical Society Published on Web 09/12/2008
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weight organogels formed by binding different pendant groups to the rims of the cyclodextrin cap.16-18 A similarly successful approach for gel formation used cyclodextrins that are bound to polymer chains such as poly(ε-lysine), poly(allylamine), and poly(ethylene oxide).19-23 Here, we demonstrate that unmodified cyclodextrins, methylated CDs, as well as sulfate-, amine-, and phosphate-modified CDs constitute a general class of gelators capable of participation with a large family of polyaromatic hydrocarbon cogelators to gelate a range of polar solvents. Moreover, we demonstrate that cyclodextrins can gelate a broad range of hydrophobic gelators that can form inclusion complexes with the CDs and retain a large hydrophobic, rigid section of the molecule outside the cyclodextrin caps. One molecule of CD can assemble more than 400 molecules of aromatic compounds to gelate the entire solution. The unprecedented ratio between the cogelator and the gelator was never reported before, though it has remote analogies in seemingly unrelated fields that deal with nucleation and crystal growth and deposit formation in supersaturated solutions in body fluids and the brain as well as in membrane systems for water treatment.
Scheme 1. β-CD and Modified β-CDs Used in This Research
Experimental Section
diode (LED) experiment25,26 with a gradient pulse length of 1 ms (to yield a total bipolar pulse of 2 ms) and a delay between bipolar gradient sets of 100 ms. The spectrum was processed by a Fourier transform in the acquisition (t2) dimension and by a LevenbergMarquardt27,28 fit to decaying Gaussians, supplied with the Bruker TOPSPIN software, in the evolution (t1) dimension. The diffusion constant of each component was evaluated from the median of the peak in the summed projection over the signals of each component. Elemental analysis was carried out by the Microanalysis Laboratory of the Hebrew University. Scanning electron microscopy (SEM) imaging was performed by using a JEOL JXA-8600 Superprobe instrument. Powder X-ray diffraction was measured with a Bruker AXC automated powder diffractometer (Long focus Cu X-ray tube) at a 2°/min scan rate. General Methods for the Preparation of Two-Component Inclusion Organogels. A suspension of the cyclodextrin with the cogelator, polyaromatic hydrocarbon (PAH) or another compound, in different ratios of water/DMF solutions was heated until a clear (yellowish for PAH) solution was formed. Usually, heating to 100 °C was sufficient. The resulting solution was cooled in an ice-water bath or to room temperature as indicated to provide, depending on concentration and ratio of the components, a gel in 1-10 min. The inverted vial approach29 was used as a general criterion for gel formation. Energy minimized molecular models were obtained with Macromodel software of Schrodinger Inc.
Materials. Dimethylformamide (DMF), acetonitrile, and pyridine were from J. T. Baker (Deventer, Holland). Toluene, 1-methyl-2pyrrolidone, heptakis(2,3,6-tri-o-methyl)-β-CD (Me-CD) were from Fluka (Bushs, Switzerland). Trifluoroacetic acid was obtained from Sigma. Naphthalene, anthracene, chrysene, pyrene, tryphenylene, 1,2;5,6-dibenzoanthracene, phenanthrene, benzo[a]pyrene, benzo[e]pyrene, anthraquinone, 2-chloroanthraquinone dibenzothiophene, Sudan II, 4,4′-dibromobiphenyl, acenaphthenequinon, acenaphthene, R-, β-, and γ-cyclodextrins, β-CD sulfated sodium salt (sulfate-βCD), and β-CD phosphate sodium salt (phosphate-β-CD) were obtained from Aldrich. Mono-6-deoxy-6-amino-β-cyclodextrin hydrochloride (Am-CD) was synthesized following the procedure in the literature.24 The different β-CD moieties are depicted in Scheme 1. Unless otherwise stated, all reagents were analytical grade and were used as received. We used deionized water (conductivity < 0.1 mS/cm) purified by a Seradest SD 2000 system. Safety note: The polyaromatic hydrocarbons chrysene, 1,2;5,6dibenzanthracene, and benzo[a]pyrene and pyridine are probable carcinogens. Analytical Procedures and Instruments. 1H NMR spectra were recorded on Bruker DRX-400 and Avance II 500 spectrometers in deuterated DMF/D2O solutions using the rightmost residual solvent peak for calibration to 2.75 ppm. 2D Nuclear Overhauser enhancement spectroscopy (NOESY) and ROESY spectra were recorded at a constant temperature (T ) 312 K) applying a standard pulse sequence with different mixing times of τ ) 225-700 ms over a sweep width of 7500 Hz using 2048 data points in the t2 dimension and 1024 increments in the t1 dimension. The relaxation delay was 1 s. Two scans were collected for each t1 increment. All the reported experiments were conducted using the 500 MHz instrument except for the temperature dependence delineated in Figure 6. Diffusion coefficients were measured using an asymmetric bipolar light-emitting (16) Choi, H. S.; Yui, N. Prog. Polym. Sci. 2006, 31, 121–144. (17) Deng, W.; Yamaguchi, H.; Takashima, Y.; Harada, A. Angew. Chem., Int. Ed. 2007, 46, 5144–5147. (18) Miyauchi, M.; Takashima, Y.; Yamaguchi, H.; Harada, A. J. Am. Chem. Soc. 2005, 127, 2984–2989. (19) Choi, H. S.; Yui, N. Prog. Polym. Sci. 2006, 31, 121–144. (20) Harada, A.; Furue, M.; Nozakura, S. Macromolecules 1976, 9, 701–704. (21) Deratani, A.; Popping, B. Macromol. Chem. Phys. 1995, 196, 343–352. (22) Huh, K. M.; Tomita, H; Lee, W. K.; Ya, T.; Yui, N. Macromol. Rapid Commun. 2002, 23, 179–182. (23) Hernandez, R.; Rusa, M.; Rusa, C. C.; Lopez, D.; Mijangos, C.; Tonelli, A. E. Macromolecules 2004, 37, 9620–9625. (24) Russell, C.; Salek, J. S.; Sikoorski, C. T; Kumaravel, G.; Lin, F.-T. J. Am. Chem. Soc. 1990, 112, 3868–3874.
Results and Discussion β-Cyclodextrin Gelation of Polyaromatic Hydrocarbons (PAHs). Table 1 delineates the minimal concentration of the cogelators necessary in order to gelate different gelators in DMF/ water solutions. The solutions were first heated in closed vials to around 90-150 °C to form a translucent liquid phase, and then the vials were either immersed at 0 °C ice bath or left to stand at room temperature. The table reports gelation either at room temperature or at 0 °C, but of course, whenever a gel was formed at room temperature it was also formed at 0 °C. In a (25) Wu, D. H.; Chen, A. D.; Johnson, C. S. J. Magn. Reson. A 1995, 115, 260–264. (26) Pelta, M. D.; Morris, G. A.; Stchedroff, M. J.; Hammond, S. J. Magn. Reson. Chem. 2002, 40, S147–S152. (27) Levenberg, K. Q. Appl. Math. 1944, 2, 164–168. (28) Marquardt, D. SIAM J. Appl. Math. 1963, 11, 431–441. (29) Murata, K.; Aoki, M.; Suzuki, T.; Harada, T.; Kawabata, H.; Komori, T.; Ohseto, F.; Ueda, K.; Shinkai, S. J. Am. Chem. Soc. 1994, 116, 6664–6676.
40 mg cm-3a (259 mM), 0 °C
43 mg cm-3a (233 mM), 0 °C 40 mg cm-3a (145 mM), 0 °C 53 mg cm-3a (170 mM), 0 °C
Table 2. CD Gelators of 176 mM Chrysenea 9% DMF in H2O R-CD β-CD γ-CD Me- β-CD amine-CD sulfate-β-CD phosphate- β-CD
23% H2O in MPD
0 °C 0 °C 0 °C
0 °C 25 °C 25 °C 0 °C
pyridine 0 0 0 0 0 0 0
°C °C °C °C °C °C °C
Figure 1. Minimal gelation concentration of R-, β-, and γ-CD gelators (from top) with chrysene cogelator as a function of r, cogelator to gelator mole ratio. Conditions: 0 °C gelation, 1:10 water/DMF solvent.
a
Incomplete solubility of the cogelator.
40 mg cm-3 (220 mM), 0 °C 40 mg cm-3 (220 mM), 0 °C
40 mg cm-3 (145 mM), 0 °C
0 °C 25 °C 25 °C 0 °C 0 °C 0 °C 0 °C
17% H2O in MPD
a MPD: 1-Methyl-2-pyrrolidone. In all cases, we used 20 mg cm-3 modified CD gelators and 176 mM chrysene.
40 mg cm-3 (145 mM), 0 °C 53 mg cm-3 (170 mM), 0 °C 40 mg cm-3 (220 mM), 0 °C
38.5 mg cm-3a (185 mM), 0 °C 40 mg cm-3a (165 mM), 0 °C 43 mg cm-3 (233 mM), 0 °C 40 mg cm-3 (145 mM), 0 °C 53 mg cm-3 (170 mM), 0 °C 40 mg cm-3a (220 mM), 0 °C 40 mg cm-3 (259 mM), 0 °C 40 mg cm-3 (165 mM), 0 °C
60 mg cm-3 (129 mM), 0 °C 38.5 mg cm-3 (185 mM), 0 °C 40 mg cm-3 (165 mM), 0 °C
38.5 mg cm-3 (185 mM), 0 °C 40 mg cm-3 (165 mM), 0 °C
60 mg cm-3a (337 mM), 0 °C 50 mg cm-3a (198 mM), 0 °C 50 mg/mLa (198 mM), 0 °C 60 mg cm-3 (337 mM), 0 °C 50 mg cm-3 (198 mM), 0 °C 50 mg/mL (198 mM), 0 °C cm-3
50 mg (198 mM), 0 °C 50 mg/mL (198 mM), 0 °C
60 mg cm-3a (297 mM), 0 °C
45 mg cm-3 (197 mM), 25 °C 51 mg cm-3a (183 mM), 0 °C
60 mg cm-3 (263 mM), 0 °C
45 mg cm-3 (197 mM), 25 °C 51 mg cm-3 (183 mM), 0 °C
60 mg cm-3 (297 mM), 0 °C 45 mg cm-3 (197 mM), 25 °C
35.3 mg cm-3 (275 mM), 0 °C
80 mg cm-3 (485 mM), 0 °C 60 mg cm-3a (263 mM), 0 °C 60 mg cm-3 (485 mM), 0 °C 60 mg cm-3 (263 mM), 25 °C
80 mg cm-3a (485 mM), 0 °C
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naphthalene anthracene chrysene pyrene triphenylene 1,2;5,6-dibenzoanthracene phenanthrene benzo[a]pyrene benzo[e]pyrene 5,15-diphenylporphyrin anthraquinone 2-chloroanthraquinone dibenzothiophene Sudan II 4,4′-dibromobiphenyl acenaphthenequinone acenaphthene
17% H2O in DMF 9% H2O in DMF DMF Compound
Table 1. Cogelators of 17.6 mM β-CD in DMF and Water-DMF Solutions
29% H2O in DMF
41% H2O in DMF
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preliminary study, we have found that 17.6 mM β-CD is most likely to form gels with our PAH cogelators, and this value was used as a common denominator for the construction of Table 1. The value of 17.6 mM is close to the maximal dissolution concentration of β-CD in DMF. The driving force for a solute to leave the solution phase in preference for the binary gel skeleton is higher under near saturation conditions of the single solute solution. Indeed, in most cases, some crystal coprecipitation could be observed in the gel phase. Here, we use the term gelator for the host cyclodextrin moieties and reserve the term cogelator for the inclusion ligands. Since Tables 1 and 2 are so extensive, covering different groups of the cogelators and gelators, it is useful to look first into the details of gels formed from an unmodified β-CD with model PAH cogelators and only then address other possible gelators and cogelators. Figure 1 depicts the minimal concentration at which the anthracene/β-CD pair forms gels in an ice bath at 9:91 water/ DMF solutions. The lack of a constant stoichiometry ratio for gel formation is already apparent from this curve, as gels can be sustained by over 10-fold stoichiometry range. The CD concentration required for gelation increases as the molar ratio between the chrysene and the CD is decreased. This is to be expected if we consider that a prerequisite for the formation of a gel is a minimal concentration of complexes between the CD and the cogelator moieties. The decrease in the total amount of CDs has to be compensated by an increase in the fraction of PAH conjugated CDs, which is facilitated by increasing the PAH levels. Another reason for the observed negative dependence is that there seems to be a need for a certain degree of PAH oversaturation, regardless of the concentration of the CD, in order to induce gelation. As the concentration of the CD is lowered, it is necessary to compensate for it by an increased ratio of PAH to CD in order to attain oversaturation. Figure 2 compares the minimum gelation concentrations as a function of the anthracene/β-CD ratio for different levels of water content. Increasing the water level reduces the minimal anthracene required for gelation. This agrees well with our basic assumption that a solubility decrease, due to a higher water level, increases the tendency to form a gel phase. Therefore, this phase tends to form even at lower PAH levels.
Nonstoichiometric Gelation of Cyclodextrins
Figure 2. Minimal gelation concentration of anthracene/β-CD gels as a function of the water to DMF ratio. Curves correspond to 9:91, 17:83, and 23:77 water/DMF solutions (from top). Gelation was carried out at 0 °C.
Direct evidence relating to the structure of the anthracene/ cyclodextrin gels is lacking. Electron microscopy studies conducted after vacuum evaporation of gel samples at room temperature shows a platelet morphology. However, we suspect that the platelet morphology, as shown in Figure 3, does not reflect the gel state, as PAH crystallization is likely to occur after and during solvent evaporation. Indeed, X-ray studies of the solid obtained after solvent evaporation show close to 90% crystallinity for the chrysene as well as the anthracene components of the gel, whereas the degree of crystallinity of most gels is much lower than 50%. The gelation of different β-CD pairs was studied in a large number of solvents. The most successful solvents were DMF, dimethylpyrrolidone, pyridine, and their water mixtures. The β-CD/anthracene pair gelates DMF solutions only in the presence of 9-29% water. For higher and lower water levels, crystal formation dominates, and the gel state is not formed. Clearly, a degree of solvent hydrophilicity is required for efficient inclusion of the PAH guest into the hydrophobic β-CD cavity. The preference of the anthracene for the CD cavity diminishes as the solvent becomes more hydrophobic. However, when the water content was increased further, the solubilities of the PAHs and the β-CD became so small, that it was impossible to obtain a clear solution with sufficiently high anthracene concentration. Additionally, the driving force for the competing crystallization of the anthracene becomes too high in water-rich solutions, resulting in crystallization rather than gel formation. On the other hand, increasing the solubility of the PAH by decreasing water content lowers the driving force for inclusion complex formation and hinders gelation. Although it is not apparent in Table 1, a parallel tendency is obeyed for the chrysene/DMF system. Too high a concentration of water induces gelation, and although a gel is formed even with pure DMF, a further increase of the hydrophobicity of the solvent (e.g., by adding 30% octanol) increases the solvent competition for the chrysene moiety, lowers hydrophobicity driven inclusion complexation, and prevents gel formation. The ability of β-CD/PAH to gelate a pyridine solution (with no added water) is interesting, since it accentuates the importance of π-π stacking (rather than hydrophobic interactions) in gel formation. Figure 4 compares the efficiency of different cogelators by depicting the minimal gelation concentration as a function of the gelator/cogelator molar ratio. Naphthalene, anthracene, chrysene, and dibenzoanthracene were chosen as a model series of cogelators. All tests were conducted at 1:10 H2O/DMF solvent. The larger the PAH, that is, the more fused aromatic rings it has, the more susceptible it is to form gels. In fact, the two-ring naphthalene does not form a gel at all at this temperature, and so it was not included in Figure 4. Again, the different tendencies
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can be explained by the CD inclusion susceptibility. The larger the PAH, the more hydrophobic it is, and the larger the tendency to form host-guest complexes, which seems to be pertinent for gel formation. Although the stability constants of the different β-CD/PAH pairs in DMF were not reported, the reported inclusion susceptibility in water certainly follows a similar trend. For example, D’Anna et al.30 reported that the complexation constants at pH 8 for anthracene and chrysene are 190 and 2800 M-1, respectively. Moreover, larger PAHs such as chrysene and pyrene form 2:1 complexes with β-CD which may enhance fiber branching that is pertinent for gel formation. The phenomenon depicted here is rather general. All three common R-, β-, and γ-CDs form gels with most PAHs. Figure 1 compares the minimal gelation concentration of R-, β-, and γ-CDs in 1:10 water/DMF solutions. Clearly, the smaller the cavity, the smaller the tendency to form gels. This is not surprising, since the tendency of the chrysene to form complexes with the three CDs increases as the cavity size is decreased. Male and co-workers31 reported that the solubility of chrysene in water/ CD solutions containing 25 nM CD was nondetectable for R-CD, 0.24 µM for β-CD, and 0.38 µM for γ-CD. This shows that, at least for chrysene, the intuitive conception that β-CD forms host-guest complexes more efficiently than the γ-species is not true for chrysene. Additionally, the larger the CD cavity, the more susceptible it is to form multiple guest-host complexes, which may provide better opportunities for gel branching. Branching of the otherwise linear supramolecular polymers formed from low molecular weight gelators is now known to be pertinent to gel formation.32-34 In order to check whether the rims of the CD caps or their outer surfaces are responsible for the observed capability to combine with the polyaromatic hydrocarbons and gel the DMF solutions, we examined the gelation capability of four additional modified CD cogelators. We chose a positively charged CD, mono-6-deoxy-6-amino-β-cyclodextrin hydrochloride (amineCD), two negatively charged CDs, sulfate- and phosphatemodified CDs (sulfate-β-CD and phosphate-β-CD), and a hydrophobically modified CD, heptakis-(2,3,6-tri-o-methyl)-βcyclodextrin (Me-β-CD). All four modified β-CDs retained the ability to combine with chrysene and gelate the pyridine and the DMF/water solutions. Me-β-CD was effective in cogelating up to 33% water/DMF solution, whereas both negatively and positively charged modified CDs lost their gelation capability when the water level was increased. The retained ability to combine with chrysene and gelate different solvents underscores the significance of the host-guest uvular structure for CD gel formation. CD modifications are limited to the periphery of the CD caps (Figure 5) and thus have relatively little influence on the host-guest interaction. The somewhat limited range of water/ DMF solutions that can undergo gelation by the amine-, sulfate-, and phosphate-derivatized CDs can be explained by the destabilizing effect caused by the interaction between the appended charged functionalities on the rim of the CD cap and the portion of the chrysene which protrudes out of the CD cap. Non-PAH Cogelators. In order to derive general guidelines about the range of cogelators, we tried to prepare gels using a large range of cogelators in a 9:91 water/DMF ratio and 17.6 mM β-CD. The positive results of this investigation are depicted in Table 1. Compounds that failed to produce gels include (30) D’Anna, F.; Riela, S.; Lo Meo, P.; Noto, R. Tetrahedron 2004, 60, 5309– 5314. (31) Male, K. M.; Brown, R. S.; Luong, J. H. T. Enzyme Microb. Technol. 1995, 17, 607–614. (32) Liu, X. Y.; Sawant, P. D. Appl. Phys. Lett. 2001, 79, 3518–3520. (33) Liu, X. Y.; Sawant, P. D. Angew Chem., Int. Ed. 2002, 41, 3641–3645. (34) Liu, X. Y.; Sawant, P. D. ChemPhysChem. 2002, 3, 374–377.
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Figure 3. SEM micrograph of vaccuum-dried chrysene/β-CD gel prepared from 1:9 water/DMF solution. Inset: Inverted vial of the gel before solvent evaporation. Preparation conditions: 0 °C gelation, chrysene/β-CD ratio ) 3:1, CD concentration ) 17.6 mM. Bar ) 100 µM.
Figure 4. Minimal gelation concentration of anthracene, chrysene, and 1,2;5,6-dibenzoanthracene as a function of r, cogelator/gelator mole ratio. Conditions: 0 °C gelation, water/DMF ratio ) 1:10.
coronene, porphyrin, met-porphyrin (where met stands for Pb2+, Fe2+, Cu2+), 5,15-(2-[1,3-dithiolanyl])-porphyrin, protoporphyrin, azobenzene, tetraphenylporphyrin, phthalocyanine, 2,3-naphthalocyanine, indigo, crystal violet, acridine, benzo[g,h,i]perylene, and phenanthroline. A qualitative model accounting for these observations is presented in the Discussion section. NMR Studies of Gel Stoichiometry. Recent investigations, particularly by NMR, revealed a dynamic equilibrium between the portion of the gelator molecules held within the gel network and the gelator molecules in the solution phase. Four different molecular populations contributing differently to the observable NMR signal can be distinguished: (i) Gelator molecules incorporated within the gel network. The large correlation time of the species in the gel network results in a very short transverse relaxation time (T2), and thus, the fraction of the molecules within the gel produce a broad signal that cannot be distinguished from the background noise. (ii) Dimers, noncoValently held oligomers, and other clusters that are still retained in the solution phase. These molecules exhibit short T2 but are nonetheless still distinguishable by NMR. In some cases, particularly when hydrogen bonding is involved in gel formation, a large peak shift may hint on a predominance of these clusters even in the liquid phase. Additionally, the observed diffusion coefficients, calculated based on the use of pulsed field gradient NMR, should be
considerably lower when clusters are the dominant species in the solution compared to a situation where discrete molecular species are dominant. Practically, a decrease of the observed diffusion coefficient should take place when the concentration of the gelator is increased under isocratic conditions, or, more relevantly to the current work, a marked decrease of the diffusion coefficient should be encountered upon the addition of the gelator to a solution containing the cogelator molecules alone. The decrease in diffusion coefficient should happen even if there is no viscosity change. Since the diffusion coefficient scales roughly as the cubic root of the molecular weight, the observed diffusion coefficient of the dissolved species should decrease by more than 20% when a dimer is the dominant species in the solution and by some 40% after the formation of a predominant quartet. A third characteristic that should prevail when the NMR signal is predominantly due to the dissolved clusters is a significant dipolar interaction manifested in a significant nuclear Overhauser effect, NOESY, or its variant, ROESY. If the NMR signals of the individual gel components are both sufficiently large, there should be observable NOESY and ROESY signals as well. The opposite is not necessarily correct, since the NOESY signal depends strongly on the interproton distance and the absence of a signal is not proof of the absence of aggregation. Intimate contact between protons may induce a very large NOE signal even when only a very small fraction of the molecules participates in nonscalar proton-proton interactions. (iii) Mobile segments of the gel. Duncan and Whitten35 attributed the observed NMR signal from p-R-cholesteryl-p′-octoxystilbenoate gel to the mobile portion of the gel. The distinction between this class and the previous one seems to be impossible based on NMR studies alone. Fortunately, the distinction between the last two classes is less relevant for the current analyses. (iV) Discrete dissolVed gelator molecules. This is the most relevant class for the current research. The signal of the dissolved species in the presence of the gel is often characterized by broadening of the NMR peaks and lower (35) Duncan, D. C.; Whitten, D. G. Langmuir 2000, 16, 6445–6452.
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Figure 5. Energy minimized chrysene inclusion complexes of R-, β-, and γ-CD and sulfate-β-CD (from left to right).
Figure 6. 1H NMR spectra of chrysene/β-CD gels in deuterated DMF as function of temperature. Total β-CD concentration ) 9. mM; total chrysene concentration ) 186 mM.
T2 values, partly due to the change in liquid viscosity. Escuder and his co-workers36 attributed the low T2 to the exchange of discrete gelator molecules between the gel network and the dissolved state. We conducted 1H NMR studies of PAH/β-CD gels in DMFd7/D2O solutions (containing 9:91 DMF-d7/D2O solvent). The solutions contained 9 mM β-CD and 185 mM chrysene. A typical set of spectra demonstrating the temperature dependence is depicted in Figure 6. At room temperature, we obtain the 1H NMR spectrum 7.9 (4H, m), 8.33 (4H, q), 9.11 (2H, d), 9.16 (2H, d) peaks for chrysene and the 3.66 (-CH-O, m), 3.92 (-CH-O-, m), 4.09 (-CH-O, -CH2-O, m), 5.14 (-CH-O, d) peaks for β-CD. The NMR determined diffusion coefficient of the chrysene was 6.9 × 10-10 m2 sec-1 compared to 6.0 × 10-10 m2 sec-1 at T ) 25 °C in the absence of cyclodextrin, and for β-CD it was 1.73 × 10-10 m2 sec-1 in the presence of the gel compared to 2.3 × 10-10 m2 sec-1 in the homogeneous solution. These small differences, particularly for the chrysene, can be attributed to small changes in the viscosity and a smaller free path in the presence of the gel. We carried out extensive efforts to obtain NOESY or ROESY signals (using the parameters delineated in the Experimental Section and conditions identical to those used in Figure 6), but all our studies failed to reveal any NOESY signal. These two tests provide conclusive evidence that the NMR signals are predominantly contributed by the discrete dissolved species of chrysene and β-CD rather than by molecular clusters or mobile gel segments. As previously observed, both the peaks of the chrysene as well as the β-CD peaks broaden gradually as the temperature is decreased. Likewise, the H2O and DMF signals were slightly broadened at lower temperature. (36) Escuder, B.; Lusar, M. L.; Miravet, J. F. J. Org. Chem. 2006, 71, 7747– 7752.
Figure 7. (a) Mole fraction of chrysene and β-CD in the gel phase and in the liquid phase as a function of temperature and (b) van’t Hoff dependence of the observed gel formation constant.
Figure 7 depicts the dependence of the dissolved concentrations of β-CD and chrysene on the temperature. The test conditions were identical to those depicted in Figure 6. The figure shows that the chrysene follows the expected logarithmic dependence, similar to the dependence obtained for the components of the cholestryl/dinitrobenzoate/anthracene gel,7 whereas β-CD does not follow any simple dependence. Moreover, the concentration
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Figure 8. Sulfate-β-CD/chrysene gel and the electrophoretic setup after electrophoretic evacuation of most of the charged CD from the gel. The gel (1) is cast as a barrier between two DMF/water electrode compartments (2). One of the platinum electrodes (3) is shown.
of the β-CD in the solution ranges from 89% to almost 100% of the β-CD that was introduced to the vial, which implies that only a minute amount of CD is dissolved in the solution phase. This surprising behavior seems to indicate that the gel was not stoichiometric and, more importantly, that the amount of β-CD that is actually incorporated into the gel skeleton is very minimal. It is possible to determine the approximate ∆H° of gel formation, by a procedure that was previously used for the nonstoichiometric donor acceptors gels,7 assuming that gel formation is given by eq 1.
Vcogelatorcogelator + gelator a gel
(1)
By assigning unit activity for the gel phase and taking the concentration in the solution phase to be equal to the dissolved concentration of the cogelator and chrysene, one may formally express the Gibbs free energy of gel dissolution by eq 2.
∆G° ) -RT ln K ) -RT ln[cogelator]Vcogelator[gelator] (2) The van’t Hoff equation can then be used on condition that the enthalpy of the reaction is approximately constant, giving
∆H° ≈ -R
d ln K d(1 ⁄ T)
(3)
Defing the expression
ln K ′ ≡ ln([cogelator][gelator]) )
1 ln K Vcogelator
(4)
gives a simple expression for the enthalpy associated with the addition of a single cogelator molecule to the gel:
∆H° d ln K′ ≈ -R Vcogelator d(1 ⁄ T)
(5)
Figure 7b depicts the graphic form of eq 5. A plot of the natural logarithm of the concentration product of the dissolved free chrysene and β-CD against the reciprocal of the absolute temperature gives a straight line with very high correlation coefficients R2 ) 0.998 (n ) 7, covering the temperature range
between 25 and 85 °C). From the slope of the curve and from the T ) 25 °C equilibrium coefficient, K′, we could derive the equilibrium constants and the standard thermodynamic values of dissolution. ∆H°/Vcogelator ) 36.5 kJ mol-1, ∆G°/Vcogelator ) 25.0 kJ mol-1, and ∆S°/Vcogelator ) 38 J mol-1 K-1. In a previous paper delineating nonstoichiometric donor acceptor gels of anthracene/cholesteryl 3,5-dinitrobenzoate cogelators, we obtained ∆H°/Vanthracene ) 41 kJ mol-1, ∆G°/Vanthracene ) 13.7 kJ mol-1, and ∆S°/Vanthracene ) 93 J mol-1 K-1. Although the enthalpy change is quite similar in the two systems, the entropy gain by dissolution is substantially lower for CD gelators, probably due the much lower ordering of the chrysene in the CD gel network. The change of the thermodynamic values by a gradual change of the gelators, cogelators, and solvent is an intriguing subject that will be dealt with in future publications. Electrophoretic Evacuation of Cyclodextrin from the Gel and Minimal Gelator/Cogelator Ratio. In order to find out the amount of CD that is actually incorporated into the gel, we repeated the gelation procedure following the conventional gelation protocol with two differences: a concentration of 3.3 mM sulfate-β-CD was used as a cogelator instead of β-CD, and we added 30 mM LiClO4 as a supporting electrolyte. The initial cogelator/gelator molar ratio was 59.0. The gel was cast at 20 °C in the form of a 2 cm wide, 0.5 cm thick barrier between two DMF compartments (Figure 8). An electric field of 200 V cm-1 was then applied between the two platinum electrodes immersed in each of the two compartments. Since sulfate-β-CD is negatively charged, it was drawn to the anode compartment and was gradually evacuated from the gel. Application of an electric field for 10 h resulted in gel collapse. However, after 7 h of electrophoretic cleanup, the gel was still intact. We evacuated the gel into a vial and then heated the vial to 85 °C to receive a transparent and clear solution. At this stage, we conducted an NMR study in an attempt to quantify the sulfate-β-CD that was retained in the gel after the electrophoretic cleanup. Figure 8 compares the NMR spectra of the gel material at 70 °C before and after the electrophoretic cleanup. Curve 2 reveals a clean background
Nonstoichiometric Gelation of Cyclodextrins
Figure 9. 1H NMR spectra of sulfate-β-CD/chrysene gel after liquefication by heat treatment before (bottom) and after (top) electrophoretic cleanup of the sulfate-β-CD from the gel.
showing that most of the sulfate-β-CD was indeed evacuated from the gel. Based on Figure 9, the concentration of the CD in the gel could be estimated to be much less than 5% of the initial concentration that was introduced into the vial. Taking the limit of detection by NMR to be roughly 5% of the original peak, that is, 35 µM CD, we obtain a molar ratio of greater than 450 between the chrysene and CD that was retained in the gel. Each CD molecule gave order to over 450 molecules of chrysene in a supramolecular structure responsible for the gel maintenance in the DMF/water solution. After the electrophoretic cleaning, the gel was heated, and we attempted to cast it at room temperature according to the usual procedure. No gel was formed by room temperature gelation, but it was possible to obtain a weak gel at 0 °C, indicating that some sulfate-β-CD was retained in the gel even after the electrophoretic cleaning (Figure 9).
Discussion Understanding the underlying molecular interactions and the structure of low molecular weight gels is a challenge even for single and dual stoichiometric gels. Occasionally, electron microscopy of freeze-dried samples gives structures that can be unequivocally associated with the structure of the solution filled gel. In some other cases, a dominant hydrogen bonding or metal ion coordination of simple molecules is sufficient to decipher the gel structure. Nonstoichiometric gels are more complex, and the platelet micromorphology that is obtained after drying (Figure 3) has probably little bearing on the morphology of the wet gel. Therefore, we had to rely on indirect data to glean the interactions between the different gel building blocks. β-CD and a large stioichiometric excess of the gelator are both necessary for gel formation. In no case (Tables 1 and 2) could we construct a gel with one component only. True, there are many other cases, that are not mentioned explicitly in this article, where a monocomponent of a known gelator (e.g., cholesterol, dodecanoic and longer carboxylic acids) produced a gel in the presence of β-CD at higher temperature, or more quickly with β-CD than without it. However, all the gelators in Table 1 are incapable of gelation of our target solvent without adding CD. Despite the fact that the solution NMR studies reveal that most of the CD is actually residing in the solution, out of the gel (Figure 7a), and despite the fact the we could clean out most of the sulfate- or phosphate-CDs from the gel by electrophoretic force while maintaining the gel structure intact, there must be a sufficient level of cyclodextrin cogelator remaining to support gel maintenance or formation. Based on the cumulative weight of indirect evidence, we can propose the following model for gel structure. The gel comprises
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hydrophobic flat molecules that are stacked into long columns or bands by a combination of π-π and hydrophobic interactions. The ends (or at least one of the ends) of the columns are capped by cyclodextrins. The columns or bands are bound by random cross-links by hydrophobic interactions or by multiple inclusion of column-end molecules in the same CD. The CD can further promote gel formation by lowering the solubility of the planar hydrophobic components and thus increase oversaturation and promote gelation.32-34 For our model to be acceptable, mandatory requirements for a gelator should include the following: (i) hydrophobicity (for inclusion complex formation); (ii) a flat or almost planar section of the gelator to support columnar or band structure away from the CD; and (iii) the gelator must be able to partially penetrate the CD to form an inclusion complex. This basic set of requirements is indeed obeyed by all of the compounds in Tables 1 and 2, and at least some are violated by all of the compounds in the list of our unsuccessful gelators. All the PAHs except for coronene and benzo[g,h,i]perylene are flat, hydrophobic, and small enough to partially penetrate the CD cavity. When the solvent is too hydrophobic (e.g., by reducing the amount of water or adding a hydrophobic cosolvent), the CD cannot compete with the solvent on the hydrophobic ligand and a gel cannot form. When the ligand is too hydrophilic and cannot form stable host-guest interactions with the CD, the gel is not maintained (e.g., acridine, phenanthroline). When the ligand becomes too large to access the CDs (e.g., coronene, benzo[g,h,i]perylene) the gel cannot form. It seems that even very partial inclusion of the gelator into the CD is sufficient. This is made clear by the energy-minimized structures of Figure 5, which show that most of the chrysene molecule is protruding out of the wider rim of the CD. This is also supported by the diphenylporphyrin gelator, where only the phenyl group is small enough to penetrate the CDs. The importance of the gelator’s ability to form long-range stacking order outside of the CD is illuminated by the dramatic effect of metal salts on the formation of the CD/diphenylporphyrin gels. Metal ions that can ligate porphyrins (e.g., Pb2+, Fe2+, Cu2+) interfere with their stacking order and with gel formation, whereas alkali ions (e.g., sodium and potassium) that do not coordinate strongly to the porphyrinato ligands do not hinder gel formation. The question of whether inclusion interaction is vital for gel formation or whether it can be substituted by hydrophobic interaction with the outer sections of the CD gelator is resolved by the gelation capability of hydrophobic, methyl-modified β-CD. None of the unsuccessful cogelators (e.g, coronene, acridine, or phenanthroline) could form gels with the Me-β-CD. If external interaction was sufficient for gelation, then gel formation should have enhanced the gelation of some of the otherwise unsuccessful candidate cogelators. It may be surprising, at first glance, to note that the sulfate, phosphate, and amine conjugation did not interfere with gel formation. However, the minimized energy model of Figure 5 shows that these polar moieties are appended to the narrow rim of the CD whereas the chrysene is protruding from its other rim. Thus, minimal interference between the included cogelator and the functional group should be expected. Two other qualitative conclusions can be gleaned by Figure 5. More than one chrysene can be included in the same CD, which endows ample opportunity for gel branching originating at a CD junction. A crude energy minimizing simulation also suggests a possible explanation for the relative tendency of R-, β-, and γ-CDs to form gels with chrysene (Figure 1). It can be seen that two chrysene molecules can hardly fit into a single R-CD, they fit better into β-CD, and they fit even better into γ-CD. The estimated binding energy of a pair of chrysene molecules in R-, β-, and γ-CDs by
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potential energy computation of the complexes gives 86, 93, and 98 kJ mol-1 for R-, β-, and γ-CDs, respectively, which again agrees with the observed affinity. These crude calculations cannot provide correct absolute energy values, but they are useful to illuminate an affinity trend similar to the one that emerges from Figure 1. Whereas we feel that the CD-gelator interactions are shown to exist by our observations, we have to admit that the configuration of the gelator molecules is hardly resolved. The way by which a few hundred molecules, far away from the vicinity of the CD building block, feel its influence and retain the gel structure is perhaps the most important unanswered question.
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supramolecular assembly. Analogous activity can be found in somewhat remote areas including the way by which trace impurities influence crystal nucleation and morphology,37 the technologically important role of minute antiscalants in preventing scale formation in the mineral-rich environments encountered in water treatment membrane processes, and perhaps the more remotely related and least understood biological processes involving amyloid deposits in brain tissue.38 Acknowledgment. The authors wish to thank the Ring foundation and the Science Infrastructure Program of the Ministry of Science of Israel. LA801592N
Concluding Remarks These findings illuminate an unusual feature whereby a minute amount of a compound influences the long-range order of a
(37) Weissbuch, I.; Lahav, M.; Leiserowitz, L. Cryst. Growth Des. 2003, 3, 125–150. (38) Harrison, R. S.; Sharpe, P. C.; Singh, Y.; Fairlie, D. P. ReV. Physiol., Biochem., Pharmacol. 2007, 159, 1–77.
