Supramolecular Inclusion Complexes of a Star Polymer Containing Cholesterol End-Capped Poly(e-caprolactone) Arms with b-Cyclodextrin

Article abstract of DOI:10.1002/pola.27408

A novel hexa-armed and star-shaped polymer containing cholesterol end-capped poly(e-caprolactone) arms emanating from a phosphazene core (N3P3-(PCL-Chol)6) was ynthesized by a combination of ring-opening polymerization and "click" chemistry techniques. For this purpose, the terminal AOH groups of the synthesized precursor (N3P3-(PCL-OH)6) were converted into Chol through a series of reaction. Both 3P3-(PCL-OH)6 and N3P3-(PCL-Chol)6 were then employed in the preparation of supramolecular inclusion complexes (ICs) with b-cyclodextrin (b-CD). The latter formed ICs with b-CD in higher yield. The hostguest stoichiometry (e-CL:b-CD, mol:- mol) in the ICs of N3P3-(PCL-Chol)6 was found to be 1.2. The formation of supramolecular ICs of N3P3-(PCL-Chol)6 with b-CD was confirmed by using Fourier transform infrared (FTIR) and 1H nuclear magnetic resonance (NMR) spectroscopic methods, wide-angle X-ray diffraction (WAXD), and thermal analysis techniques. WAXD data showed that the obtained ICs with N3P3-(PCL-Chol)6 had a channel-type crystalline structure, indicating the suppression of the original crystallization of N3P3- (PCL-Chol)6 in b-CD cavities. Moreover, the thermal stabilities of ICs were found to be higher than those of the free star polymer and b-CD. Furthermore, the surface properties of N3P3- (PCL-Chol)6 and its ICs with b-CD were investigated by static contact angle measurements. The obtained results proved that the wettability of N3P3-(PCL-Chol)6 successfully increased with the formation of its ICs with b-CD.

Full text of DOI:10.1002/pola.27408

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Supramolecular Inclusion Complexes of a Star Polymer Containing
Cholesterol End-Capped Poly(e-caprolactone) Arms with b-Cyclodextrin
Erdinc Doganci,1,2 Mesut Gorur,3 Cavit Uyanik,4 Faruk Yilmaz1
1Department of Chemistry, Gebze Institute of Technology, 41400 Gebze, Kocaeli, Turkey
2Department of Science Education, Kocaeli University, 41380 Kocaeli, Turkey
3Department of Chemistry, Istanbul Medeniyet University, 34720 Istanbul, Turkey
4Department of Chemistry, Kocaeli University, 41380 Kocaeli, Turkey
Correspondence to: F. Yilmaz (E-mail: fyilmaz@gyte.edu.tr)
Received 28 March 2014; accepted 7 September 2014; published online 25 September 2014
DOI: 10.1002/pola.27408
ABSTRACT: A novel hexa-armed and star-shaped polymer con-
taining cholesterol end-capped poly(e-caprolactone) arms ema-
techniques. WAXD data showed that the obtained ICs with
N3P3-(PCL-Chol)6 had a channel-type crystalline structure, indi-
cating the suppression of the original crystallization of N3P3-
(PCL-Chol)6 in b-CD cavities. Moreover, the thermal stabilities
of ICs were found to be higher than those of the free star poly-
mer and b-CD. Furthermore, the surface properties of N3P3-
(PCL-Chol)6 and its ICs with b-CD were investigated by static
contact angle measurements. The obtained results proved that
the wettability of N3P3-(PCL-Chol)6 successfully increased with
nating from
a phosphazene core (N3P3-(PCL-Chol)6) was
synthesized by a combination of ring-opening polymerization
and “click” chemistry techniques. For this purpose, the termi-
nal AOH groups of the synthesized precursor (N3P3-(PCL-OH)6)
were converted into –Chol through a series of reaction. Both
N3P3-(PCL-OH)6 and N3P3-(PCL-Chol)6 were then employed in
the preparation of supramolecular inclusion complexes (ICs)
with b-cyclodextrin (b-CD). The latter formed ICs with b-CD in
higher yield. The host–guest stoichiometry (e-CL:b-CD, mol:-
mol) in the ICs of N3P3-(PCL-Chol)6 was found to be 1.2. The
formation of supramolecular ICs of N3P3-(PCL-Chol)6 with b-CD
was confirmed by using Fourier transform infrared (FTIR) and
1H nuclear magnetic resonance (NMR) spectroscopic methods,
wide-angle X-ray diffraction (WAXD), and thermal analysis
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the formation of its ICs with b-CD.
2014 Wiley Periodicals,
Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 3406–3420
KEYWORDS: cholesterol; click chemistry; b-cyclodextrin; e-capro-
lactone; inclusion chemistry; inclusion complex; star polymers;
supramolecular structures
chemical stability, and bioavailability of poorly soluble drugs,
to reduce toxicity and to control the rate of release.2,16–18
Besides, these macrocycles have been used in analytical scien-
ces,13 material science,19 separation technology,20 catalysis,21
cosmetic,22 textile,23 food,8,24 and packaging industry.22,25
INTRODUCTION Supramolecular inclusion complexes (ICs)
formed between cyclodextrins (CDs) and polymers have
attracted much attention because of their potential biomedical
applications in drug delivery systems and tissue engineer-
ing.1–5 CDs are water-soluble macrocyclic oligosaccharides,
which are composed of six (a-CD), seven (b-CD), eight (c-CD)
glucose units connected by a-1,4 bondings.6–10 The peculiar
geometric structure of these compounds resembling a hollow
truncated cone and the presence of hydroxyl groups only on
the outer surface of CD molecules provide a hydrophobic
internal cavity and hydrophilic outer surface.2,11,12 Their geo-
metries give a hydrophobic cavity having a depth of about 8.0
Å, and an internal diameter of about 4.5 Å for a-, about 7.0 Å
for b-, and about 8.5 Å for c-CD.6,8,13,14 CDs have the feature of
forming ICs with various hydrophobic guest molecules with
suitable polarity and dimension (e.g., adamantane, cholesterol)
in their inner cavities and thus, enhance the solubility of these
molecules in aqueous media.15 Therefore, they can be
employed in pharmaceutical industry to enhance solubility,
Complexation studies of CDs with polymers started with the
work by Harada and Kamachi and they reported that a-CD
gave stoichiometric ICs with poly(ethylene glycol) (PEG) of
various molecular weights.26 Since CDs are biocompatible,
biodegradable, water-soluble, and environmentally safe com-
pounds, their ICs with biodegradable polyesters have exten-
sively been investigated by many research groups. Harada
and coworkers investigated ICs of CDs with linear aliphatic
polyesters, such as poly(e-caprolactone) (PCL), poly(ethylene
adipate) (PEA), poly(trimethyleneadipate) (PTA), and
poly(1,4-butylene adipate) (PBA).27–29 Tonelli and coworkers
reported that the formation of CD-ICs reduced phase separa-
tion in immiscible polymer blends, like poly(e-caprolactone)/
Additional Supporting Information may be found in the online version of this article.
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poly(L-lactide) (PCL/PLLA) and poly(methyl methacrylate)/
polycarbonate (PMMA/PC), or microphase-separated block
copolymer systems, like poly(e-caprolactone)-b-poly(L-lac-
tide) (PCL-b-PLLA) and poly(e-caprolactone)-b-poly(propyl-
ene glycol)-b-poly(e-caprolactone) PCL-b-PPG-b-PCL.30–33
Shin and coworkers compared the formation of ICs between
biodegradable polyesters (such as poly(3-hydroxypropio-
nate), poly(4-hydroxybutyrate), and PCL) and a-CD.34
heteroatom chemistry. The halogen “R” groups can easily be
replaced by alkoxy, aryloxy, and amino groups via nucleo-
philic reactions.57,58 Depending on the nature of the substitu-
ent moieties, phosphazene compounds can be tailored to
possess a wide variety of physical and chemical properties,
such as flame retardancy,59 super hydrophobicity,60 ion con-
ductivity,61 biocompatibility,62,63 and so on. Besides, they
exhibit high thermal and chemical stabilities. Therefore,
cyclophosphazenes with proper functional groups were
employed as initiators or starting compounds in the prepara-
tion of dendrimers,64 star,65 and cyclomatrix polymers.66
Recently, ICs of star-shaped polymers with CDs have
attracted increasing attention due to their unique supramo-
lecular structures and properties. Jiao et al. have reported
that CDs can form crystalline ICs with star-shaped PEG with
different branch arms.35 Dong and coworkers and Kwak and
coworkers prepared the ICs between a-CD and star-shaped
PCL having a dipentaerythritol core.36,37 Ren and coworker
also synthesized a penta-armed star-block poly(L-lactide)-b-
poly(ethylene oxide) (PLLA-b-PEO) copolymer with pentae-
rythritol core to form ICs with a-CD.38 In another work, PCL
star polymer with a metal-free porphyrin core was used in
the preparation of water-soluble IC with a-CD, which has
potential to be used in photodynamic therapy.39 Chan et al.40
and Huang et al.41 investigated CD-ICs of silsesquioxane-
cored star polymers having PCL and PEG arms, respectively.
With these backgrounds, we report the synthesis of a novel
hexa-armed and cholesterol (Chol) end-capped star-shaped PCL
with phosphazene core (N3P3-(PCL-Chol)6) (P4) by a combina-
tion of ring-opening polymerization (ROP) and “click” chemistry
techniques with the motivation of investigating the effect of
cholesterol end groups on the inclusion complexation behavior
of the star polymer having six PCL arms (P4) with b-CD
(Scheme 1). To the best of our knowledge, this is the first report
on the synthesis of polypseudorotaxanes composed of a star
polymer having cholesterol end-capped PCL arms with b-CD.
The synthesis of linear PCL having cholesterol end groups at
both ends (Chol-PCL-Chol) (L4) and cholesterol end-capped
phosphazene compound (N3P3-(Chol)6) (5) without PCL arms
is also reported herein to investigate their complexation behav-
iors with b-CD (Schemes 2 and 3, respectively). The modified
polymers, their ICs with b-CD, and the intermediates at various
stages of synthesis were characterized using Fourier transform
infrared (FTIR), 1H NMR, 31P NMR, and gel permeation chroma-
tography (GPC) as well as differential scanning calorimetry
(DSC), thermogravimetric analysis (TGA), and Wide-angle X-ray
diffraction (WAXD). The surface properties of b-CD formed
complexes with the cholesterol end capped structures (P4, L4,
and 5) were investigated by static contact angle measurements.
Cholesterol is one of the most important sterols in the mem-
branes of eukaryotic cells because of its high thermodynamic
affinity and its ability to change the membrane’s permeability
and fluidity.42,43 This ability of cholesterol arises from the
rigidity of the steroid ring system and plays an important role
in self-association of molecules in biological systems. Even
though the contents of cholesterol in polymers are very low, it
has a strong tendency for self-association.44 As these proper-
ties are important for cell attachment and proliferation, the
cholesteryl end-capped oligomers/polymers are expected to
have promising applications in drug delivery system45–48 and
tissue engineering scaffolds.49,50 In addition, cholesterol has
unique features such as chirality, amphiphilicity, liquid crystal-
linity, and biocompatibility.51 Cholesterol has the ability to
form ICs with CDs. Thus, cholesteryl end-capped oligomers/
polymers have been studied to form supramolecular struc-
tures via complexation with CDs forming ICs.52–54
EXPERIMENTAL
Materials
b-Cyclodextrin (b-CD, Merck, ꢀ98%) was used without fur-
ther purification. e-caprolactone (e-CL, Aldrich, 97%) was
dried over calcium hydride (CaH2, Sigma-Aldrich, 95%), dis-
tilled at 97 ꢁC under 10 mmHg and stored over dry 4 Å
molecular sieves. Cholesteryl chloroformate (C28H45ClO2, Alfa
Aesar, 98%) was used as supplied. Sodium hydride (NaH,
Merck, 60% in mineral oil) was washed with dry hexane just
prior to use. Triethylamine (TEA, ꢀ99.5%) was obtained
from Fluka, dried over CaH2 and stored over 3 Å molecular
sieves. Dichloromethane (DCM, Merck, 99.8%) was dried
over phosphorus pentoxide. Dimethylformamide (DMF,
Merck, 99.8%) was both dried and stored over activated 4 Å
molecular sieves. Ethanediol (Fluka, ꢀ99.5%), tin(II) 2-
ethylhexanoate (Sn(Oct)2, Aldrich, 95%), 2-bromo-2-
methylpropanoyl bromide (C4H6Br2O, Aldrich, 98%), sodium
azide (NaN3, Sigma-Aldrich, 99.5%), propargyl alcohol
(C3H4O, Merck), N,N,N0,N00,N00-pentamethyldiethylenetriamine
(PMDETA, Aldrich, 99%), copper(I) bromide (CuBr, Sigma-
Aldrich, 98%), methanol (Merck, 99.9%), methylene iodide
(CH2I2, Sigma-Aldrich, 99%), and 1-bromonaphthalene (Br-
Recently, cholesterol end-capped star polymers were synthe-
sized to form supramolecular structures via complexation
with CDs. Setijadi et al. prepared ICs of cholesterol end-
capped three-armed star-shaped poly(polyethylene glycol)
acrylate (polyPEG-A) with b-CD.55 In another study, star
shaped PEG with cholesterol end-groups and star-shaped
PEG with b-cyclodextrin end-groups (b-CD) are prepared in
order to obtain hydrogels via the ICs of cholesterol/b-
CD.12,56 Nevertheless, there is no publication in the literature
which reports ICs formed between b-CDs and cholesterol
end-capped PCL star-like architectures.
Phosphazenes, having [N@PR2]- repeating units, are cyclic,
linear short-chain or high molecular weight polymer com-
pounds and constitute a very important compound family in
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SCHEME 1 Synthesis of the star polymer containing cholesterol end-capped PCL arms and a phosphazene core (P4).
Naphthalene, Sigma-Aldrich, 97%) were used as purchased
without further purification. Azido functional Merrifield resin
was prepared according to the literature.67
MS (nitrogen UV-laser ionization at 337 nm) spectrometers.
Fourier-transform IR spectra were recorded on Perkin–Elmer
Paragon 1000 spectrometer equipped with PIKE MIRacleTM
Diamond ATR and the results were uncorrected. Average
molecular weights and molecular weight distributions of the
polymers were estimated on an Agilent GPC Instrument
(Model 1100) consisting of a pump, a refractive index detec-
tor, and two Waters Styragel column (HR 5E) and using THF
as eluent at a flow rate of 0.5 mL/min at 23 ꢁC. Melting
points (Tm) and crystallization temperatures (Tc) of the poly-
mers were measured on Mettler Toledo DSC 822 calorimeter
under nitrogen flow (10 mL/min). All the samples were first
Measurements
UNITY
1H and 31P NMR spectra were obtained in on a Varian
INOVA 500 MHz (202 MHz for 31P) spectrometer at 25 ꢁC
using CDCl3 and d6-DMSO as the deuterated solvents. TMS
was the internal reference for 1H NMR, while 85% H3PO4
was the external reference for 31P NMR. Mass spectra meas-
urements were obtained by Bruker MicroTOF LC–MS (elec-
tron spray ionization) and Bruker microflex LTMALDI-TOF
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SCHEME 2 Synthesis of a,x-cholesterol end-capped linear PCL (L4).
ꢁ
ꢁ
ꢁ
heated from 225 C to 100 C with a heating rate of 10 C/
min and kept isothermal at 100 ꢁC for 5 min to erase the
thermal history, then cooled to 225 ꢁC at 10 ꢁC/min, and
finally heated to 100 ꢁC at 10 ꢁC/min. TGA was performed
on a Mettler Toledo TGA/SDTA 851 thermogravimetric ana-
lyzer from room temperature to 700 ꢁC with a heating rate
room temperature on a Rigaku D-MAX 2200 X-ray diffrac-
tometer using Cu Ka radiation with a wavelength of 1.54 Å
over a 2h range from 2ꢁ to 40ꢁ at a speed of 0.1ꢁ min21
.
The voltage and the current were set to 40 kV and 40 mA,
respectively. KSV-CAM 200 contact angle meter apparatus
was used to measure the static contact angles of the liquids
(water, methylene iodide, and 1-bromonaphthalene) under
air at room temperature. Equilibrium (he) contact angles of
ꢁ
of 10 C/min under inert nitrogen atmosphere. X-ray diffrac-
tion (XRD) patterns of powder samples were obtained at
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SCHEME 3 Synthesis of cholesterol functionalized phosphazene derivative (5).
these liquids were measured by using 3 lL droplet volumes
to neglect the gravity flattening effect. Contact angle meas-
urements were taken over three different areas for each
polymer sample. Average and standard deviation of h values
were calculated as less than 62.
NaCl mixture. Then, cholesterylchloroformate (2.0 g, 4.45
mmol) was dissolved in dry DCM (10 mL) and added drop-
wise to the mixture within 30 min. The reaction mixture was
stirred for additional 48 h at room temperature. It was then
diluted with DCM and washed with saturated NaHCO3 solu-
tion (2 3 25 mL) and deionized water (2 3 25 mL). After
the organic layers were combined and dried with MgSO4, the
solvent was removed via rotary evaporator. The crude prod-
uct was purified by column chromatography over silica using
dichloromethane as the eluent. Yield: 1.64 g (79%). m.p.: 72–
75 ꢁC. MS (m/z): calcd for C31H48O3, 468,71; found, 468,31
[M1K]1. FTIR (ATR, cm21): 3299 and 3259 (BCAH); 2131
(ACBCA); 2936 and 2876 (CAH), 1742, 1471, 1367, 1294,
1240, 1162, 1047, 959, 840, 749, 733. 1H NMR (500 MHz,
CDCl3, d, ppm): 0.60–2.35 (overlapping multiplets, 43H),
Synthesis of Cholesteryl 2-Propyn-1-yl Carbonate (1)
Cholesteryl 2-propyn-1-yl carbonate (1) was synthesized
according to the literature method with minor modifica-
tions.68 Prop-2-yn-1-ol (0.30 g, 5.35 mmol) was dissolved in
dry DCM (20 mL) in a three-necked flask equipped with a
pressure-equalized dropping funnel under inert argon atmos-
phere. After the addition of TEA (0.90 g, 8.89 mmol), the
reaction mixture was cooled to 215 ꢁC by means of ice–
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SCHEME 4 Synthesis of supramolecular inclusion complexes of N3P3-(PCL-Chol)6 (P4) with b-CD (P4-b-CD).
2.41 (s,1H, ACBCH), 4.44 (m, 1H, ACOOCH<), 4.65 (s, 2H,
ACH2OCOA), 5.32 (d, 1H, >C@CHA).
CH2CH2O(C@O) in PCL); 0.65–2.46 (overlapping multiplets
of cholesterol).
The linear PCL with cholesterol groups at both ends (Chol-
PCL-Chol) (L4) and cholesterol end-functional phosphazene
compound (N3P3-(Chol)6) (5) were synthesized via “click
chemistry” technique as shown in Schemes 2 and 3, respec-
tively. They were also employed in the preparation of supra-
molecular ICs with b-CD (see the Supporting Information for
experimental details).
Synthesis of Hexa-Armed Star Polymer Containing
Cholesterol End-Capped PCL Arms (N3P3-(PCL-Chol)6)
(P4)
P1, P2, and P3 were synthesized according to the literature
method.65 P3 (0.30 g, 0.02 mmol) and cholesteryl 2-propyn-
1-yl carbonate (1) (0.12 g, 0.26 mmol) were dissolved in
degassed DMF (10 mL) under inert argon atmosphere.
PMDETA (0.06 g, 0.35 mmol) was added and the solution
was gently purged with argon for 10 min. Then, copper (I)
bromide (0.05 g, 0.35 mmol) was added to the reaction mix-
ture, and it was again degassed by purging argon for addi-
tional 5 min. The reaction mixture was stirred at room
temperature for 48 h. After the solution was diluted to
150 mL with DCM, it was washed successively with brine
(2 3 50 mL) and water (50 mL). Subsequent to collecting
and drying of organic phases with MgSO4, the solvent was
concentrated to 5 mL by rotary evaporator. Then, P4 was
isolated as a white product by precipitating from cold hex-
ane. Yield: 0.34 g (95%). FTIR (ATR, cm21): 2946 and 2866
(CAH); 1722 (O@CO2); 1470 (CAH); 1239 ((C@O)AO);
1294 and 1178 (P@N); 1046 (CAOAC); 959 (PAOAC). 1H
NMR (500 MHz, CDCl3, d, ppm): 7.79 (d, C2HN3 (triazole
ring); 7.18, 7.16, and 6.91, 6.90 (AA0 BB0 pattern, C6H4); 5.38
(d, 1H, >C@CHA in cholesterol); 5.28 (s, 2H, ACH2OCOA);
5.05 (s, C6H4CH2O); 4.37 (m, 1H, ACOOCH< in cholesterol);
4.13 (m, terminal CH2O(C@O)C(CH3)2-triazole); 4.05 (m,
CH2O(C@O) in PCL); 2.28 (m, O(C@O)CH2 in PCL); 1.93 (m,
terminal O(C@O)C(CH3)2-triazole); 1.65 (m, O(C@O)CH2CH2
CH2CH2CH2O(C@O) in PCL); 1.38 (m, O(C@O)CH2CH2CH2
Preparation of Inclusion Complexes of N3P3-(PCL-Chol)6
with b-CD (P4-b-CD)
P4 (0.25 g, 0.01 mmol) was dissolved in 20 mL of acetone
and b-CD (2.12 g, 1.87 mmol) was dissolved in 15 mL of dis-
tilled water. Then P4 solution was added dropwise to the
FIGURE 1 FTIR spectra of (a) P3 and (b) P4. [Color figure can
be viewed in the online issue, which is available at wileyonline-
library.com.]
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FIGURE 2 1H NMR spectra of (a) P3 and (b) P4 in CDCl3.
b-CD solution at 60 ꢁC with vigorous stirring. After stirring
at 60 C for 3 h, the heat bath was removed and the mixture
CD); 5.68 (d, 8H, O(8)H of b-CD), 4.83 (d, 8H, C(1)H of b-
CD); 4.48 (t, 8H, O(9)H of b-CD); 4.1 (m, CH2O(C@O) in
PCL); 3.73–3.25 (m, 48H, C(5)H, C(6)H, C(3)H, C(2)H and
C(4)H of b-CD); 2.38 (m, O(C@O)CH2 in PCL); 1.20 (m,
O(C@O)CH2CH2CH2CH2CH2O(C@O) in PCL); 0.81 (m,
O(C@O)CH2CH2CH2CH2CH2O(C@O) in PCL).
ꢁ
was left stirring at room temperature overnight. The precipi-
tates were collected by filtration, washed with acetone (23
15 mL) and distilled water (2 3 15 mL) to remove free poly-
mers and uncomplexed b-CD, respectively. The obtained
white powder product was dried in vacuo at 45 ꢁC until a
constant weight. The structures of b-CD formed complexes
The same procedure was employed for the preparation of
1
ICs of N3P3-(PCL-OH)6 with b-CD (P1-b-CD). Yield: 1.52 g
with P4 are depicted in Scheme 4. Yield: 1.59 g (63.5%). H
1
(56.7%). H NMR (500 MHz, DMSO-d6, d, ppm): 5.72 (d, 8H,
NMR (500 MHz, DMSO-d6, d, ppm): 5.74 (d, 8H, O(7)H of b-
TABLE 1 Results of the Cholesterol End-Capped PCLs.
O(7)H of b-CD); 5.67 (d, 8H, O(8)H of b-CD), 4.82 (d, 8H,
C(1)H of b-CD); 4.47 (t, 8H, O(9)H of b-CD); 3.98 (m,
CH2O(C@O) in PCL); 3.74–3.26 (m, 48H, C(5)H, C(6)H,
C(3)H, C(2)H and C(4)H of b-CD); 2.27 (m, O(C@O)CH2 in
PCL); 1.32 (m, O(C@O)CH2CH2CH2CH2CH2O(C@O) in PCL);
0.86 (m, O(C@O)CH2CH2CH2CH2CH2O(C@O) in PCL).
Polymers [M]/[I]a Mn,NMR
Mn,GPC
Mw/Mn
Yield (%)d
b
c
c
P4
L4
20/1
20/1
17365
5207
13100
5100
1.53
1.36
95
96
T 5 115 ꢁC; bulk; 49/[SnOct2] 5 300; polymerization time 5 24 h.
Preparation of Physical Blend of N3P3-(PCL-Chol)6
with b-CD (P4/b-CD)
The physical blend of N3P3-(PCL-Chol)6 with b-CD, (P4/b-
CD), were prepared by using the same weight ratio as
related to ICs. P4 was mixed with b-CD and pulverized in a
a
M 5 e-CL, I5 initiator.
b
Mn,NMR was determined by 1H NMR spectroscopy.
c
Mn,GPC and Mw/Mn were determined by GPC analysis with polystyrene
standards. THF was used as eluent (RI detector).
d
Determined gravimetrically.
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The disappearance of azide peak in the FTIR spectrum of P4
clearly confirms the completeness of the click reaction [Fig.
1(b)]. Also, the strong and sharp peak at 1723 cm21 in FTIR
spectra of both P3 and P4 is attributed to the carbonyl
groups in the repeating units of the PCL chains.
In the 1H NMR characterization, the comparison of the 1H
NMR spectrum of P3 [Fig. 2(a)] with that of P4 [Fig. 2(b)]
also supports the complete attachment of cholesterol groups
after “click” reaction. The peak (Hi) depicted at 1.47 ppm in
the 1H NMR spectrum of P3 [Fig. 2(a)] shifted to the lower
field by 0.46 ppm on Cu(I) catalyzed click reaction [Fig.
2(b)]. The methyl protons of the terminal 2-methylpropanoyl
group was deshielded by the triazole and cholesterol groups
and therefore shifted to the lower magnetic fields. Beside
1
this, some new peaks also appeared in the H NMR spectrum
of P4. The methylene protons next to the triazole ring (5.27
ppm, Hl), methine proton in the triazole ring (7.68 ppm, Hk),
and finally cholesterol protons (5.44 ppm (6-H, d), 4.37 ppm
(3a-H, m), and 0.65–2.46 ppm) came out as a result of the
click reaction. Moreover, the experimental and theoretical
integral ratios between the proton signal of the methylene
group adjacent to the benzene ring (Hc) and the cholesterol
proton (Hm) are very close to each other (Hc/Hm,
experimental 5 1.94, the theoretical value should be 2.0),
indicating the complete and successful end functionalization
of PCL arms with cholesterol moiety.
FIGURE 3 FTIR spectra of (a) b-CD, (b) P1-b-CD IC, (c) P4-b-CD
IC, and (d) P4/b-CD physical blend. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.
com.]
mortar with pestle to obtain very fine powdery homogene-
ous blend.
RESULTS AND DISCUSSION
Synthesis of Hexa-Armed Star Polymer Containing
Cholesterol End-Capped PCL Arms (P4)
The number- and weight-average molecular weights of the
cholesterol end-functional linear and star-shaped PCLs as
well as its polydispersity index values were determined by
GPC and related data are summarized in Table 1. The 1H
NMR spectra of the polymers enabled us to calculate the
composition and Mn,NMR values as well. The average number
of e-CL units per branch of P4 was calculated to be 20, using
the ratio of the integral value of methylene protons in PCL
chains (ACH2CH2CH2CH2CH2O(C@O)A) to that in the initia-
tor (AC6H4CH2OA). Thus, the number-average molecular
weight of P4 was determined using the following formula:
The hexa-armed star polymer containing cholesterol end-
capped PCL arms (P4) was synthesized following four-step
synthetic procedures using “core-first” methodology as
depicted in Scheme 1. In the first step, the hydroxyl end-
capped star polymer was prepared via the ROP of e-CL in
the presence of tin(II) octoate (Sn(Oct)2) as the catalyst. The
end groups of the obtained star polymer were transformed
into bromide via the esterification reaction with 2-
bromoisobutyryl bromide and then the conversion of bro-
mide into azide groups was accomplished through the reac-
tion with sodium azide. The complete attachment of the
cholesterol groups was succeeded by taking the advantage of
the Cu(I) salt catalyzed 1,3-dipolar cycloaddition reaction
between azide groups of the polymers and ethyne group of
cholesteryl 2-propyn-1-yl carbonate (1) in DMF at room tem-
perature. The synthetic importance of the Cu(I) catalyzed
“click chemistry” stems from its versatility, reliability, and
specificity. Moreover, this method hardly demands functional
group protection and has an exceptional selectivity for 1,4-
triazole formation.69–72
Mn,NMR 5 a 3 [20 (number of e-CL in PCL chains) 3
114.14] 1 MW of the initiator 1 a 3 MW of chain end group,
where a is 6 (a 5 2 for L4). The discrepancies between
Mn,GPC and Mn,NMR values are due to hydrodynamic volume
differences between the synthesized PCL polymers and poly-
styrene standards with the same molecular weight.73,74
Inclusion Complexes of P4 with b-CD (P4-b-CD)
The key parameters affecting the stability of ICs are intermo-
lecular interactions and size compatibility between host and
guest molecules. Internal diameter of the b-CD molecules do
not closely fit external diameter of PCL chains as in the case
of a-CDs, resulting in weaker interactions between b-CD mol-
ecules and PCL chains. This was reflected by the complexa-
tion ratios, in that, e-CL:b-CD ratio reported in the
literature27 was around 1.5, considerably higher than e-CL:a-
CD27,28 (close to 1.0). In fact, these ratios were observed
notably higher for star-shaped polymers due to steric effects
induced by increasing number of arms around core unit.36,39
The chemical structure of the cholesterol end-functional star
PCL polymer (P4) was verified by FTIR and 1H NMR spec-
troscopic techniques and GPC analysis. Figure 1 shows the
FTIR spectra of azide and cholesterol end-capped star-
shaped PCL polymers (P3 and P4, respectively). Upon azidi-
fication of the precursor bromide functional star polymer
(P2), the peak emerged at 2110 cm21 indicates the presence
of azide functional groups in the structure of P3 [Fig. 1(a)].
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FIGURE 4 1H NMR spectra of (a) P1-b-CD and (b) P4-b-CD ICs in DMSO-d6.
It is known from the literature that cholesterol molecules
can be threaded by 2 or 3 b-CD; whereas, monomer units of
PCL have a tendency to form 1:1 complex with b-CD.28,75,76
Therefore, this motivated us to prepare cholesterol end-
capped star-shaped PCL polymer (P4) and to investigate to
what extent cholesterol end-groups would hold together b-
CD molecules threaded on the PCL arms and thus would
decrease e-CL:b-CD ratio in IC of the star polymer with b-CD.
The star polymer with OH end-functional groups (P1) was
also used in the preparation of supramolecular ICs with b-
CD in order to investigate the effect of cholesterol-end group
on the complexation yield. The complexation behavior of the
synthesized cholesterol end-capped polymers with b-CD was
thoroughly characterized in detail by means of 1H NMR,
FTIR, DSC, TGA, and WAXD. ICs of P4 with b-CD were suc-
cessfully prepared by adding dropwise polymer solutions in
acetone into aqueous b-CD solution, followed by rigorous
stirring.
FTIR is a very useful tool to obtain the evidence for the
inclusion complexation. It can give information about the for-
mation of ICs and confirm the existence of both host and
guest components in ICs. Figure 3 shows the FTIR spectra of
P1-b-CD and P4-b-CD together with pure b-CD. The broad
signal at 3311 cm21 in the spectrum of b-CD [Fig. 3(a)] is
due to symmetric and asymmetric OH stretching bands. The
other notable signals are observed at 1155 cm21 (CAOAC),
1078 cm21 (CAC) and 1025 cm21 (CAO). Comparing the
FTIR spectrum of P4-b-CD with the spectra of its compo-
nents (the physical blend of P4 and b-CD), almost all bands
for P4-b-CD can be related to its individual components with
slight up-shifting and decrease in the intensity of carboxyl
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TABLE 2 Type of ICs of the PCLs with CD
Polymer
CD
Yield (wt %)
e-CL:b-CD (mol:mol)
Mn,GPC
References
Chol-(CL)n
Chol-(CL)n
LPCL
a-CD
c-CD
a-CD
a-CD
b-CD
c-CD
a-CD
a-CD
a-CD
a-CD
a-CD
a-CD
a-CD
a-CD
c-CD
a-CD
c-CD
a-CD
c-CD
70
80
75
79
52
71
69.2
60.6
66
52.5
67.6
52.2
54.5
–
1.49
ꢂ1.0
1
3,040
3,040
830
Guo et al.52
Guo et al.53
Harada et al.28
Kawaguchi et al.27
LPCL
0.9-1.0
1.5
530
LPCL
530
LPCL
1.7-1.9
1.08
1.27
1.56
1.66
1.39
1.58
1.02
1.9
530
LPCL
5,980
6,460
6,060
7,160
11,820
29,460
50,710
1,200a
1,200a
4,500a
4,500a
7,800a
7,800a
Wang et al.36
2LPCL
4sPCL
6sPCL
6sPCL2
4sPCL
4sPCL
8sPCL
8sPCL
8sPCL
8sPCL
8sPCL
8sPCL
Dai et al.39
Chan et al.40
–
3.1
–
1.6
–
2.7
–
1.3
–
2.2
a
The number-average molecular weights (Mn) of a single arm were characterized by 1H NMR spectroscopic functional groups analysis.
group; no additional bands are observed [Fig. 3(b)]. It
reflects that b-CD molecules were threaded onto the branch
chains of P4 in the ICs, as shown in Scheme 4. Additionally,
the shift of the bands in P4-b-CD IC could be connected to
hydrogen bonds formation, which mainly took place between
the b-CD hydroxyl groups and the carbonyl groups in the
guest PCL polymers, as well as between b-CD hydroxyl
groups threaded onto neighboring chains of the PCL poly-
mers.34,39 Moreover, the intensity of carbonyl signal in the
FTIR spectra of P4-b-CD IC [Fig. 3(c)] is more suppressed
than that in the FTIR spectra of P1-b-CD IC, indicating that
complexation yield is higher in the former.
Further evidence for the inclusion complexations of P1 and
P4 with b-CD was carried out by 1H NMR measurement. 1H
NMR spectra of P1-b-CD and P4-b-CD is given in Figure
4(a,b), respectively. The host–guest stoichiometry of P1-b-CD
was determined by integral ratio of CH proton (H1) signal of
b-CD to that of methylene protons (Hg) signals in the e-CL
repeating units of P1. The stoichiometric ratio of e-CL to b-
CD for P1-b-CD was 1.5. Due to the steric hindrance, a few
e-CL units close to the phosphazene core might not have
been included by b-CD molecules, resulting in increased e-
CL:b-CD ratio as reported in the literature.36 As for the b-CD
ICs of cholesterol-containing star-shaped polymers (P4-b-
FIGURE 5 31P NMR spectra of (a) P4 and (b) P4-b-CD.
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TABLE 3 The Preparation and Thermal Properties of ICs of all PCLs with b-CD.
Td,free (ꢁC)b
PCL Polymers
Td,ICs (ꢁC)c
Entry
Yield (wt %)
e-CL:b-CDa (mol:mol)
b-CD
b-CD
PCL Polymers
P1-b-CD
P4-b-CD
L1-b-CD
L4-b-CD
57
64
50
59
1.5
1.2
1.3
ꢂ1
307.4
307.4
307.4
307.4
371.9
289.7
278.4
294.3
315
393.3
390.5
378.2
389.5
320.1
316.2
325.3
a
c
The stoichiometry (e-CL:b-CD, mol:mol) of each monomeric repeating
unit PCL/b-CD was determined by 1H NMR.
Td,free denotes the initial decomposition temperature of free b-CD and
Td,ICs denotes the initial decomposition temperature of the host b-CD
and the guest cholesterol end-capped PCL polymers included in the ICs,
respectively.
b
cholesterol end-capped PCL polymers, respectively.
CD), e-CL:b-CD ratio was found to be 1.2. This is less than
the e-CL:CD values reported in the literature for the CD ICs
of 8-, 6-, and even 4-armed star-shaped polymers with the
close molecular weight.36,40 The decreased branch chain den-
sity can be induced by the increasing polymer molecular
weight or the increasing branch arm length.36,39 It is known
from the literature that, the internal diameter of a-CDs fits
well to the cross-sectional diameter of PCLs, whereas, the
FIGURE 6 DSC thermograms of b-CD, L4, L4-b-CD, L4/b-CD physical blend, P4, P4-b-CD, and P4/b-CD physical blend in (a) the first
heating run, (b) cooling run, and (c) second heating run. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
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FIGURE 8 TGA thermograms of (a) b-CD, (b) L4, (c) L4-b-CD,
(d) P4, and (e) P4-b-CD. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
FIGURE 7 XRD patterns of (a) b-CD, (b) L4, (c) L4-b-CD, (d) L4/
b-CD, (e) P4, (f) P4-b-CD, and (g) P4/b-CD physical blend. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
In this study, the ICs of b-CD with hydroxyl and cholesterol
end-capped linear PCL polymers (L1 and L4, respectively)
together with cholesterol end-capped phosphazene derivative
(5) were also prepared in order to compare their complexa-
tion behaviors with b-CD to that of P4-b-CD and to investi-
gate the effect of cholesterol end units on complexation
behavior (see the Supporting Information for experimental
and characterization details of L1, L4, 5, and their ICs with
b-CD). The host–guest stoichiometries (e-CL:b-CD) in L1-b-
CD and L4-b-CD ICs were determined using the same
method as in the case of P4-b-CD IC. Since steric hinderence
effects seen in IC of the star polymers (P1-b-CD and P4-b-
CD) were not effective to that of linear polymers (L1-b-CD
and L4-b-CD), the host–guest stoichiometries in the com-
plexes of linear polymers were found to be lower than those
of star polymers (see Table 3). Besides, e-CL:b-CD ratio was
considerably lower in the IC of cholesterol end-capped linear
PCL polymer (L4-b-CD) than that of hydroxyl end capped
linear polymer (L1-b-CD).
larger diameter of b-CDs brings about lower affinity and the
twisting of PCL polymer to fill the internal cavity of b-CDs.
Therefore, in general, less b-CD molecules can be threaded
onto PCL chains than a-CDs do.27 In the present study, the
bulky cholesterol end-units held together the b-CDs, which
were threaded onto the PCL chains like the string of beads,
due to close fitting of their outer radius to the internal diam-
eters of b-CDs.76 Besides, each of the cholesterol end-groups
can be encapsulated by one or two b-CD units,55 this phe-
nomenon also makes contribution to low e-CL:b-CD values in
the corresponding ICs. It can be also said that these ratios
approximately vary as the incorporated cholesteryl moiety
can form stable inclusion complex with b-CD. The internal
diameter of c-CDs is the largest of all. Since c-CDs can
accommodate more than one PCL chain,27 they were kept
out of the scope of this comparison.
DSC was used to determine the melting and crystallization
behaviors of cholesterol functional P4, L4, and their ICs; the
related thermograms are presented in Figure 6. The DSC
curves of b-CD and the polymer/b-CD physical blends are
also given for comparison. The melting peaks of P4 and L4
were observed at 52.5 and 53.2 ꢁC, respectively, in the first
heating run; on the contrary, the DSC plots of b-CD and the
ICs did not exhibit any observable melting peaks [Fig. 6(a)].
In a similar way, in the cooling [Fig. 6(b)] and in the second
heating runs [Fig. 6(c)], both the crystallization and the sec-
ond melting peaks of P4 and L4 disappeared upon complex-
ation with b-CD. These observations agreed with the
literature and showed that the crystallization of the choles-
terol end-capped star and linear polymers threaded by b-CD
were totally inhibited. Besides, DSC thermograms of the
physical blends were nearly identical to those of P4 and L4.
The signals belonging to b-CD and cholesterol end-capped
PCL star polymer can be clearly seen in 1H NMR spectrum
in Figure 4(b). These results are in accordance with the liter-
ature findings on the CD ICs of PCLs, which are summarized
in Table 2.
Moreover, the structure of the phosphazene core of P4 was
determined by means of 31P NMR [Fig. 5(a)]. The appearance
of only one signal at 8.30 ppm in the 31P NMR is interpreted
as a reliable indication for P4 having phosphazene core.
Additionally, the absence of any signal in 31P NMR of P4-b-
CD is a clear evidence for suppression of phosphorous signal
after complexation process between P4 and b-CD [Fig. 5(b)].
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FIGURE 9 Equilibrium contact angle results of test liquids on free PCL polymers (P4 and L4), 5 and their ICs.
The X-ray diffraction (XRD) is a strong method to clarify the
crystalline structure of ICs in the solid state. Figure 7
showed XRD patterns of the uncomplexed polymers with sig-
nificant peaks at 21.4ꢁ and 23.7ꢁ for P4 and at 21.5ꢁ and
23.8ꢁ for L4, which were consistent with those of linear PCL
crystals located at 21.4ꢁ and 23.8ꢁ. This indicates that cho-
lesterol end-capped PCL polymers have crystalline structure
similar to that of linear PCL in the solid state. For the ICs,
major diffraction peaks were observed at 7.5ꢁ and 38.4ꢁ for
P4-b-CD and at 6.9ꢁ, 39.9ꢁ, and 28.0ꢁ for L4-b-CD, while the
main crystalline peaks for the pure PCL polymers disap-
peared. The diffraction patterns of the ICs were quite differ-
ent from those of their constituents and polymer/b-CD
physical blends, pointing to the existence of different packing
pattern and the formation of ICs between cholesterol end-
capped PCL polymers and b-CD. Also, due to long chain
nature of the cholesterol end-capped PCL polymer guests,
their ICs with b-CD were thought to have a channel-type
crystalline structure, which is a typical structure of ICs
formed by the linear stack of b-CD rings on a polymer chain.
and the related thermograms are depicted in Figure 8. As
seen from the figure, thermal degradation of the ICs
occurred in two steps, which were assigned to the decompo-
sitions of b-CD host molecules and threaded polymer chains,
respectively, which is very similar to those of other CD-PCL
ICs reported in the literature.40,52,53 Table 3 summarizes the
preparation and the initial decomposition temperatures of all
ICs, the free PCL polymers, and b-CD. According to these
data, the host and guest constituents of ICs started to
decompose at higher temperatures than their free states,
which indicates that formation of ICs between free PCL poly-
mers and b-CD enhanced the thermal stability of both the
guest PCL polymers and the host b-CD and that the ICs were
more thermally stable.
Contact Angle
The contact angle measurements of P4, L4, and 5 and their
ICs with b-CD were conducted in the solid state using MeI2
and BrNaphthalene as the test liquids and the static he val-
ues are given in Figure 9. Also, the water contact angles
were measured for P4, L4 and 5 as 104ꢁ, 89ꢁ, and 105ꢁ,
respectively. But the water contact angles for both the
cholesterol-functionalized phosphazene derivative (5) and
PCL polymers (P4 and L4) ICs could not be measured
Thermal properties of P4, L4, their ICs, and free b-CD were
analyzed by TGA technique from room temperature up to
21
ꢁ
ꢁ
700 C at a rate of 10 C min under nitrogen atmosphere
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4 X. Shuai, T. Merdan, F. Unger, T. Kissel, Bioconjugate Chem.
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because of the rapid spreading of water on these surfaces.
The films of the samples on glass slides were prepared using
the sample solutions of 15 mg/mL and dried under vacuum
at 45 ꢁC. Equilibrium (he) contact angles of MeI2 and
BrNaphthalene were determined by static contact angle
measurements using 3 lL droplet volumes. b-CD is a very
hydrophilic material due to its OH groups. Therefore, the for-
mation of the ICs of the cholesterol end-capped macromole-
cules with b-CD was expected to increase their polarity and
hydrophilicity. As expected, complexation of the macromole-
cules with b-CD induced a significant reduction in he values
of MeI2 and BrNaphthalene as compared with their uncom-
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via Cu(I) catalyzed “click” reactions. P4 was then utilized to
form supramolecular structures with b-CD. The linear PCL
with cholesterol groups at both ends (L4) and cholesterol
end-capped phosphazene compound (5) without PCL arms
were also synthesized to compare their complexation behav-
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with b-CD while decreasing the crystallinity of the PCL back-
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AUTHOR CONTRIBUTIONS
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript. The authors declare no competing finan-
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27 Y. Kawaguchi, T. Nishiyama, M. Okada, M. Kamachi, A.
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