Superstructures of double functionalized host-guest acrylmonomers containing chiral phenylalanine-click-cyclodextrin and polymers

Article abstract of DOI:10.1021/ma3002164

We report the preparation of acrylic monomers d- or l-mono-(6- phenylalanine-acrylamido-6-deoxy)-β-cyclodextrin 3_D/3 _L and their corresponding copolymers 4_D/4_L bearing NIPAAm and d- or l-phenylalanine as guest a

Full text of DOI:10.1021/ma3002164

Article
pubs.acs.org/Macromolecules
Superstructures of Double Functionalized Host−Guest
Acrylmonomers Containing Chiral Phenylalanine-click-cyclodextrin
and Polymers
S. Gingter, B. Mondrzik, and H. Ritter*
Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich-Heine-University Duesseldorf, Universitaetsstraße 1,
D-40225 Duesseldorf, Germany
S
* Supporting Information
ABSTRACT: We report the preparation of acrylic monomers D- or L-
mono-(6-phenylalanine-acrylamido-6-deoxy)-β-cyclodextrin 3D/3L and
their corresponding copolymers 4D/4L bearing NIPAAm and D- or L-
phenylalanine as guest and β-cyclodextrin as host moieties. To
implement the cyclodextrin resin (CD) into the monomer, microwave
accelerated cycloaddition (click-reaction) was performed. For the new
design of polymers having both host and guest species in the polymer
side chain, inter- and intramolecular interactions could be observed.
The resulting supramolecular structures were characterized by NMR,
DLS, TEM, and LCST measurements.
tions.22 Next to calixarenes and cucurbiturils particularly
cyclodextrins (CDs) are important macrocyclic hosts, because
INTRODUCTION
Supramolecular structures are ubiquitous in nature particularly
■
they are water-soluble, natural products suitable for medical
in biological systems, the most common are DNA, microtubuli,
applications.23,24 Although cyclodextrins are frequently used for
chiral separation of racemates in column chromatography, the
phenomena of chiral recognition of synthetic polymers has not
yet been extensively investigated.25−29 Thus, we want to report
about the preparation and properties of a new typ of
polymerizable acrylic monomer containing chiral β-CD as
host and phenylalanine as guest moiety in the same molecule.
We chose CD as a host and phenylalanine as a guest compound
because the aromatic moiety builds stable complexes with CD
and phenylalanine is an important, chiral biomolecule.
or microfilaments which are built out of proteins.1 Scientist
have been inspired by nature and have investigated various
systems mimicking biomolecules by synthetic supramolecular
structures with interesting properties and functions.2−6 Super-
structures formed by hydrogen bonds were reported for the
first time by Lehn et al.7 Many contributions about the
formation of supramolecular polymers formed by hydrogen
bonding can be found in literature.8−12 However there have
been few works dealing with the self-assembly into supra-
molecular polymeric structures via host−guest interaction.13,14
For example Harada et al. reported about the formation of
supramolecular helical polymers, recently.15 The self-assembly
behavior of phenyl modified β-cyclodextrins has been
investigated by Liu et al.16
Also self-assembly of gels through shape selective molecular
recognition with CD for linear and cyclic guest molecules was
investigated on a macroscopic scale very recently.17 Further-
more there have been few works dealing with self-assembly of
chiral compounds. For example a monomer end-capped with a
cholesteryl group was threaded with CD to form a helical
polymer.18 Star polymers and polymer brushes were synthe-
sized from amphiphilic chiral monomers and their self-assembly
investigated.19,20
MATERIALS AND EXPERIMENTAL SECTION
■
All reagents used were commercially available (Sigma-Aldrich, Acros
Organics) and were used without further purification. β-cyclodextrin
was obtained from Wacker Chemie GmbH, Burghausen, Germany,
and used after drying overnight at a vacuum oil pump over P4O10. D-
and L-Phenylalanine (98.5%) were purchased from Alfa Aesar GmbH
& CoKG, Germany. Acryloylchloride (97%) and N-isopropylacryla-
mide (NIPAAm, 97%) were obtained from Sigma-Aldrich, Germany,
and used as received. Azoisobutyronitrile (AIBN) (96%) and N,N-
dimethylformamide (DMF) were purchased from Fluka, Germany.
Dimethyl sulfoxide-d6 (99.9 atom % D) and deuterium oxide, D2O,
were obtained from Deutero GmbH, Germany.
1H NMR was performed using a Bruker Advance DRX 200
spectrometer operating at 200.13 or 500 MHz for protons using
However there have been few works dealing with supra-
molecular structures based on host−guest interaction from
chiral monomers.21 Monomers based on macrocyclic hosts
comprising both host and guest moiety offer a wide range of
opportunities for new supramolecular materials and applica-
Received: January 30, 2012
Revised: February 2, 2012
Published: February 14, 2012
© 2012 American Chemical Society
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Scheme 1. Synthesis of Monomers 3D, 3L and Copolymers 4D, 4L
DMSO-d6 or Deuteriumoxide 99.9% as solvents. The chemical shifts
(δ) are given in ppm using the solvent peak as an internal standard.
FT-IR spectra were recorded on a Nicolet 6700 FT-IR spectrometer
equipped with an ATR unit. MALDI−TOF mass spectrometry
(MALDI−TOF MS) was performed on a Bruker Ultraflex TOF
time-of-flight mass spectrometer using a 337 nm nitogen laser. The
samples were dissolved in acetonitrile/water and mixed with dithranol
matrix. Molecular weights and molecular weight distributions were
measured by size exclusion chromatography (SEC) using a Viscotek
GPCmax VE2001 system that contained a column set with 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 at
60 °C. N,N-Dimethylformamide (DMF, 0.1 M LiCl) was used as
eluent at a flow rate of 1 mL × min−1. A Viscotek VE 3500 RI detector
and a Viscotek Viscometer model 250 were used. The system was
calibrated with polystyrene standards with a molecular range from
580 D to 1 186 kD.
Turbidity experiments were performed on a Tepper cloud point
photometer TP1. Relative transmission of a laser beam with a
wavelength of 670 nm was recorded for each experiment. The
measurements were performed at a temperature range between 5 and
70 °C and a heating rate of 1 °C min−1 using Hellma Suprasil precision
cells 110 Q-S. Critical solution temperatures derived from these
experiments were determined at 50% relative transmission. Dynamic
Light Scattering (DLS) experiments were carried out with a Malvern
Zetasizer Nano; ZS ZEN 3600 at a temperature of 20 °C. The particle
size distribution is derived from a deconvolution of the measured
intensity autocorrelation function of the sample by a General Purpose
Methode (non-negative least squares) algorithm included in the DTS
software. Each experiment was performed at least five times.
Polarimetric measurements were performed at T = 20 °C in dimethyl
sulfoxide or water (λ = 590 nm). Microwave-assisted synthesis was
performed using a CEM Discover synthesis unit (monomode system).
The temperature was measured by infrared detection with continuous
feedback temperature control and maintained at a constant value by
power modulation. Reactions were performed in closed vessels under
controlled pressure. Transmission electron microscopy (TEM) images
were recorded on a Zeiss EM902 A microscope at 80 kV.
chloroformiate, a white precipitate of N-methylmorpholine hydro-
chloride was formed. Propargylamine (10 mmol, 0.55 g) was then
added to the reaction mixture. A slight formation of CO2 could be
observed. The mixture was further stirred for 1 h at room temperature.
The hydrochloride salt was then filtered, and the clear solution
evaporated to dryness. The product was further dried at a high vacuum
pump to yield 1.3 g (47%) of white solid. Polarimetric measurement
20
20
(DMSO) 2L αD = 30°; 2D αD = −28°. 1H NMR (200 MHz,
DMSO-d6) δ (ppm): 8.60 (s, 1H), 8.43 (d, J = 8.7, 1H), 7.36 − 7.07
(m, 5H), 6.36 − 6.18 (m, 1H), 6.02 (dd, J = 2.4, 17.1, 1H), 5.57 (dd, J
= 2.4, 10.0, 1H), 3.94−3.78 (m, 2H), 3.16 (t, J = 2.5, 1H), 3.00 (dd, J
= 4.8, 13.7, 1H), 2.79 (dd, J = 9.7, 13.6, 2H). FT- IR (diamond)
ν(cm−1): 3273.3 (ν NH), 3069.6, 2961.5, 1645.7 (amide I), 1622.4
(CC), 1547.2 (amide II), 1496.1 (Ar), 1436.2, 1382.4, 1325.0,
1241.4, 1224.6, 1192.7, 990.8. Anal. Calcd: C, 69.7; H, 5.43; N, 11.61.
Found for 2L: C, 69.7; H, 6.6; N, 10.6. Found for 2D: C, 70.02; H, 6.4;
N, 10.59.
D- or L-Mono(6-phenylalanine-acrylamido-6-deoxy)-β-cyclo-
dextrin, 3D/3L. We approached microwave-assisted cycloaddition by
giving 2D/2L (0.2 g, 0.82 mmol) to a solution of mono-(6-azido-6-
desoxy)-β-CD (1.42 g, 1.23 mmol) in 2 mL DMF in a pressure-
resistant test tube. To the clear solution were added sodium ascorbate
(25 mg, 0.1 mmol) and copper(II) sulfate pentahydrate (40 mg, 0.2
mmol). The tube was sealed and placed in the CEM monomode
microwave and irradiated at 85 °C and 140 W for 60 min. After
precipitating with acetone (50 mL) the products were collected by
filtration to yield 1.5 g (80%) product. FT-IR (diamond) ν (cm−1):
3356.4 (ν OH), 2927.2, 2102.7, 1652.1, 1497.1, 1437.5, 1385.8,
1254.9, 1082.1, 1029.1, 1003.0, 936.0, 863.9. MALDI TOF MS m/z =
1416 [M + Na]+.
Copolymer 4D/4L. A 0.5 g sample of 3D/3L (0.18 mmol) was
solved with 0.24 g (1.8 mmol) N-Isopropylacrylamide in 10 mL DMF.
The solution was flushed with argon for 15 min, and then 7.4 mg
(1 wt %) AIBN in DMF was added to the solution. The mixture was
further stirred at 80 °C for 24 h. The product was obtained by
precipitation in diethylether and afterward purificated by dialysis in a
1
MWCO 3500 and lyophilized to yield 0.6 g. H NMR (200 MHz,
D2O): δ = 7.93−7.83 (m), 7.44−7.06 (m), 5.31−4.82 (m), 3.86 (s),
3.14−2.69 (m), 1.10 (s). FT-IR (diamond) ν (cm−1): 3295.3 (OH),
2971.1, 2931.4, 1640.5 (amide I), 1536.8 (amide II), 1459.2 (Ar),
• The N-acrylated aminoacid 1D/1L was prepared according to
the method described before.30
20
1387.1, 1367.1, 1240.5, 1153.7, 1130.7, 1080.7, 1032.0, 1004.3. 4L αD
= 14° 4D αD20 = 18°, SEC measurement: 4D, Mn = 45 000, PD 1.3; 4L,
Mn = 42 000, PD 1.3.
• Mono(6-azido-6-desoxy)-β-CD was synthesized according to
the method described before.31
D- or L-N-(1-Oxo-3-phenyl-1-(prop-2-yn-1-ylamino)propan-
2-yl)acrylamide, 2D/2L. The respective N-acrylated amino acids 1D/
1L (10 mmol, 2.19 g) were solubilized in THF (100 mL) at room
temperature. N-Methylmorpholine (1.01 g, 10 mmol) was then added
to the amino acid solution, followed by further addition of isobutyl
chloroformiate (10 mmol, 1.37 g). During the addition of the isobutyl
RESULTS AND DISCUSSION
■
Monomers N-acryloyl-D-phenylalanine (1D) and N-acryloyl-L-
phenylalanine (1L) were prepared according to the method
described before. Further modification of monomers 1 was
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Figure 1. 2D ROESY NMR experiment of 3D showing the correlation between protons of the phenyl ring and protons of the inner cavity of CD.
carried out by condensation of the carboxylic group with
propargylamine to obtain the corresponding alkin moiety N-(1-
oxo-3-phenyl-1-(prop-2-yn-1-ylamino)propan-2-yl)acrylamide,
2D/2L. The microwave accelerated click-reaction employing
Cu(I) catalysis with sodium-ascorbate lead to the desired
monomers mono-(6-phenylalanine-acrylamido-6-deoxy)-β-cy-
clodextrin, 3D and 3L. To confirm that the monomers did not
racemize significantly during the synthesis, polarimetric
measurements were performed in dimethyl sulfoxide as solvent,
20
20
3D exhibited αD = −28° and 3L αD = +30°, respectively.
Copolymers 4D and 4L comprising N-isopropylacrylamide
(NIPAAm), D-mono-(6-phenylalanine-acrylamido-6-deoxy)-β-
cyclodextrin (3D) and L-mono(6-phenylalanine-acrylamido-6-
deoxy)-β-cyclodextrin (3L), respectively, were obtained by free
radical polymerization with AIBN as initiator (Scheme 1). The
structures of all synthesized polymeric compounds have been
characterized by spectroscopic methods, elemental analysis and
polarimetric measurements. The molecular weights and molar
weight distribution of polymers 4D and 4L were determined by
size exclusion chromatography (SEC) showing similar results.
To confirm the formation of the proposed intermolecular
interaction between the hydrophilic and hydrophobic moieties
in case of the monomers 3D and 3L 2D ROESY-NMR-
spectroscopy was carried out to show the expected correlation
between the inner cavity protons of β-CD and the protons of
the phenyl ring. Figure 1, as an example for a 2D ROESY NMR
spectrum of 3D, illustrates clearly interactions of protons from
the phenyl group with protons of the CD cavity (for ROESY of
3L, see Supporting Informations).
Figure 2. DLS measurement of monomers 3D (2 mg/mL) and 3D
complexed with potassium adamantylcarboxylate (1 mg) and
schematic illustration of complexes.
suitable competing guest molecule with a higher complex
stability with β-CD than the phenylring of 3D. After addition of
ad-COO− K+ to the aggregate of 3D the hydrodynamic
diameter decreases as mentioned above down to 25 nm, as
the β-CD moieties have the tendency to aggregate, the
diameter does not further decrease even after addition of ad-
COO− K+ in great excess.
Furthermore, we were able to show that the supramolecular
aggregates of 3 can also be disassembled by increasing the
temperature of the solution and that the formation of the
supramolecular structure can be monitored over time
(Supporting Information).
1
In addition the H NMR spectra of the monomer exhibits
1
clear peak shifts compared to the H NMR spectra of β-CD
which can be assigned to the complexation of the monomer 3D
(Supporting Information).
The formation of large supramolecular structures formed by
intramolecular interactions were found in DLS measurements
of the monomers 3D and 3L exhibiting hydrodynamic diameters
with a mean coil size of about 100 nm (Figure 2 as an example
for 3D). The structure can then be disassembled by addition of
adamantylcarboxylate (ad-COO− K+)in slight excess, which is a
In order to qualify the structure and nature of the
supramolecular inclusion complexes, TEM (Transmission
Electron Mikroscopy) was conducted. The microscope image
(Figure 3) shows the formation of large linear structures for the
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Figure 3. TEM measurement of 3D exhibiting tube-like super-
structures.
Figure 5. Hydrodynamic diameters of polymers 4D and 4L (1 mg/
mL).
supramolecular structure formed from the monomers. In
comparison the picture of the copolymers 4 exhibits round
vesicles with a higher order than the aggregates of 3. Both
samples exhibit aggregation induced by the intermolecular
host−guest interaction.
CONCLUSION
■
We have investigated the formation of a new cyclodextrin- and
phenylalanine-based monomer and the resulting supramolecule.
The intermolecular interaction was proven by 2D ROESY
NMR experiments. The quality of the supramolecule was
investigated via TEM and DLS, exhibiting large formations of
100 nm in diameter, which could be disassembled by addition
of potassium adamantylcarboxylate. Thus we conclude that we
have succeeded in synthesizing a new type of monomer bearing
both host and guest moiety forming supramolecular structures.
Furthermore we were able to show enantioselective recognition
of copolymers containing D- or L-phenylalanine moieties by use
of DLS and LCST measurement. The results clearly indicate
that enantioselective recognition of the polymeric attached
chiral amino acid takes place due to host−guest interaction with
β-CD. The D-enantiomer of polymeric attached phe shows a
much stronger increase in hydrodynamic diameter than the L-
enantiomer due to CD-interaction.
Furthermore, the solution properties of copolymers 4D and
4L were investigated. As expected, copolymers 4D, 4L (1:10) are
soluble in cold water below the critical solution temperature
(LCST). However, due to the presence of incorporated
hydrophilic comonomers 3D, 3L a significant affect on the
cloud point value of pure Poly-(NIPAAm) is shifted from 32 to
39.0 °C (3L) and to 40.5 °C (3D) respectively. The cloud point
shift difference of 1.5 °C regarding the D- or L-enantiomer is a
strong hint to different stereoinduced interactions (Figure 4).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
DLS measurements, H NMR spectra, FT-IR spectra, and 2D
ROESY NMR. This information is available free of charge via
the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: h.ritter@uni-duesseldorf.de.
Figure 4. LCST measurements of 4D and 4L in comparison to
Poly(NIPAAm) (10 mg/mL).
Notes
The authors declare no competing financial interest.
To confirm the supposed diastereomeric effects, DLS
measurements of the copolymers were carried out. Surprisingly,
in contrast to the small difference in cloud points copolymers
exhibited strong differences of hydrodynamic diameters of 16
nm for the 4L and 63 nm for the 4D, respectively (Figure 5).
Since SEC measurements of 4D and 4L confirm nearly
identical masses and mass distributions; the big difference of
supramolecular aggregates in aqueous solution is a result of the
phe chirality.
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