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Inclusion Complex Formed between Star-Poly(ethylene glycol) and Cyclodextrins Edvaldo Sabadini*,†,‡ and Terence Cosgrove† School of Chemistry, The University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom, and Instituto de Quimica, Universidade Estadual de Campinas, Caixa Postal 6154, CEP 13084-862 Campinas, Brazil Received July 22, 2003. In Final Form: August 19, 2003 Aqueous solutions of R- and γ-cyclodextrins can form spontaneous inclusion complexes with poly(ethylene glycol), PEG, in which the hydrophobic cavities of the cyclic oligosaccharides can be threaded onto the polymer chain. Linear or multiarm PEGs with low molecular weight can be decorated with cyclodextrins, yielding crystalline phases. In this work, we report for the first time the complexation of cyclodextrin with star-poly(ethylene glycol), s-PEG, with high molecular weight, containing 13 and 15 arms. The final result of the complexation is a hydrogel. The kinetics of gelation is strongly affected by the size of the cyclodextrin cavity. The effects of the polymer molecular weight and number of arms on the yield of the complexation and on the gel structure are discussed.
Introduction Cyclodextrins (CDs) are cyclic oligosaccharides consisting of six (R-CD), seven (β), or eight (γ) glucose units linked by 1,4-R-glucosidic bonds. They have a shallow truncated cone shape (Figure 1) and hydrophobic cavities that are nonpolar relative to their outer surface.1-3 The cavities can act as hosts for a great variety of molecular guests.4 Aqueous solutions of R, β, or γ-CD can form stable complexes (polypseudorotaxanes) with some polymers. The complexes are supramolecular adducts produced by the threading of the chain into the empty cavity of the CD. Polypseudorotaxanes are the starting chemical architectures for other interesting stuctures such as molecular necklaces, molecular trains, and molecular tubes.5,6 The complex formed between linear poly(ethylene glycol), PEG, and R-CD was the first described.7 Recently, Goh et al. also reported the crystalline inclusion complex formed by low molecular weight (MW) multiarm PEGs (4 and 6 arms) with R- and γ-CD.8 In this work, we report our study on the formation of the inclusion complex between high-MW star-poly(ethylene glycol), s-PEG, containing 13 and 15 arms, and R- and γ-CD. The final result of the complexation of s-PEG with both CDs is a hydrogel, and this is reported here for the first time. The effects of MW and the number of arms on the kinetics and the yields of the gel phase are discussed. * To whom correspondence should be addressed. E-mail:
[email protected]. † The University of Bristol. ‡ Universidade Estadual de Campinas. (1) Szejtli, J. In Comprehensive Supramolecular Chemistry; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon: Exeter, 1996; Vol. 3, p 12. (2) Wenz, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 803. (3) Rusa, C. C.; Luca, C.; Tonelli, A. E. Macromolecules 2001, 34, 1318. (4) Rusa, C. C.; Bullions, T. A.; Fox, J. Porbeni, F. E.; Wang, X.; Tonelli, A. E. Langmuir 2002, 18, 10016. (5) Lo Nostro, P.; Lopes, J. R.; Ninham, B. W.; Baglioni, P. J. Phys. Chem. B 2002, 106, 2166. (6) Harada, A.; Li, J.; Kamachi, M. Nature 1993, 364, 516. (7) Harada, A.; Li, J.; Kamachi, M. Macromolecules 1990, 23, 2821. (8) Jiao, H.; Goh, S. H.; Valiyaveettil, S. Macromolecules 2002, 35, 1980.
Figure 1. Schematic representation of R-, β-, and γ-CD molecules (as a cone shape) and some of their approximate molecular dimensions (in angstroms) (ref 1). Table 1. Some Characteristics of the s-PEG Used in This Work name
MW/g mol-1
number of arms
number of EOs/arm
s-PEG 631 s-PEG 429
150 000 260 000 ( 39 000
15 13
227 455
Experimental Section R- and γ-CD (Wacker) were purified by recrystallization in Milli-Q Plus water and dried at 80° C for 48 h; β-CD (Wacker) was used without any previous purification. Two samples of s-PEG (Shearwater) (see Table 1) were used as received. All the solutions were prepared in D2O (Goss). The mixtures of the components were prepared by weight (within (0.1 mg) from a solution of s-PEG (3%) and solutions of R-CD (11.6%) and γ-CD (11.8%). The mixtures of s-PEG and CD solutions were made to give a final solution of s-PEG of 0.5% (w/w). The system was left for 10 days to reach a final equilibrium (at this time, no further changes in the amount of gel phase were observed). The samples were centrifuged for 5 min (3200 rpm). The solid phase was then separated from the supernatant, washed with D2O to remove free CD, and then dried in an oven at 70 °C for 48 h. The yield was determined from the weight of s-PEG and CD used: yield ) weight of complex/(weight of s-PEG + weight of CD). 1H NMR spectra of the supernatants were obtained by using a JEOL GX
10.1021/la0353273 CCC: $25.00 © 2003 American Chemical Society Published on Web 10/08/2003
Inclusion Complexes of PEG and Cyclodextrins
Langmuir, Vol. 19, No. 23, 2003 9681 Table 2. Clouding and Gelation Time for D2O Solutions Containing s-PEG (0.5%) and r-CD (9.4%) or γ-CD (9.6%)
Figure 2. Photographs comparing the supramolecular gels produced from D2O solutions containing 0.5% of s-PEG 429 and (A) 9.4% of R-CD or (B) 9.6% of γ-CD. 400 MHz to verify the presence of s-PEG. The X-ray diffraction measurements for the dried complexes were performed with a powder diffractometer (Bruker D8 Advanced; Cu KR radiation, λ ) 1.542 Å).
Results and Discussion The complexation of s-PEG was carried out following our previous work9 on the inclusion complex of R-CD with the tails of PEG adsorbed on colloidal silica. A comparative study is interesting because in the case of s-PEG several polymer arms are attached to a small central point.10 Table 1 shows some characteristics of the s-PEG used in this work, including the number of -(OCH2CH2)-, EO units, per arm. The result of the complexation is clearly visualized as after the threading of CD onto the PEG, the complexed chains become hydrophobic and a two-phase system can be observed. The interactions between the hydrophobic complexed chains produce a crystalline or a white-gel
s-PEG/CD
clouding
gelation
631/R 631/γ 429/R 429/γ
0 12 h 0 12 h
2h 3 days 2h 5 days
phase depending mainly on the PEG molecular weight. In the gel case, the threaded CD acts as a “cross-linking” agent producing a hydrogel network.9 Figure 2 shows the gels formed between s-PEG 429 (0.5%) and R- and γ-CD (≈9%). The volume of gel phase for the complex formed with R-CD is higher than for γ-CD. No complex was observed for s-PEG and β-CD. In Figure 3, the X-ray diffraction patterns for the dried gel formed between s-PEG 631 and R- and γ-CD are shown. The peak at 2θ ) 20° corresponds to the dried gel formed with R-CD, and it is associated with a channeltype crystalline structure by virtue of the polymeric nature of the guest molecule.8,11-15 The X-ray patterns of s-PEG complexed with R-CD are very similar to those involving linear PEG, indicating the presence of a similar columnar structure. In the case of s-PEG with γ-CD, the X-ray diffraction pattern reveals an amorphous matrix, without the characteristic peak at 2θ ) 8°,8 associated with the γ-CD columnar structure. This means that the fraction of s-PEG molecules with two vicinal arms threaded by γ-CD is low or disordered due to the geometric restrictions imposed by the long arms of the stars. No characteristic peaks of the s-PEG were observed in the X-ray diffraction of the dried gel matrixes, indicating that free EO units of the polymer (not complexed by CD) are present in the amorphous phases. The onset times for phase separation and gelation for the two polymers with the two CDs were determined (Table 2). The solution of both stars became cloudy instantaneously after the addition of a saturated R-CD solution. Contrary to expectation, the gelation time only shows a weak dependence on molecular weight and the number of arms. After 10 days, no further visual changes were observed in the gel phase and the amount of gel was measured. Figure 4 shows the dependence of the amount of gel formed with s-PEG 631 and 429
Figure 3. X-ray diffraction patterns for dried gel formed from s-PEG 631 with R- and γ-CD.
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Sabadini and Cosgrove Table 3. Yields for the Complexation and Average Number of EO Units Complexed and Uncomplexed per Arm of s-PEG
Figure 4. Diagram showing the dependence of the amount of dried gel formed with 0.5% of s-PEG 631 and s-PEG 429 as a function of R-CD concentration.
Figure 5. Schematic representation of a complex formed between a 13-arm s-PEG and R-CD (emphasizing the formation of a columnar structure with one arm) or γ-CD (with two vicinal arms of the star molecule).
(0.5%, w/w) as a function of R-CD concentration. The onset for the gel formation in terms of R-CD concentration is approximately the same for both s-PEGs, ≈2%. Apparently there is a critical number of R-CD molecules that need to thread onto the arms to give phase separation. In the range of concentrations between 2 and 6%, the gelation is partial, and a weak dependence of the amount of gel with the molecular weight and number of arms is observed. For concentrations of R-CD beyond 7%, the whole sample is a gel and when separated gives ≈5% of dried solid. The clouding and gelation kinetics for s-PEG 631 and R-CD is more than 30 times faster than the gelation with
s-PEO/CD
yield/ %
NCD/ arm
NEO complexed/ arm
NEO uncomplexed/ arm
631/R 631/γ 429/R 429/γ
37 37 40 33
59 47 130 80
118 94 260 160
109 133 195 295
γ-CD. The difference is even larger in the case of s-PEG 429. This very large difference between the two cyclic oligosaccharides can be rationalized by considering that one or two arms of the star must be fitted in the cavities of R- and γ-CD,7,15 respectively, to form a stable complex (Figure 5). The molecular weight effect can be related to the splaying of the arms of the star, which increases with arm length. The yields for the complexation were determined, using 0.5% of s-PEG and high concentrations of R- and γ-CD, and all values are similar (Table 3). The averaged number of R-CD molecules threaded on each arm of s-PEG was determined (Table 3). First, the 1H NMR of the supernatant was obtained in each case to ensure that all the s-PEG molecules were present just in the gel phase. As shown in Figure 6, the signal of s-PEG present in the supernatant is easily detectable. The concentration of R-CD, in this case, was adjusted in order to produce an incomplete gelation, such that part of the complex [s-PEG/ R-CD] remains soluble. In the case of γ-CD, the ratios were also determined; however, these values reflect averages in the inclusion complex formed either between arms of the same s-PEG or between arms of different molecules. The number of EO units complexed and those that remain uncomplexed for each arm of s-PEG were also estimated using a stoichiometry of EO units/CD of 2:1.7,16 The same stoichiometry of EO (per arm) with R-CD and γ-CD is expected, as the depth of the cavity is equal for both cyclodextrins (H ) 7.8 Å), as shown schematically in Figure 1. The results shown in Table 3 clearly indicate that fewer EO units of s-PEG are complexed (per arm) in γ-CD/s-PEG than in R-CD/s-PEG; this is reasonable as it is more difficult to include two PEG chains in the γ-CD cavity. The amount of solids (complex) in the gels is almost the same: approximately 5% in relation to the total weight of gel. This indicates that the structure of the gel in the
Figure 6. A high-resolution 1H NMR of the supernatant in equilibrium with the gel phase, in which both components (s-PEG and R-CD) were mixed in a composition to produce only partial gelation. The peaks of s-PEG and R-CD are indicated.
Inclusion Complexes of PEG and Cyclodextrins
case of γ-CD is more compact than that of the gel formed with R-CD; in the latter case, the volume of the gel phase is higher (Figure 2). It is possible to envisage changes in the shape of the s-PEG, more specifically, a reduction in the effective number of arms due to the interaction between two or more vicinal arms threading in s-PEG. A reduction in the number of arms has been observed in small-angle neutron scattering experiments when the arms of s-PEG complex with sodium dodecyl sulfate micelles.17 Conclusions
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to fit into one cavity. Evidently, one arm is too narrow to remain in the cavity of β-CD and two arms are too large to fit. The final result of the complexation is a hydrogel in all cases. The X-ray diffraction patterns of the dried solid state show a typical columnar structure for the complex formed with R-CD. However, the geometric restriction of including two s-PEG arms in each γ-CD does not allow a columnar formation in the case of the complex with γ-CD. Acknowledgment. The authors thank WackerChemicals AG for the samples of CD, David Jones for the photographs, and Wirach Taweepreda for the X-ray diffractograms. E.S. thanks the University of Bristol and CNPq-Brazil for founding this work via a Senior Research Fellowship.
High-MW s-PEGs with 13 and 15 arms complex spontaneously with R- and γ-CD; however, no complex was observed in the case of β-CD. The kinetics of complexation is strongly dependent on the size of the CD cavities. The low complexation rates in the case of γ-CD are probably due to the necessity for two arms of s-PEG
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(9) Sabadini, E.; Cosgrove, T.; Taweepreda, W. Langmuir 2003, 19, 4812. (10) Grest, G. S.; Fetters, L. J.; Huang, J. S.; Richter, D. Adv. Chem. Phys. 1996, 94, 67. (11) Huh, K. M.; Ooya, T.; Lee, W. K.; Sasaki, S.; Kwon, I. C.; Jeong, S.Y.; Yui, N. Macromolecules 2001, 34, 8657. (12) Rusa, C.; Tonelli, A. E. Macromolecules 2000, 33, 1813.
(13) Harada, A.; Li, J.; Kamachi, M. Macromolecules 1993, 26, 5698. (14) Harada, A.; Okada, M.; Kamachi, M. Macromolecules 1995, 28, 8406. (15) Huang, L.; Allen, E.; Tonelli, A. Polymer 1999, 40, 3211. (16) Harada, A.; Li, J.; Kamachi, M. Nature 1994, 370, 126. (17) Wesley, R. D.; Cosgrove, T.; Thompson, L. Langmuir 1999, 15, 8376.
