Thermosensitive hydrogels composed of cyclodextrin pseudorotaxanes. Role of [3]pseudorotaxane in the gel formation

Article abstract of DOI:10.1039/b911667b

Pseudorotaxanes composed of an alkylpyridinium and α-cyclodextrin (α-CD) form supramolecular hydrogels which show sol-gel transitions at 7-67 °C depending on the type and amount of the guest compound. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b911667b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Thermosensitive hydrogels composed of cyclodextrin pseudorotaxanes.
Role of [3]pseudorotaxane in the gel formationw
Toshiaki Taira, Yuji Suzaki and Kohtaro Osakada*
Received (in Cambridge, UK) 16th June 2009, Accepted 16th September 2009
First published as an Advance Article on the web 6th October 2009
DOI: 10.1039/b911667b
Pseudorotaxanes composed of an alkylpyridinium and a-cyclo-
dextrin (a-CD) form supramolecular hydrogels which show
sol–gel transitions at 7–67 1C depending on the type and amount
of the guest compound.
d = 81 and 98 whose positions are unique to C-1 and C-4
carbons of free a-CD.9 These data indicate that the xerogel
contains pseudorotaxanes as its components and that the
original hydrogel is also composed of the pseudorotaxanes
rather than free a-CD and 1b.
Heating the hydrogel formed from 1b (50 mM) and a-CD
(100 mM) at 32 1C changes it into a clear sol, as is observed by
the absorbance at 600 nm (Fig. 2). Thermally induced gel-to-sol
transition of a similar gel composed of 1c (50 mM), which has
a longer alkyl chain, and a-CD (100 mM) is observed at 50 1C.
Formation and degradation of the hydrogel occurs reversibly
by temperature change as shown in the insets of Fig. 2. The
latter hydrogel is thermally more stable than the former.
Concentration of the two components, 1b (or 1c) and a-CD,
changes the sol–gel phase transition temperature, Tgel. Fig. 3a
summarizes the relationship between the concentration of the
components and Tgel; the phase transition temperature ranges
from 7 1C ([1b] = 60 mM, [a-CD] = 60 mM) to 32 1C ([1b] =
80 mM, [a-CD] = 100 mM). Amphiphile 1c and a-CD form
hydrogels at lower concentrations than 1b and a-CD at the
same temperature, as shown in Fig. 3b. The highest Tgel of 1c
and a-CD is 67 1C ([1c] = 80 mM, [a-CD] = 100 mM).
Hydrogel formation was not observed in aqueous solutions
containing 1a and a-CD under similar conditions.
Compounds 1b and a-CD are expected to form [2]pseudo-
rotaxanes [{py-N-(CH2)10OC6H3-3,5-(OMe)2}(a-CD)]+(Clꢀ)
(1bꢁa-CD) and [3]pseudorotaxanes [{py-N-(CH2)10OC6H3-
3,5-(OMe)2}(a-CD)2]+(Clꢀ) (1bꢁ(a-CD)2), which are equilibrated
in aqueous media as shown in Scheme 1. 1H NMR measurements
of the mixtures revealed details of the actual species in them.
Fig. 4 compares the 1H NMR spectra of 1b and mixtures of 1b
and a-CD ([1b] = 50 mM, [a-CD] = 50–200 mM). The
solution containing 1b and a-CD ([1b] = [a-CD] = 50 mM)
shows signals at d 8.72 (c0), 6.06 (e0), 5.95 (d0), 1.93 (f0) of
1bꢁa-CD (Fig. 4b). These peaks are at lower magnetic field
positions than the corresponding signals of the mixture with
low [a-CD]0 (d 8.57 (c), 5.79 (e), 5.73 (d), 1.74 (f)) (Fig. 4a).
The 1H NMR spectrum of the hydrogel formed from 1b
(50 mM) and a-CD (100 mM) in D2O shows broadened
signals of a0–f0 as well as a new set of signals d 1.86 (f00),
5.63 (d00) and 6.19 (e00) (Fig. 4b–d). The latter signals are
Polymer molecules containing hydrophilic and hydrophobic
parts aggregate in aqueous media, forming micelles or gels,
depending on the concentration of the polymer and the
temperature of the solution.1 Polysaccharides, functionalized
with hydrophobic cholesteric groups, are able to form hydrogels
with stimulus responsive properties.2 Polyrotaxanes of inter-
locked hydrophobic polymers and macrocyclic cyclodextrin
(CD) were also reported to form hydrogels.3 Hydrogels
composed of CD and azobenzene derivatives were reported
to exhibit photo-responsive properties.4 Use of a cyclodextrin
dimer as the macrocyclic component of the polyrotaxane
enabled formation of topological gels with unique properties.5
Hydrogels, composed of host–guest complexes or pseudo-
rotaxanes with cyclodextrins and cucurbit[7]uril as the cyclic
components, were studied by several research groups as a
bottom-up approach to hydrogel formation which may be
controlled by the external conditions.6,7 In this communication,
we report that pseudorotaxanes, simply obtained by mixing
a-CD and common amphiphiles, form hydrogels with precise
temperature control of the sol–gel transition and that a
[3]pseudorotaxane is essential for the formation of the gel.
Alkylpyridiniums with a 3,5-dimethoxyphenyl end group,
[py-N-(CH2)nOC6H3-3,5-(OMe)2]+(Xꢀ) (1a: n = 8, X = Cl;
1b: n = 10, X = Cl; 1c: n = 12, X = Br), are soluble both in
water and in organic solvents such as CH2Cl2, CHCl3, and
DMSO (Fig. 1).8 Mixing 1b and a-CD in an aqueous solution
([1b] = 50 mM, [a-CD] = 100 mM) at 60 1C and cooling it to
room temperature gave a hydrogel. Addition of an excess
amount of urea turned the hydrogel into a sol, indicating that
host–guest complexes of urea and a-CD are not aggregated to
form the hydrogel.7
A xerogel was obtained by slow evaporation of the hydrogel
containing 1b (108 mM) and a-CD (206 mM) or by washing
the hydrogel with acetone. The MALDI-TOFMS spectrum
shows peaks at m/z = 1344.6 and 2316.7 which are assigned to
the 1:1 and 1:2 complexes of 1b and a-CD, respectively. 13C
CP/MAS NMR spectra of the xerogel do not exhibit signals at
Chemical Resources Laboratory R1-3, Tokyo Institute of Technology,
4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan.
E-mail: kosakada@res.titech.ac.jp; Fax: +81-45-924-5224;
Tel: +81-45-924-5224
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/b911667b
Fig. 1 Structures of the amphiphiles and a-cyclodextrin (a-CD).
Chem. Commun., 2009, 7027–7029 | 7027
ꢂc
This journal is The Royal Society of Chemistry 2009

View Article Online
Fig. 4 1H NMR spectra (D2O, RT) of (a) 1b (50 mM), (b) a mixture
of 1b and a-CD ([1b]0 = 50 mM, [a-CD]0 = 50 mM), (c) a mixture of
1b and a-CD ([1b]0 = 50 mM, [a-CD]0 = 100 mM) (hydrogel), and (d)
a mixture of 1b and a-CD ([1b]0 = 50 mM, [a-CD]0 = 200 mM)
(hydrogel). Spectra (c) and (d) correspond to the molecules dissolved
in the entrapped solvent in the gel network.
Fig. 2 Sol–gel transitions of (a) a mixture of 1b (50 mM) and a-CD
(100 mM), (b) a mixture of 1c (50 mM) and a-CD (100 mM)
monitored by absorbance at 600 nm. Repeated transition behaviour
is shown in the insets.
Fig. 3 Phase transition temperatures Tgel at various concentrations of
(a) 1b and a-CD, (b) 1c and a-CD in H2O.
assigned to [3]pseudorotaxane 1bꢁ(a-CD)2. Reaction of 1c
and a-CD forms [3]pseudorotaxane 1cꢁ(a-CD)2 as the major
product even at low concentrations ([1c] = 5 mM, [a-CD] =
15 mM). Reaction of 1a with a-CD does not form the
[3]pseudorotaxane but does form the [2]pseudorotaxane
1aꢁa-CD. The 1H NMR spectrum at 80 1C contains the signals
due to 1bꢁa-CD only and does not show the signals of 1bꢁ(a-CD)2.
Fig. 5a shows the composition of the [2]- and [3]pseudo-
Fig. 5 Titration curves for (a) 1b (J, [1b]0 = 50 mM), 1bꢁa-CD (’),
and 1bꢁ(a-CD)2 (m); (b) 1c (J, [1c]0 = 20 mM), 1cꢁa-CD (’), and
1cꢁ(a-CD)2 (m) monitored by 1H NMR signals of d, d0 and d00 in D2O
at 25 1C.
they are expected to be aggregated in aqueous media. Amphiphilic
compound 1b forms micelles due to intermolecular inter-
actions of the hydrophobic long alkyl chains, similar to related
1
rotaxanes ([1b]0 = 50 mM) detected by H NMR in the sol
and gel mixtures, monitored by the change in the integration
of the 1H NMR signals of d, d0 and d00. At low concentrations
of a-CD (o70 mM), 1bꢁa-CD is formed as the major product.
Further addition of a-CD to the solution leads to a decrease in
1bꢁa-CD and an increase in 1bꢁ(a-CD)2. Hydrogel formation is
observed at [a-CD] 4 70 mM when the [3]pseudorotaxane
1bꢁ(a-CD)2 is contained in the mixture.
1
compounds.10 2D ROESY H NMR spectra of the solution
([1b] = 100 mM, [a-CD] = 50 mM) indicated the close
positions of the 3,5-dimethoxyphenyl group and the pyridyl
group of the axle molecule. Thus, 1bꢁa-CD is aggregated via
the interaction between the end groups of 1b, although the
degree of aggregation is less significant than that of free 1b in
the micellar form (vide infra). The two species do not form
hydrogels, but formation of [3]pseudorotaxane 1bꢁ(a-CD)2
causes gelation of the system. Fig. 3a and b indicate that a
mixture of 1b and a-CD in a 1:2 molar ratio tends to form the
hydrogel more easily than mixtures with different ratios in the
same total concentration. [3]Pseudorotaxane is essential for
the gelation based on the results in Fig. 5(a). [3]Pseudorotaxanes
are important also in hydrogel formation from 1c and a-CD
(Fig. 5b), while 1a and a-CD do not form the [3]pseudorotaxane
of the compounds or the hydrogel.
Dilute aqueous solutions of 1b and a-CD ([a-CD] o 30 mM
or [1b] o 10 mM) should contain free 1b and 1bꢁa-CD, and
Scheme 2 summarizes the change in aggregation of 1b (1c)
and a-CD in aqueous media. The amphiphilic molecule 1b
forms micelles above the critical micelle concentration in
water. Addition of a-CD to the solution causes formation of
the [2]pseudorotaxane 1bꢁa-CD (1cꢁa-CD). Existence of inter-
molecular close contact suggests association of the individual
Scheme
1 [2]- and [3]pseudorotaxane formation of a-CD and
1b. Isomers of 1bꢁa-CD and 1bꢁ(a-CD)2 are omitted.
ꢂc
This journal is The Royal Society of Chemistry 2009
7028 | Chem. Commun., 2009, 7027–7029

View Article Online
temperature can also be controlled around body temperature
by changing the molar ratio of the organic amphiphile and
a-CD. Easy construction of a supramolecular hydrogel from
simple components may provide a new bottom-up approach
for the design of biodegradable hydrogels and a delivery
matrix for drugs.
This work was supported by a Grant-Aid for Scientific
Research for Young Scientists from the Ministry of
Education, Culture, Sports, Science and Technology, Japan
(19750044), and by the Global COE program ‘‘Education and
Research Center for Emergence of New Molecular Chemistry’’.
T.T. acknowledges the scholarship by the Japan Society for
the Promotion of Science. We thank Dr Yoshiyuki Nakamura
for 13C CP/MAS NMR measurements and Dr Masato Koizumi
for MALDI-TOFMS measurements.
Scheme 2 Plausible mechanism of the formation of the supra-
molecular hydrogel.
Notes and references
[2]pseudorotaxane species via stacking of the terminal aromatic
groups, but they do not form tight micelles due to weak
interaction between the polyalkyl chains bearing a-CD rings.
Further addition of a-CD to the solution of [2]pseudorotaxane
causes [3]pseudorotaxane formation, which leads to hydrogel
formation at a concentration higher than the critical gel
concentration. Interaction of two a-CDs of a [3]pseudorotaxane
with those of another pseudorotaxane probably forms the
network structure of the aggregated supramolecules required
for the gel formation. Hydrogel formation of polypseudo-
rotaxane derived from b-CD with a trinitrobenzene-containing
group requires head-to-tail aggregation of b-CDs.7 Molecular
dynamics simulations compared the relative stability of the
head-to-tail and head-to-head conformations of a-CDs in a
[3]rotaxane in aqueous solution.11 An analogous reaction of
cetylpyridinium chloride, which has a similar structure to
1a–c, with a-CD was reported to form [3]pseudorotaxanes
with a head-to-head arrangement of the two a-CDs, forming
an insoluble solid.12 These results suggest that head-to-tail
linkage of two a-CDs in [3]pseudorotaxane 1bꢁ(a-CD)2 and 1cꢁ
(a-CD)2 in aqueous solution may contribute to the hydrogel
formation.
1 T. Tanaka, Phys. Rev. Lett., 1978, 40, 820; S. Katayama,
Y. Hirokawa and T. Tanaka, Macromolecules, 1984, 17, 2641;
S. Aoshima and S. Sugihara, J. Polym. Sci., Part A: Polym. Chem.,
2000, 38, 3962; S. Kanaoka, N. Yagi, Y. Fukuyama, S. Aoshima,
H. Tsunoyama, T. Tsukuda and H. Sakurai, J. Am. Chem. Soc.,
2007, 129, 12060.
2 K. Akiyoshi, S. Deguchi, N. Moriguchi, S. Yamaguchi and
J. Sunamoto, Macromolecules, 1993, 26, 3062; N. Morimoto,
F. M. Winnik and K. Akiyoshi, Langmuir, 2007, 23, 217.
3 J. Li, A. Harada and M. Kamachi, Polym. J., 1994, 26, 1019.
4 P. Zheng, X. Hu, X. Zhao, L. Li, K. C. Tam and L. H. Gan,
Macromol. Rapid Commun., 2004, 25, 678; Y.-L. Zhao and
J. F. Stoddart, Langmuir, 2009, 25, 8442.
5 Y. Okumura and K. Ito, Adv. Mater., 2001, 13, 485.
6 I. Hwang, W. S. Jeon, H.-J. Kim, D. Kim, H. Kim, N. Selvapalam,
N. Fujita, S. Shinkai and K. Kim, Angew. Chem., Int. Ed., 2007,
46, 210; L. Zhu, X. Ma, F. Ji, Q. Wang and H. Tian, Chem.–Eur.
J., 2007, 13, 9216; X. Ma, Q. Wang, D. Qu, Y. Xu, F. Ji and
H. Tian, Adv. Funct. Mater., 2007, 17, 829.
7 W. Deng, H. Yamaguchi, Y. Takashima and A. Harada, Angew.
Chem., Int. Ed., 2007, 46, 5144; W. Deng, H. Yamaguchi,
Y. Takashima and A. Harada, Chem.–Asian J., 2008, 3, 687.
8 Y. Suzaki, T. Taira and K. Osakada, Dalton Trans., 2006, 5345.
9 P. C. Manor and W. Saenger, J. Am. Chem. Soc., 1974, 96, 3630;
M. J. Gidley and S. M. Bociek, J. Am. Chem. Soc., 1988, 110,
3820.
10 Y. Suzaki, T. Taira, D. Takeuchi and K. Osakada, Org. Lett.,
2007, 9, 887; Y. Suzaki, T. Taira and K. Osakada, Transition Met.
Chem., 2007, 32, 753; T. Taira, Y. Suzaki and K. Osakada, Chem.
Lett., 2008, 37, 182; T. Taira, Y. Suzaki and K. Osakada,
Chem.–Asian J., 2008, 3, 895; Y. Suzaki, T. Taira, K. Osakada
and M. Horie, Dalton Trans., 2008, 4823.
11 Y. Yu, W. Cai, C. Chipot, T. Sun and X. Shao, J. Phys. Chem. B,
2008, 112, 5268.
12 D.-R. Yei, S.-W. Kuo, H.-K. Fu and F.-C. Chang, Polymer, 2005,
46, 741.
13 A. R. Hirst and D. K. Smith, Chem.–Eur. J., 2005, 11, 5496.
In summary, we presented a facile two component hydrogel
composed of an organic amphiphile and a-CD, where
complexation of the hydrogen bond donor and acceptor was
known to induce self-assembly and formation of a gel
network.13 We demonstrated that hydrogelation is induced
by [3]pseudorotaxane formation, and the sol–gel transition of
the hydrogel can be controlled by temperature change and by
adding urea as a denaturing reagent. The phase transition
ꢂc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 7027–7029 | 7029