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Unusual Solubility Properties of Polymethacrylamides as a Result of Supramolecular Interactions with Cyclodextrin.

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Communications
Supramolecular Chemistry
DOI: 10.1002/anie.200501374
Unusual Solubility Properties of Polymethacrylamides as a Result of Supramolecular Interactions
with Cyclodextrin
Sarah Schmitz and Helmut Ritter*
Hydrophilic polymers with so-called LCST behavior are
soluble within a certain temperature range but undergo phase
separation or a change in volume above a critical temperature
value, the lower critical solution temperature (LCST).[1]
These phenomena can also be observed when other parameters are changed such as pH value,[2] electric field, and ionic
strength.[3] For example, poly(N-isopropylacrylamide) shows
a LCST at 34 8C in pure aqueous solution. This means that the
polymer is soluble in water below 34 8C and precipitates
simply when the solution is heated above that critical
temperature.[4] The LCST value can be influenced, for
example, by copolymerization of N-isopropylacrylamide or
by chemical modification of the acrylamide polymer itself.
The slightly cross-linked LCST polymers, so-called hydrogels,
find potential application in the medical and biochemical
fields, for controlled drug delivery[5] and as materials for
bioreactors.[6] Although this LCST behavior of polymers
cannot yet be explained, many studies have focused on this
topic. One general explanation of the LCST effect is that
strong hydrogen bonds exist between water molecules and the
hydrophilic groups of the polymer at low temperature.[7] With
increasing temperature, intramolecular interactions between
hydrophobic chain components of the polymer increase.
Reaching the LCST, polymer aggregation takes place, and the
solubility in water decreases suddenly. We report here on a
similar LCST-type solubility effect based on the reversible
complexation of suitable polymers with b-cyclodextrin.
Although the formation of complexes of hydrophobic polymers with cyclodextrins (CDs) has already been reported,[8] a
characteristic LCST-type behavior has not yet been observed.
A functionalized polymer suitable for complexation with
b-CD was prepared by the synthesis and radical polymerization of monomer 5 according to Scheme 1. Intermediate 3
was obtained from the reaction of 1 and 2 (Scheme 1).[9] The
esterification of 3 with 4 led to formation of methacrylamide
monomer 5, which contains a bulky group suitable for
complexation with CD and a bromine atom, which opens up
the possibility of further modification by atom-transfer
radical polymerization (ATRP).[10]
[*] Dipl.-Chem. S. Schmitz, Prof. Dr. H. Ritter
Institut f(r Organische Chemie und Makromolekulare Chemie II
Heinrich-Heine-Universit/t D(sseldorf
Universit/tsstrasse 1, 40225 D(sseldorf (Germany)
Fax: (+ 49) 211-8115-840
E-mail: h.ritter@uni-duesseldorf.de
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5658 –5661
Angewandte
Chemie
Scheme 1. Synthesis of monomer 5.
The water-insoluble monomer 5 was treated with b-CD,
and the resulting complex 5 a was soluble in water
(Scheme 2). With a [CD]/[5] ratio of less than 1.5:1, it was
Scheme 2. Complex formation of monomer 5 with b-CD at room temperature in water.
possible to complex the monomer, but the polymer precipitated afterward polymerization. At larger [CD]/[5] ratios the
polymer remained in the aqueous phase as a result of
sufficient complexation.
The preferred stoichiometry of the monomer/b-CD complex can be evaluated by using Job;s method[11, 12] which was
transferred to NMR spectroscopy by Blanda et al.[13] In this
case monomer 5 represents the guest molecule, while b-CD
corresponds to the host molecule. (For further information on
the method see the Supporting Information.) A curve with a
maximum around 0.4 was obtained (Figure 1 a), which
suggests that the stoichiometry of the 5/b-CD complex is
1.5:1. That means that a temporary complexation of two
monomer molecules by one b-CD ring takes place. The
increase in the chemical shift of the NMR signal of the methyl
protons with an increasing amount of b-CD is shown in
Figure 1 b. A 2D ROESY NMR spectrum indicates the
interactions between the b-CD ring and the monomer 5
(Figure 2). The protons of the two methyl groups
(CBr(CH3)2) at d = 1.9 ppm are directly correlated to the
protons of b-CD at d = 3.3–3.9 ppm. We can assume that bCD preferably includes the CBr(CH3)2 group of 5 (see the
Supporting Information).
The free-radical polymerization of the complexed monomer 5 a was carried out in presence of a redox initiator at
room temperature (Scheme 3). The average molar masses M̄
Angew. Chem. Int. Ed. 2005, 44, 5658 –5661
Figure 1. a) Job plot of monomer 5: the chemical shift of the six protons of the methyl groups (CBr(CH3)2) was observed. b) Stacked plot
of the NMR spectra. The chemical shift of the six protons [CBr(CH3)2
group (*)] and of the three protons [C(CH3)=CH2 group (~)] of monomer 5 was observed with increasing amount of b-CD (500 MHz, D2O).
Figure 2. 2D ROESY NMR experiment with a monomer/b-CD solution
(5 a).
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
stable enough to keep the monomer in solution independent
of temperature. In contrast, the polymer complex 6 a showed
a definite clouding point at a temperature of 54 8C for the
heating run (Figure 4 a) and a clearing point of about 50 8C for
Scheme 3. Free-radical polymerization of the monomer/b-CD complex
5 a to give the complexed water-soluble polymer 6 a.
of the obtained polymers, as determined by MALDI-TOF
measurements, are in the range between 4300 (7) and
5400 g mol 1 (6) depending on the amount of initiator
(Table 1). In the mass spectrum (Figure 3) the differences
between the signals of the main series correspond to the
molar mass of the monomer unit, 278 g mol 1, as expected.
Table 1: Pseudo-LCST behavior of the polymers.
Polymer
Initiator
[mol %]
M̄
[g mol 1][a]
Clouding point
[8C][b]
Clearing point
[8C][c]
6
7
2.5
5
5400
4300
54
68
50
61
[a] Determined by MALDI-TOF mass spectrometry. [b] Determined by
turbidity measurement during heating. [c] Determined by turbidity
measurement during cooling.
Figure 4. Transmittance of a solution of complexed polymer 6 a versus
temperature during a) heating and b) cooling.
the cooling run (Figure 4 b). These temperatures were found
to be a function of the molecular mass M̄ of the b-CD-free
polymers. The corresponding values are listed in Table 1.
Scheme 4 shows the reversible decomplexation–complexation process of polymer 6 in water.
The transmittance change of a solution of 6 a is plotted as
a function of temperature in Figure 4. The decrease in the
transmittance of the complexed polymer to 0 % occurs within
a temperature interval of roughly 5 8C. In the subsequent
Figure 3. MALDI-TOF mass spectrum of polymer 6.
When the optically clear aqueous solutions of the
complexed polymers 6 a (see the Experimental Section for
the synthesis of polymer 6) were heated above 70 8C, a sudden
turbidity was observed. Surprisingly, when the solution was
cooled, transparency was completely restored. Exact turbidity
measurements were performed to evaluate the solubility as a
function of the temperature. We found that the complexed
monomer 5 a is completely soluble in the temperature range
from 10 up to 85 8C. This means that the monomer complex is
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Scheme 4. Temperature-dependent reversible unthreading of CD from
the bulky side group of 6 a during the heating procedure.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5658 –5661
Angewandte
Chemie
cooling step the polymer returns to solution by new formation
of polymer/b-CD complex. In contrast, the b-CD-free polymer is not soluble in water at any temperature in this range.
The interesting polymer-solubility behavior led us to compare
this phenomenon with classical LCST effects. In our case,
because of the reversible complex formation between the
polymer 6 and cyclodextrin, the optical effect is based on
supramolecular interactions. This means that the discovered
pseudo-LCST behavior is a result of noncovalent interactions
between the CD host and polymer guest. Furthermore, in this
system competitive inhibition or control of the LCST is
possible by addition of other suitable guest molecules of low
molecular weight, for example, potassium 1-adamantylcarboxylate. CD complexes these molecules preferably, and the
polymer precipitates. This special effect cannot be observed in
“normal” LCST systems.
To prove the postulated dissociation of the polymer/CD
complex at temperatures higher than the clouding point, the
total amount of b-CD in solution was determined by 1H NMR
measurements before polymerization and after filtration of
the precipitated polymer. DMSO was added to the monomer/
b-CD solution as an internal standard. After polymerization,
the solution was heated and the precipitated polymer was
filtered off. Integration of the NMR signals showed the same
amount of b-CD relative to DMSO at each time. The filtered
polymer was nearly free of CD. This is in accordance with the
“pseudo-LCST” effect described above which is caused by
reversible complex formation.
These experiments and results clearly show that the
investigated system of b-CD and polymethacrylamide (5)
reveals new opportunities in the field of thermosensitive
systems based on noncovalent interactions between host and
guest compounds. The noncovalently attached b-CD ring
keeps the insoluble polymer in aqueous solution at lower
temperature. At higher temperatures the CD ring slips off and
the polymer precipitates; this process is reversible. Currently
detailed studies about the temperature-dependent formation
of aggregates and changes in viscosity are underway for a
better understanding of the observed phenomenon and to
investigate the suitability of polymer/b-CD solutions as novel
thermosensitive gels.
Polymer 6: Monomer 5 (1 g, 3.6 mmol) was added to a stirred
aqueous solution of b-CD (40 wt %). After the solution had been
flushed with argon for 20 min, a mixture of potassium peroxodisulfate
(24.3 mg) and sodium disulfite (17.1 mg, 2.5 mol %) was added. The
polymerization was carried out at room temperature for 12 h. The
synthesized polymer was purified by several precipitation cycles in a
low concentrated sodium chloride solution first from the crude
solution and then from methanol. NMR and IR data are given in the
Supporting Information.
Received: April 21, 2005
Published online: July 29, 2005
.
Keywords: cyclodextrins · host–guest systems · LCST · polymers
[1] P. R. Washington, O. Steinbock, J. Am. Chem. Soc. 2001, 123,
7933 – 7934.
[2] J. Zhang, N. A. Peppas, Macromolecules 2000, 33, 102 – 107.
[3] H.-C. Chin, Y.-F. Lin, S.-H. Hung, Macromolecules 2002, 35,
5235 – 5242.
[4] E. Tepper, O. Sadowski, H. Ritter, Angew. Chem. 2003, 115,
3279 – 3281; Angew. Chem. Int. Ed. 2003, 42, 3171 – 3173.
[5] J. H. Han, J. M. Krochta, M. J. Kurth, Y. -L. Hsieh, J. Agric. Food
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[6] J. Heo, K. J. Thomas, G. Seong, R. M. Crooks, Anal. Chem. 2003,
75, 22 – 26.
[7] H. Feil, Y. H. Bae, J. Feijen, S. W. Kim, Macromolecules 1993, 26,
2496 – 2500.
[8] H. Ritter, M. Tabatabai, “Cyclodextrin in Polymer Synthesis” in
Encyclopaedia of Polymer Science and Technology, WileyInterscience, New York, 2004, published online.
[9] J. Song, E. Saiz, C. R. Bertozzi, J. Am. Chem. Soc. 2003, 125,
1236 – 1243.
[10] K. Matyjaszewski, T. P. Davis in Handbook of Radical Polymerization, Wiley-Interscience, New York, 2002.
[11] P. Job, C. R. Hebd. Seances Acad. Sci. 1925, 180, 928 – 930.
[12] K. A. Connors, Binding Constants, The Measurement of Molecular Complex Stability, Wiley, New York, 1987.
[13] M. T. Blanda, J. H. Horner, M. Newcomb, J. Org. Chem. 1989,
54, 4626 – 4636.
Experimental Section
For materials and methods, see the Supporting Information. Monomer 3 was synthesized according to the work of Bertozzi and coworkers.[9]
Monomer 5: 2-Bromoisobutyryl bromide (4; 10.12 mL,
81.9 mmol) was added dropwise to a cold mixture of 3 (8.8 g,
68.2 mmol) and triethylamine (14.1 mL, 100.8 mmol) in 180 mL of
THF over 20 min. The mixture was stirred for 4 h at 0 8C and 42 h at
room temperature. The precipitated salt was removed by filtration.
The solvent was removed under vacuum, and the resulting yellow oil
was then purified by column chromatography (silica gel, ethyl acetate/
petroleum ether 1:1) (Rf = 0.4). Yield: 85 %. For elemental analysis
and NMR and IR data, see the Supporting Information.
Complex 5 a: Monomer 5 (1 g, 3.6 mmol) was added to a stirred
aqueous solution of b-CD (40 wt %; 7.2 g of b-CD in 10.8 mL of
doubly distilled water). The molar ratio of monomer 5 to b-CD was
1:1.5.
Angew. Chem. Int. Ed. 2005, 44, 5658 –5661
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5661
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