Switchable hydrogels obtained by supramolecular cross-linking of adamantyl-containing LCST copolymers with cyclodextrin dimers

Article abstract of DOI:10.1002/anie.200504539

En route to intelligent hydrogels: Copolymers of N-isopropylacrylamide containing adamantyl groups can be cross-linked noncovalently with cyclodextrin dimers. This results in thermosensitive hydrogels with cloud points that are lower than those of the pure copolymers. Addition of monomeric methylated cyclodextrin results in an increase in the cloud points but has no significant influence on the viscosity of the copolymer solution. (Figure Presented)

Full text of DOI:10.1002/anie.200504539

Angewandte
Chemie
Hydrogels
DOI: 10.1002/anie.200504539
Switchable Hydrogels Obtained by Supramolec-
ular Cross-Linking of Adamantyl-Containing
LCST Copolymers with Cyclodextrin Dimers**
Oliver Kretschmann, Soo Whan Choi,
Masahiko Miyauchi, Itsuro Tomatsu, Akira Harada,
and Helmut Ritter*
Intelligent hydrogels that are sensitive to external stimuli like
temperature, light, pH, or salt effects are of increasing interest
because of potential applications in materials science and
medicine.[1] Not only covalently cross-linked gels but also
associatively cross-linked gels are of interest. Various types of
polymer inclusion complexes (PICs) formed by noncovalent
host–guest interactions have been reported and investigated
extensively for the construction of supramolecular sys-
tems.[2–4] Cyclodextrins (CDs) have been the most widely
used host molecules because they are water-soluble and
capable of selectively including a wide range of hydrophobic
guest molecules.[5,6] Low-molecular-weight as well as poly-
meric molecules can interact with one or more CD mole-
cules.[7] Since the first report in 1992, which described a
“molecular necklace”, CD-based PICs have been investigated
extensively. They are important in fundamental research on,
for example, noncovalent binding based on macromolecular
[*] O. Kretschmann, Dr. S. W. Choi, Prof. Dr. H. Ritter
Heinrich-Heine-Universität Düsseldorf
Institut für Organische Chemie und Makromolekulare Chemie
Universitätsstrasse 1, 40225 Düsseldorf (Germany)
Fax: (+49)211-811-5840
E-mail: h.ritter@uni-duesseldorf.de
Dr. M. Miyauchi, I. Tomatsu, Prof. Dr. A. Harada
Department of Macromolecular Science
Graduate School of Science
Osaka University
Toyonaka, Osaka, 560-0043 (Japan)
[**] LCST=lower critical solution temperature.
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Communications
recognition.[7–9] Tonelli et al. prepared various PICs and
demonstrated several interesting applications.[8]
In 2003 we reported on the influence of polymer-bound
adamantyl and cyclohexyl components in an N-isopropyl-
acrylamide copolymer on the lower critical solution temper-
ature (LCST),[9a] and more recently we described the syn-
thesis of physical polymeric gels from CD-mediated tert-butyl
methacrylate.[9b] We have introduced many PICs and pseudo-
polyrotaxanes by a series of combination of CDs, usually a-,
b-, and g-CD (six, seven, and eight glucose units, respec-
tively), and the corresponding linear polymers.[10] We also
reported on a thermosensitive PIC formed from a polyme-
thacrylamide and randomly methylated b-CD which shows
solubility behavior similar to that of established LCST
polymers.[10f] In related work Huh et al. prepared a hydrogel
with supramolecular structure, which shows a reversible
phase transition, by inclusion complexation between poly-
(ethylene glycol)-grafted dextran and a-CD.[11] Li et al.
introduced a PIC-based supramolecular hydrogel for an
injectable delivery system.[12] Pluronics (commercial triblock
copolymers of poly(ethylene oxide) and poly(propylene
oxide)) were used for complexation with a-CD. Wenz et al.
showed that the formation of a physical gel can be achieved
by a specific host–guest interaction between CD polymers
and suitable guest polymers.[13]
Table 1: Copolymerization of 1 and 2 and the adamantyl-containing
monomers 3 and 4 with AIBN in DMF.
Copolymer
Monomers
n/m
Mn [gmolÀ1 [a]
]
PD[a]
Tg [8C][b]
5
6
7
2+3
1+3
1+4
20:1
20:1
20:1
50000
66000
76000
2.0
3.1
3.2
101
139
135
[a] Mn and PD were calculated by GPC. [b] The glass temperatures (Tg)
were estimated by DSC.
Recently we also studied the interaction between a
polymer bearing b-CD moieties and a polymer bearing
azobenzene moieties. We found that the b-CD polymer
interacted with the polymer having trans azobenzene units to
form a gel-like mixture. In contrast, the polymer with cis
azobenzene units did not lead to formation of a gel under the
same conditions.[14] More recently, we have successfully
constructed aqueous systems that undergo gel-to-sol and
sol-to-gel transitions and a photosensitive hydrogel system
utilizing the formation of inclusion complexes of a-CD with
dodecyl side chains in modified poly(acrylic acid).[15] We
report here on a new type of supramolecular cross-linked
hydrogel that shows LCST behavior and consists of polymers
complexed to CD dimers.
viscosity data, pure copolymers 5–7 and mixtures of the
copolymers and monofunctional b-CD were investigated and
compared (Figure 1).
Adamantyl groups are known to be included and held
strongly in b-CD. To obtain noncovalent cross-linked gel
structures, we used a CD dimer and adamantyl-containing
polymers for our study. Guest copolymers 5–7 were prepared
in DMF by free-radical copolymerization; the molar ratio of
1-adamantylacrylamide (3) or 6-acryloylaminohexanoic acid
1-adamantylamide (4) to N-isopropylacrylamide (NIPAAM,
1) or N,N-dimethylacrylamide (DMAA, 2) was 1:20. The
As expected, the viscosity of the solutions of pure
polymers increased with increasing molecular weight. How-
ever, the comparison can only be qualitative because of the
different kinds of monomers used for copolymerization.
Addition of native b-CD or methylated b-CD (me-b-CD) to
these polymer solutions had no significant effect on the
viscosity. The slight decrease of viscosity in the case of
polymer 7 after addition of b-CD might result from the
disruption of some intermolecular assemblies when the
hydrophobic side chains are included into the b-CD cavity.
In the case of polymers 5 and 6, a decrease in viscosity after
addition of b-CD could not be observed. These copolymers do
not bear a flexible side group. Apparently no aggregates are
formed that could be disrupted by complex formation.
Interestingly, when aqueous solutions of copolymers 5–7
were mixed with the CD dimer 8, the viscosity of the solutions
increased dramatically. Within seconds, stable gels formed.
This demonstrates successful complex formation between the
1
polymers were characterized by H and 13C NMR spectros-
copy, differential scanning calorimetry (DSC), and gel
permeation chromatography (GPC). The molecular weights
and compositions of the copolymers used in this study are
listed in Table 1. The b-CD dimer 8 was prepared by
condensation of terephthalic acid with 2 equiv of 6-amino-b-
CD using N,N’-dicyclohexylcarbodiimide (DCC) and 1-hy-
droxy-1H-benzotriazole (HOBT) in DMF.[16]
The strong supramolecular cross-linking between the CD
dimer 8 and copolymers 5–7 at 108C became evident by zero-
shear viscosity measurements. Aqueous solutions of 5–7 were
mixed with a defined amount of CD dimer 8. To evaluate the
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Figure 1. Comparison of zero-shear viscosities of polymer solutions
without CDs, with b-CD, and with the CD dimer: CP =50 gLÀ1
CD =25 gLÀ1, and CCD dimer =25 gLÀ1, 108C.
,
C
CD dimer 8 and the adamantyl units of the copolymers. As
expected, the CD dimer acts as a noncovalent cross-linker
between the adamantyl-containing copolymers, leading to
hydrogels with supramolecular structure (Figure 2).
Figure 3. Turbidity measurements of aqueous solutions of the poly-
mers a) 6 and b) 7 without addition of host molecules and measure-
ments of the supramolecular complexes of the polymers with CD
dimer 8 and me-b-CD respectively. CP =10 gLÀ1, Cme-b-CD =10 gLÀ1, and
C
CD dimer =5 gLÀ1, 108C.
to the LCST of pure poly(NIPAAM). This increase of the
cloud points relative to the cloud points of pure 6 and 7 results
from the inclusion of the hydrophobic adamantyl units by me-
b-CD.[9a]
Figure 2. Estimated structure of the obtained hydrogels.
The thermosensitive properties of aqueous solutions of
copolymers 5–7 and of their noncovalent cross-linked net-
works were investigated by monitoring the changes of
turbidity as a function of temperature. As expected, the
N,N-dimethylacrylamide-containing copolymer 5 shows no
turbidity point at temperatures between 108C and 908C in
water. For copolymer 6 we obtained the LCST transition at
238C (Figure 3a); for copolymer 7 we found a cloud point of
218C (Figure 3b). Both copolymers showed a sharp phase
transition in response to a small temperature change. The fact
that the turbidity points of copolymers 6 and 7 are signifi-
cantly lower than that of poly(NIPAAM) itself (358C) is
caused by the hydrophobic adamantyl units in the copoly-
mers; copolymers 6 and 7 are less soluble in water than a
homopolymer of NIPAAM is.
To investigate the effect of adding monomeric and dimeric
CD on the change of phase transition temperature of the
polymers 6 and 7, we performed turbidity measurements at
the same polymer concentration as above in the presence of a
defined amount of me-b-CD and CD dimer, respectively. As
reported previously, [9] we found that addition of me-b-CD led
to cloud points of polymers 6 and 7 of 358C, which correlates
When the CD dimer was added to the aqueous polymer
solutions at half the molar ratio (relative to the amount of me-
b-CD), the cloud points decreased significantly. This observed
effect again can be explained by the cross-linkage of single
polymer chains upon complexation of the CD dimer. The
resulting supramolecular structures are restricted in their
mobility and solubility, which is reflected in cloud points of
14.08C for polymer 6 and 15.78C for polymer 7. As a result of
the LCST behavior of the polymer/CD dimer mixtures the
obtained hydrogels show different transparencies. The gel
formed from copolymer 5 is transparent at room temperature,
whereas those from polymers 6 and 7 are turbid at room
temperature and transparent below their cloud points of
14.08C and 15.78C, respectively.
Supramolecular hydrogels were constructed by the for-
mation of inclusion complexes between adamantyl-containing
copolymers and CD dimers. Interactions between the copoly-
mers and CD dimers have been studied below the LCST by
viscometry. These inclusion complexes show different macro-
scopic behavior relative to complexes with b-CD. In addition,
the LCSTs of the supramolecular networks consisting of
NIPAAM copolymers and CD dimers are significantly lower
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diethyl ether (100 mL) and allowed to crystallize in the refrigerator
overnight. The precipitate was collected and purified by column
chromatography (CH2Cl2/CH3OH 19:1). Yield: 52%. 1H NMR
(500 MHz, CDCl3): d = 6.30 (brs (overlapped), 1H), 6.26 (dd, 1H),
6.10 (dd, J = 9.8, 2.4 Hz, 1H), 5.56 (dd, J = 17.0 Hz, 1H), 5.25 (m, 1H),
3.30 (pseudo-q, 2H), 2.06 (t, J = 7.3 Hz, 2H), 2.04 (m, 3H), 1.98 (m,
6H), 1.64 (m, 6H), 1.16–1.60 ppm (brm, 2H); 13C NMR (500 MHz,
CDCl3): d = 172.23, 165.70, 131.12, 126.09, 51.90, 41.68, 36.36, 37.25,
29.43, 28.85, 26.13, 24.50 ppm; MS (70 eV, EI): m/z: 316.2 [M+];
elemental analysis calcd (%) for C19H26N2O2: C 72.12, H 8.92; found:
C 71.96, H 9.12.
Representative synthesis of copolymers 5–7: synthesis of copo-
lymer 5: N,N-dimethylacrylamide (4.16 mL, 4.00 g, 40 mmol) and 1-
adamantylacrylamide (410.6 mg, 2 mmol) were dissolved in DMF
(16 mL). The solution was flushed with argon for 30 min and AIBN
(34.5 mg, 0.21 mmol) was added under argon atmosphere. The
mixture was heated to 658C and stirred overnight. The solvent was
removed under reduced pressure. The dry polymeric material was
dissolved in water, dialyzed, and freeze-dried. Composition, glass
temperatures, and GPC data of all synthesized copolymers are
reported in Table 1.
than those of pure NIPAAM copolymers. The obtained
hydrogels show a switchable transparency in a narrow
temperature range and can be constructed easily by mixing
two low-viscosity aqueous solutions. As a result of their
hydrophilic and uncharged structure they are of potential
interest for applications in biomedical science.
Experimental Section
Materials: b-CD was purchased from Tokyo Kasei Inc. and Wacker
and used after recrystallization and drying at 808C under vacuum.
Methylated b-CD (me-b-CD)(CAVASOL, W7M, technical grade)
was purchased from Wacker. para-Toluenesulfonyl chloride, sodium
hydroxide, sodium azide, 28% ammonium solution, triphenylphos-
phine, DCC, and HOBT were obtained from Nacalai Tesque Inc.
Mono-6-para-toluenesulfonyl-b-CD[17–19] and mono-6-amino-b-CD[20]
were prepared according to literature methods.
Measurements: GPC analyses were performed with a Viscotek
GPCmax VE2001, using DMF as the eluent at 608C (flow rate:
1 mLminÀ1). Samples of 100 mL were injected on the arrangement of
columns consisting of one Viscotek TSK guard column HHR-H
6.0 mm(ID) ” 4 cm(L) and two Viscotek TSK GMHHR-M
7.8 mm(ID) ” 30 cm(L) columns. A Viscotek Viscometer model 250
and a Viscotek VE 3500 RI detector were used for detection.
Evaluation was performed using OmniSEC 4.0 software. Polystyrene
standards were used for universal calibration. MALDI-TOF-MS was
performed on a Bruker Ultraflex TOF mass spectrometer using a 337-
nm nitrogen laser. NMR spectra were recorded with a Bruker AC500
instrument at 208C. Chemical shifts were referenced to the solvent
values (d = 2.50 ppm for [D6]DMSO and d = 4.70 ppm for HOD).
Cloud points were determined by transmission changes (at 500 nm) of
the solutions heated at 0.1–0.2KminÀ1 in a magnetically stirred cell;
values of the cloud points were defined as the temperature at which
the transmission decreases by 50%. DSC measurements were
performed on a Mettler DSC-30 instrument in a temperature range
of À40 to 1508C at a heating rate of 10KminÀ1. For calibration,
standard tin, indium, and zinc samples were used. The Tg values are
reported as the average of three measurements using the midpoint
method. Viscosity measurements were performed with a REOLOG-
ICA DynAlyser 100 stress-controlled rheometer equipped with a
cone and plate at 108C and using a circulating water bath. The radius
of the cone was 25 mm, and the angle between the cone and plate was
48C. Zero-shear viscosities were estimated from the shear-rate
dependence of the viscosities measured under applied stress of 0.1–
2 Pa.
Synthesis of the cyclodextrin dimer 8: Terephthalic acid bridged
b-CD-dimer was synthesized according to known procedures.[16]
A
solution of mono-6-amino-b-CD (2.96 g, 2.61 mmol) in DMF (50 mL)
was treated with terephthalic acid (114 mg, 0.686 mmol). After the
solution was cooled to 08C, 1-hydroxybenzotriazole (223 mg,
1.65 mmol) and N,N’-dicyclohexylcarbodiimide (367 mg, 1.78 mmol)
were added. The resulting mixture was stirred at room temperature
for seven days. After the insoluble materials were removed by
filtration, the filtrate was poured into acetone (1.5 L). The precipitate
was collected, washed with acetone, and dried under vacuum to give
3.36 g of the crude product. The crude product was purified by column
chromatography on DIAION HP-20 (eluting with water/methanol
100:0 to 50:50). The 60:40 (water/methanol) fraction of the eluent was
concentrated and the residue recrystallized from water/ethanol to
1
give 1.08 g of the desired product. Yield: 65%. H NMR (500 MHz,
[D6]DMSO): d = 8.24 (brs, 2H), 7.88 (s, 4H), 5.82–5.65 (m, 28H),
4.96–4.84 (m, 14H), 4.44–4.30 (m, 18H), 3.85–3.16 ppm (m, overlaps
with HOD); 13C NMR (500 MHz, [D6]DMSO): d = 165.90, 136.40,
127.01, 101.87, 83.70, 81.50, 72.98, 72.37, 72.03, 59.93, 56.00 ppm;
MALDI-TOF: m/z: 2419.3 [M+ÀNa]; elemental analysis calcd (%)
for C92H144N2O70·9.4H2O: C 43.04, H 6.39, N 1.09; found: C 43.05, H
6.43, N 1.30.
Zero-shear viscosities were determined in water at 108C using
following concentrations of polymers and cyclodextrins: CP =
50 gLÀ1, CCD = 25 gLÀ1, CCD dimer = 25 gLÀ1
.
Turbidity measurements were performed in aqueous solutions at
Synthesis of monomer 3: A solution of 1-adamantylamine (7.56 g,
0.050 mol) and triethylamine (7.66 mL, 0.055 mol) in THF (200 mL)
was cooled down to 08C. Subsequently a solution of acryloyl chloride
(4.47 mL, 0.055 mol) in THF (50 mL) was added dropwise within
30 min. After complete addition the solution was stirred at room
temperature for 2 h. The precipitate was filtered off, and the solvent
was removed under reduced pressure. The obtained crude product
was purified by column chromatography (hexane/ethyl acetate 3:1).
Yield: 95%. 1H NMR (500 MHz, CDCl3): d = 6.22 (dd, J = 1.6 Hz,
1H), 6.02 (dd, J = 10.3 Hz, 1H), 5.56 (dd, J = 1.4 Hz, 1H), 5.24 (brs,
1H), 2.06 (m, 9H), 1.69 ppm (m, 6H); 13C NMR (500 MHz, CDCl3):
d = 164.51, 132.18, 125.57, 52.10, 41.61, 36.36, 29.44 ppm; MS (70 eV,
EI): m/z: 205 [M+].
Synthesis of monomer 4: 6-N-Acrylamidohexanoic acid was
synthesized according to known procedures.[9a,21] A solution of 6-N-
acrylamidohexanoic acid (1.85 g, 0.01 mol) and triethylamine
(1.39 mL) in THF (50 mL) was cooled to 08C. Subsequently ethyl-
chloroformiate (0.96 mL, 0.01 mol) was added. After 40 min, 1-
adamantylamine (1.51 g, 0.01 mol) was added. The reaction mixture
was stirred at 08C for 2 h. After further stirring for 16 h at room
temperature, the mixture was filtrated. The filtrate was diluted with
108C using following concentrations of polymers and cyclodextrins:
CP = 10 gLÀ1, Cme-b-CD = 10 gLÀ1, CCD dimer = 5 gLÀ1
.
Received: December 21, 2005
Revised: March 9, 2006
Published online: May 31, 2006
Keywords: cyclodextrins · host–guest systems · hydrogels ·
.
LCST · supramolecular chemistry
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