Poly(p-phenylene ethynylene)s with facially amphiphilic pendant groups: Solvatochromism and supramolecular assemblies

Article abstract of DOI:10.1002/chem.200800986

Novel functionalized poly(p-phenylene ethynylene)s (PPEs) bearing facially amphiphilic cholic and deoxycholic acid units are synthesized by a Pd-catalyzed Sonogashira cross-coupling reaction. Some interesting properties, particularly their optical and self-assembly characteristics, are unraveled. The PPEs that carry bile acid substituents exhibit remarkable solvatochromism in a wide range of solvent systems, and judicious choice of the solvents can adjust the size and morphology of the formed nanoscale supramolecular aggregates. The incorporation of these naturally occurring building blocks can also impart bio-compatibility to the conjugated system and stimulate the growth of living cells.

Full text of DOI:10.1002/chem.200800986

FULL PAPER
DOI: 10.1002/chem.200800986
Poly(p-phenylene ethynylene)s with Facially Amphiphilic Pendant Groups:
Solvatochromism and Supramolecular Assemblies
Yan Li,[a] Guangtao Li,*[a] Xinyan Wang,[b] Changxu Lin,[a] Yihe Zhang,[b] and
Yong Ju*[a]
Abstract: Novel functionalized poly(p-
phenylene ethynylene)s (PPEs) bearing
facially amphiphilic cholic and deoxy-
cholic acid units are synthesized by a
Pd-catalyzed Sonogashira cross-cou-
pling reaction. Some interesting prop-
erties, particularly their optical and
self-assembly characteristics, are unrav-
eled. The PPEs that carry bile acid sub-
stituents exhibit remarkable solvato-
chromism in a wide range of solvent
systems, and judicious choice of the
solvents can adjust the size and mor-
phology of the formed nanoscale
supramolecular aggregates. The incor-
poration of these naturally occurring
building blocks can also impart bio-
compatibility to the conjugated system
and stimulate the growth of living cells.
Keywords: amphiphiles · polymers ·
self-assembly · solvatochromism ·
supramolecular chemistry
Introduction
bone seems to be a promising method to obtain supramolec-
ular architectures that are capable of converting biomolecu-
lar structural information into physicochemical signals.[4]
Bile acids are a class of naturally occurring compounds
with a facially amphiphilic steroid nucleus, and include the
biologically important detergent-like substances cholic acid
and deoxycholic acid.[5] The synthesis and structure elucida-
tion of bile acid derivatives have been intensely studied
from a pharmaceutical point of view.[6] Besides their biologi-
cal importance, due to their unique facially amphiphilic
character, bile acids have recently been presented as a ver-
satile platform for the construction of environmentally re-
sponsive amphiphiles and functional supramolecular sys-
tems.[7] Regen et al. have described cholic acid based “mo-
lecular umbrellas” that can change their conformation as a
function of solvent polarity.[8] Maitra et al. reported bile acid
based chiral dendrons, which can act as both intramolecular
normal and inverse micelles.[9] Recently, by taking advantage
of the facial amphiphilicity and natural curvature, Zhao
et al. described a type of cholate oligomer that could fold
into a helical structure with a nanometer-sized hydrophilic
cavity.[10]
The construction of supramolecular architectures by the
spontaneous self-assembly of conjugated polymers is under
enthusiastic investigation owing to a wide academic interest
and their important technological applications.[1] To tune the
optoelectronic properties of the conductive polymer-based
devices, the assembly of the polymer chains needs to be con-
trolled. Amphiphilic block copolymers can generate various
morphologies and their assembling mechanisms have been
well studied.[2] However, their syntheses often requires time-
consuming steps with nontrivial effort, especially for p-con-
jugated systems.[3] To minimize the tedious synthetic work in
designing new self-assembling macromolecules, one can imi-
tate and modify natural designs. Consequently, integration
of biologically important molecules to a p-conjugated back-
[a] Y. Li, Prof. Dr. G. Li, C. Lin, Prof. Dr. Y. Ju
Department of Chemistry, Key Lab of Organic Optoelectronics
& Molecular Engineering and
Key Lab of Bioorganic Phosphorus Chemistry
& Chemical Biology, Tsinghua University
Beijing 100084 (China)
In the present work, the synthesis of two functionalized
poly(p-phenylene ethynylene)s (PPEs) bearing cholic and
deoxycholic acid units, respectively (polymers P1 and P2 in
Scheme 1), was demonstrated. These polymers were de-
signed to preserve some properties of bile acids, such as
facial amphiphilicity, capacity for self-assembling, biocom-
patibility, and the high chemical stability of the steroid nu-
cleus, and also impart new optoelectronic properties through
Fax : (+86)10-6279-2905
E-mail: lgt@mail.tsinghua.edu.cn
juyong@mail.tsinghua.edu.cn
[b] X. Wang, Prof. Dr. Y. Zhang
School of Materials Science and Technology
China University of Geosciences
Beijing 100083 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800986.
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Scheme 1. Chemical structure of PPEs decorated with cholic (P1) and de-
oxycholic acid units (P2) as well as the model compound (P3). Inset: the
stereochemical structure of bile acid.
Scheme 2. Synthesis of the corresponding monomers: a) Br
ACHTUNGTRENNUNG(CH2)4Br,
KOH, CH3CN, RT; b) AcOH/H2SO4/H2O 30:1:2, KIO3, I2, 608C;
the large p-conjugated system. It is worth mentioning that
the first synthesis of bile acid derived polymers was de-
scribed in 1988,[11] followed by a lot of contributions from
Zhuꢁs group,[12] due to the important biological applications.
So far, however, most of the bile acid derived polymers syn-
thesized rely on radical polymerization of the methacrylate
group or direct condensation between carbonyl and hydrox-
yl groups. Much less is known about bile acid decorated con-
jugated polymers, and the incorporation of the bile acid
moiety into conjugated systems to mediate the organization
of polymer chains has never been reported.[13]
c) sodium cholate, NaI, DMF, 658C; d) TMS, [PdCl
DMF, 608C; e) THF, CH3OH, K2CO3.
2ACHTUNGTRNE(UNNG PPh3)2], CuI, Et3N,
THF and DMF, to form clear blue/green fluorescent solu-
tions. Figure 1 indicates that the UV/Vis and emission spec-
tra of P1 in the solid state were significantly broadened and
red-shifted relative to its solution spectra, due to aggrega-
tion and excimer formation (also see Table S1 in the Sup-
porting Information). However, the difference in the optical
spectra of P1 in THF solution and spin-cast thin films is rel-
atively small compared to those for the model compound
P3, which suggests that the large, rigid bile acid skeletons
can ensconce the polymer chain to some extent, and act as
an insulator against intermolecular chain interaction.
Results and Discussion
Synthesis: Scheme 2 displays the detailed synthetic routines.
The cholic acid substituted monomers 4 were synthesized in
three steps. The starting material was 4-methoxyphenol,
which was etherified with 1,4-dibromobutane to obtain 1-(4-
bromobutoxy)-4-methoxybenzene (75%). This intermediate
was treated with iodine in the presence of an oxidant, which
resulted in 1-(4-bromobutoxy)-2,5-diiodo-4-methoxybenzene
(80%). Subsequent esterification with sodium cholate gave
the desired monomer (86%). The polymers P1 and P2 were
then obtained in relatively high yield (69 and 73%, respec-
tively) by Sonogashira cross-coupling between their corre-
sponding diiodide monomers (4 and 5) and 1,4-diethynyl-
benzene. This strategy is quite straightforward and simple,
which eliminates the need for protection and deprotection
of terminal hydroxyl groups on the steroid nucleus. For con-
trol experiments, a similar polymer P3 without a bile acid
pendant group was also synthesized and used as the model
compound.
The solvatochromism of the conjugated polymer system is
due to the transition between a twisted conformation to
planar or nearly planar assemblies in solvents with different
polarity, which is well demonstrated through the introduc-
tion of side chains, especially alkyl or polyethylene oxide
substituents, into the conjugated backbone.[14] As described
in the Introduction, cholic acid is an interesting compound
that is uniquely suitable for solvophobically driven confor-
mational changes.[15] The integration of such an environmen-
tally sensitive building block into the conjugated p system
was expected to endow the prepared polymers with remark-
able solvatochromism. Figure 2a shows the UV/Vis absorp-
tion spectra of P1 in dioxane/water mixtures. An absorption
band with a maximum at l=408 nm was observed for P1 in
pure 1,4-dioxane, which is a good solvent for both hydro-
philic and hydrophobic moieties. With the progressive addi-
tion of water, the absorption band becomes broader and the
maximum of the UV/Vis absorption gradually shifts from
408 to 448 nm, accompanied by an 80% loss of fluorescence
(Figure 2b). The facially amphiphilic character of the bile
acid unit prompted us to examine the solvatochromic behav-
ior in nonpolar media. Indeed, with the gradual addition of
Optical and self-assembly properties: The newly synthesized
polymers (P1 and P2) are sparingly soluble in toluene and
water, but dissolve well in aprotic polar solvents, such as
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Conjugated Polymers with Bile Acid Groups
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absorption should be a reflection of different aggregate
states of the polymers in solution. To test our hypothesis, a
dynamic light scattering (DLS) experiment was performed.
Figure 3 shows the effect of water content on the effective
diameter (ED) of the resulting aggregates measured from
solutions of P1 and P2 in water/dioxane mixtures. At a
water content of less than 20%, the EDs for the two poly-
mers are less than 200 nm. As the water content increases,
both polymers show a rapid increase in the particle size as
well as the polydispersity (Figure S1 in the Supporting Infor-
mation).
We wondered how the presence of nonsolvents could
affect the morphological transitions of bile acid derived
PPEs. To address this question, the assembling of polymer
P1 in dioxane (0.1 mgmLÀ1) with increasing percentage of
water was monitored by SEM. Such an approach was in line
with the methodology that has been successfully set up by
Eisenbergꢁs group for self-directed assemblies of block poly-
mers.[17] At a volume fraction of water of 20%, spherical
particles with a diameter of 200 to 400 nm were observed
(Figure 4a). A few of the particles formed open holes on
their surfaces, which suggests that they had a hollow interi-
or. TEM was used to confirm this possibility and substanti-
ate whether or not these spherical particles are hollow in
nature. Both capsulelike and solid structures were observed
in the TEM images, thus indicating that the spherical aggre-
gates in the SEM images were in fact a mixture of small
vesicles and micelles (see Figure 4 and Figure S2 in the Sup-
porting Information).
With the progressive addition of water, the aggregates
grew bigger and the size distribution became broader. When
the water content was increased to about 40%, much larger
vesicles with diameters up to 1 mm and remarkably thick
membrane walls turned out to be the dominant structure
(Figure 4b). Interestingly, unlike many other reported vesi-
cles that showed an immediate collapse on solid surfaces,[18]
the SEM images revealed that in our case the formed PPE
vesicles retained their shape upon drying, presumably due
to the rigid steroid nucleus and the conjugated backbone. A
similar self-assembly behavior can also be produced by the
incremental addition of water to THF instead of dioxane
(Figure 4c). However, when only a few drops of DMF or
DMSO (a powerful hydrogen-bond breaker[19]) are present,
the vesicle-like structure collapses and ill-defined precipi-
tates form (Figure 4d), thus indicating that hydrogen bonds
play an essential role in the formation of the observed nano-
structures.
The self-assembly properties of P1 in nonpolar media
were also investigated. In this respect, cyclohexane was pro-
gressively added to a 1,4-dioxane solution of P1. Notably,
well-defined, small, spherical solids were found in the SEM
images on addition of small amounts of cyclohexane. The
TEM image in Figure 5a reveals that the uniform spherical
particles have a solid interior with a diameter of approxi-
mately 300 nm. The aggregates gradually changed to rela-
tively large spherical particles with an increase in the cyclo-
hexane content (Figure 5b). This result demonstrates that
Figure 1. a) Normalized UV/Vis absorption spectra of P1 and P3. b) Nor-
malized emission spectra of P1 and P3.
cyclohexane to dioxane, a dramatic red shift of the UV/Vis
spectra and a modest quenching of fluorescence were also
observed for P1 (Figure 2c and d). The maximum absorption
at l=408 nm continuously red-shifts to l=441 nm, which is
also typical of a PPE chain with a high conformational
order. The profile of this UV/Vis spectrum is sharper and
quite different from the absorption in the polar medium,
which suggests that different modes of intermolecular asso-
ciation are involved in the aggregation.
The optical transition described above can be manipulat-
ed continuously and reversibly by varying the ratio of the
selective solvents in the polymer solution. The aggregation
of cholate units induced by the presence of water or cyclo-
hexane could lead to a more planar conformation of the
PPE backbone, which should be the most probable reason
for the observed solvatochromism.[16]
With the increase of water content, it is interesting to
note that the transparent blue fluorescent solution of P1 in
dioxane changes to a yellowish green cloudy liquid, which
exhibits scattering of daylight (Tyndall effect, characteristic
of nontrue solutions; see Figure 3). The optoelectronic fea-
tures of conductive polymers are strictly related to their ag-
gregation states and strongly depend on the microstructural
environment; therefore, the dramatic difference in UV/Vis
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G. Li, Y. Ju et al.
Figure 2. a) UV/Vis absorption and b) emission spectra of P1 in dioxane at 208C as a function of added water; c) UV/Vis absorption and d) emission
spectra of P1 in dioxane at 208C as a function of added cyclohexane. Insets: the content of nonsolvent in %.
Figure 3. Effective diameter (ED) determined by dynamic light scattering
(DLS) of P1 and P2 (0.1 mgmLÀ1) in water/dioxane solution as a func-
tion of the volume fraction of water at 208C. Inset: color transition of P1
in water/dioxane mixtures. See Figure S1 in the Supporting Information
Figure 4. a,b) SEM and TEM (insets) images of the supramolecular ag-
gregate formed from P1 by using a water/dioxane system with a volume
fraction of water of a) 25 and b) 50%. Arrows in inset of (a): slightly
tilted membrane site (see text). c) SEM image of the aggregate from P1
in water/THF solution with a volume fraction of water of 40%; d) as in
(c), but with 50 mL dimethyl sulfoxide (DMSO) added.
&
*
for the original DLS spectrum of P1. : P1; : P2.
the polymer P1 exhibits quite different self-assembly behav-
ior in polar and nonpolar media.
To clarify the role of the facially amphiphilic moiety in
the solvatochromic behavior and in the formation of supra-
molecular aggregates, polymer P2, in which pendant groups
with less facial amphiphilicity were attached, was also inves-
tigated. It was found that the deoxycholic acid decorated po-
lymer (P2) exhibited similar solvatochromic behavior to
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Conjugated Polymers with Bile Acid Groups
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Figure 5. SEM and TEM (insets) images of the supramolecular aggregate
formed from P1 by using a cyclohexane/dioxane solvent mixture with a
volume fraction of cyclohexane of a) 30 and b) 60%.
that of the cholic acid decorated polymer (P1) in the water/
dioxane system (Figure 6a). Large vesicles were also found
in the freshly prepared water/dioxane solution, though the
uniformity and stability of the formed vesicles have clearly
deteriorated compared to those of P1 (Figure 7a). Although
most of the P1-derived vesicles retained their shape without
obvious changes in morphology during storage, P2-derived
vesicles deformed seriously and many of them turned into
irregular aggregates after two days at room temperature
(Figure 7c and d). Different from the water/dioxane system,
only modest solvatochromism was observed for P2 in non-
Figure 7. a,b) SEM and TEM (inset) images of the supramolecular aggre-
gate formed from P2 by using a) a water/dioxane mixture with a volume
fraction of water of 40% and b) a cyclohexane/dioxane mixture with a
volume fraction of cyclohexane of 70%. c,d) SEM images of the aggre-
gates formed from c) P1 and d) P2 which was stored in a water/dioxane
mixture (Xwater =40%) for 48 h at room temperature.
polar media (Figure 6b). In contrast to the solid spherical
particles observed for P1, there is only a round, disklike res-
idue upon natural evaporation of a cyclohexane/dioxane so-
lution of polymer P2 (Figure 7d). As a control experiment,
polymer P3 without facially amphiphilic side chains shows a
negligible solvatochromism (Figure S3 in the Supporting In-
formation) and does not afford any regular self-assembled
aggregate under the same conditions (Figure S4). The results
described above unambiguously indicate that the attached
facially amphiphilic cholate groups can mediate the organi-
zation of PPE chains and donate remarkable solvatochrom-
ism in cooperation with a conjugated polymer system.
Mechanism of self-assembly: The self-assembly of bile acid
conjugates has recently been used to prepare a number of
distinct nanostructured materials, such as micelles, vesicles,
giant needles, and nanotubes.[20] The mechanism of their for-
mation is quite complex and often involves complicated
“secondary assemblies”. Figure 8a summarizes the aggrega-
tion behavior of cholic acid decorated PPE, which shows dif-
ferent buildups of supramolecular assemblies dependent
upon the conditions used. This novel cholic acid functional-
ized PPE has a unique structure that is distinguishable from
that of the classical amphiphilic block polymers: every pend-
ant group possesses two distinguishable faces and as such is
capable of showing aggregation behavior in both polar and
nonpolar media through different modes of intermolecular
association.
In polar media, the self-assembly should be a combination
of three driving forces. One is the hydrophobic interaction
that is attributed to the polymer backbone and the hydro-
phobic face of cholic acid and the spacer between the above
two moieties. Another is the p–p stacking interaction pro-
vided by the large p-conjugated system. Considering the
Figure 6. UV/Vis absorption spectrum of P2 in dioxane at 208C as a func-
tion of added a) water and b) cyclohexane. Insets: the content of nonsol-
vent in %.
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G. Li, Y. Ju et al.
Figure 9. XRD patterns of the vesicular structures formed from a) P1
and b) P2.
nized that bile acid derivatives tend to assemble in a head-
to-tail fashion with two distinguishable faces of the cholates
tilted up and down alternately,[20] whereas PPE derivatives
with long alkyl or alkoxy groups were expected to form a la-
mellar or doubly lamellar morphology in which the structure
of the polymer is dominated by side-chain packing.[23] Based
on the data and results described above, we proposed that
the molecular packing in the membrane of the formed vesic-
ular structure has a multilayer lamellar structure through a
combination of hydrogen bonding, hydrophobic interaction,
and p–p stacking, in which the conjugated molecule is ar-
ranged in a highly organized pattern and the bile acid units
are in an antiparallel interlocked configuration (Figure 8b).
Measurement of the membrane-wall thickness at the slightly
tilted membrane site (marked by the arrows in Figure 4a)
gave an edge width of about 20–25 nm for the relatively
small vesicles. These distances across the membrane wall fit
approximately with 9–11 layers of the proposed structural
units. The alkyl tail might be a little coiled because the lon-
gitudinal length is a bit longer than the distance calculated
from the Bragg equation. The XRD result also suggests that
the molecular packing of P2 in the membrane was less or-
ganized than that of P1 (Figure 9b), which accounts for the
poor stability of the vesicle formed. The poor stability is
consistent with the fact that the hydroxyl group at position 7
plays an important role in building the amphiphilic structure
and forming the stable interdigitated structure.[24]
Figure 8. Schematic illustration of a) the morphology transition of cholic
acid decorated PPE in solvents with different polarity and b) the pro-
posed molecular packing model of cholic acid decorated PPE in the
membrane of the formed vesicular structure.
fact that DMSO interferes with the self-assembly process,
hydrogen bonding probably also plays a key role in the for-
mation of vesicles. The occurrence of hydrogen bonds is at-
tributed to the hydroxyl groups on the adjacent cholic acid
units. Very likely, one or two water molecules might also be
present and act as bridging groups between cholate hydroxyl
groups, as is seen in the crystal structure of cholic acid.[21]
In the case of nonpolar media, hydrogen bonding and p–p
stacking should be strongly involved in the self-assembly
process. Cyclohexane is a good solvent for the hydrophobic
face of cholic acid, but a nonsolvent for the hydroxyl groups
on the steroid nucleus. Thus, the hydrophilic face tends to
aggregate through intermolecular hydrogen bonding. Proba-
bly due to the absence of hydrophobic interactions, the
packing among the polymer chains was less compact and or-
ganized compared to that in the polar media, which might
be responsible for the distinctive profiles of UV/Vis absorp-
tion in solvents with different polarity.
X-ray diffraction (XRD) experiments on the supramolec-
ular aggregate formed from P1 in polar medium were used
to probe the molecular packing in the membrane of the ve-
sicular structure. The XRD patterns showed Bragg peaks at
2q=3.9, 16.3, and 22.48, corresponding to the d spacing at
2.3, 0.6, and 0.4 nm, respectively (Figure 9). Theoretically,
the space between the p-conjugated backbone and the end
of the steroid nucleus (C3 atom) is about 2.0 nm, based on
the assumption that the alkyl spacer takes the fully extended
conformation. The thickness of the cholate unit is about
0.5 nm[20c] and the distance between p-stackings of PPE is
estimated as about 0.4 nm.[22] It has been generally recog-
Different from the vesicular structure, P1 affords spheri-
cal solid particles in nonpolar media that reveal a very
broad diffraction peak between 15 and 258 (2q) in the XRD
spectrum (not shown), thus indicating the amorphous nature
of these aggregates. However, it is still not clear how to ex-
plain the formation of these well-defined solid particles with
diameters of a few hundred nanometers, and further investi-
gation is required.
The origin of large vesicles and micelles was expected to
be the fusing of small aggregates. The driving force behind
the fusion process might be the release of strain in the ini-
tially formed small assemblies, which have high curvature
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Conjugated Polymers with Bile Acid Groups
FULL PAPER
and many surface defects, and as such lead to a more ther-
modynamically stable state.[25] Increasing the content of
poor solvents, such as cyclohexane and water, leads to the
aggregation of cholate moieties and facilitates the fusion
step. This process is accompanied by the stacking and plana-
rization of p-delocalized backbones, which results in
quenching of the fluorescence and a concomitant red shift in
the UV/Vis spectra.
Perfectly regular stacking of identical p-conjugated sys-
tems would lead to a ribbonlike structure;[26] the formation
of spherical aggregates requires bending of the semirigid
PPE backbone. However, it is still unclear where the curva-
ture comes from in our case. The report by Bunz et al.
shows that bending of the conjugated backbone can be in-
duced by the large side-chain substituent according to mo-
lecular mechanics calculations.[27] In this respect, we specu-
lated that the curvature of P1 and P2 in the formed aggre-
gates was contributed to by the large, rigid steroid moiety
and/or by the inhomogeneity of the polymer chain length,
which is related to the polydispersity.
Figure 10. Influence of P1 and P2 on the growth of HeLa cells at differ-
ent concentrations.
Bioactivity test: Compounds derived from bile acids are ex-
pected to be safe and nontoxic when used in the biomedical
and pharmaceutical fields.[28] Decorating the synthetic poly-
mers with these naturally occurring pendant groups is ex-
pected to impart biocompatibility to the conjugated poly-
mers. To check whether our bile acid-containing PPEs are
biocompatible, we studied the cytotoxicity of P1 and P2 to
living HeLa cells. DMSO solutions of P1 and P2 with a con-
centration of 1 mgmLÀ1 were prepared and further diluted
1000 times with the culture medium. Different amounts of
P1 and P2 were added to 24-well plates a few hours after
the cells were seeded. A well without the addition of poly-
mer solution served as a control. All data shown are means
of values in three independent experiments, and the mean
values of each group were compared with the blank control
also in nonpolar systems. Of particular significance is the
fact that judicious choice of the solvents affords the synthe-
sis of nanoscale assemblies with adjustable size and mor-
phology. Besides being the first example of bile acid group
mediated self-assembly of PPEs, the current work offers a
new means to control the association and optoelectronic
properties of conjugated backbones, which is anticipated to
be extendable to other conjugated polymer systems. More-
over, the combination of bile acids and conjugated polymers
leads to biocompatible functional materials, which could
find various applications in photosensitive therapy, con-
trolled-release systems, or as a scaffold material in tissue en-
gineering.
experiment (see Figure 10). At
a
concentration of
Experimental Section
0.1 mgmLÀ1, the cell population of P1 is comparable to that
of the blank experiment. Interestingly, with the increase of
the polymer concentration the cell population became even
higher, which proves that this polymer is cytocompatible.
On the contrary, P2 shows slight cytotoxicity at high concen-
tration. The better biocompatibility of P1 is probably de-
rived from its remarkable facially amphiphilic structure that
enables the polymer to interact more favorably with the bio-
logical environment. We have attempted to study the cyto-
toxic effect of the model compound P3, but were hindered
by its poor solubility in the aqueous media.
Cholic acid, deoxycholic acid, trimethylsilylacetylene (TMS), and 1-bro-
mododecane were purchased from Sigma Company. [PdACTHNUTRGNE(UNG PPh3)4] was ob-
tained from Pingyang Chemical Company and washed with cold ethanol
prior to use to remove the oxidized impurity. Other reagents and solvents
were received from Beijing Chemical Company and used without further
purification unless otherwise stated. 1,4-Diethynylbenzene[29] and 4-dode-
cyloxy-2,5-diiodo-1-methoxybenzene[30] were prepared and characterized
according to previously published procedures. Full experimental details
are included in the Supporting Information.
1-(4-Bromobutoxy)-4-methoxybenzene (2): A mixture of 4-methoxyphe-
nol (3.723 g, 30 mmol), potassium carbonate (6 g), and 1,4-dibromohex-
ane (10.795 g, 50 mmol) in acetone (70 mL) was heated at reflux for 20 h.
The precipitated potassium bromide was isolated by filtration and ace-
tone was removed with a rotary evaporator. The final product 2 was re-
crystallized from methanol as a white solid (5.8 g, 75%). M.p.: 46–478C;
1H NMR (CDCl3, 300 MHz): d=1.88–1.98 (m, 2H; CH2), 2.02–2.12 (m,
2H; CH2), 3.48 (t, 2H; CH2Br), 3.76 (s, 3H; OCH3), 3.94 (t, 2H; OCH2),
6.82 ppm (s, 4H; Ar-H); 13C NMR (CDCl3, 75 MHz): d=24.98, 28.65,
33.68, 55.83, 68.35, 114.76, 115.56, 153.25, 153.91 ppm.
Conclusion
We have demonstrated that the incorporation of facially am-
phiphilic bile acid moieties is an effective approach to guide
the self-assembly of PPE chains. Due to their unique facially
amphiphilic character, bile acid decorated PPEs exhibit re-
markable solvatochromism not only in polar solvents but
1-(4-Bromobutoxy)-2,5-diiodo-4-methoxybenzene (3): Water (2 mL),
acetic acid (30 mL), concentrated sulfuric acid (1 mL),
7.5 mmol), potassium iodate (856 mg, 4 mmol), and iodine (2.0 g,
2 (1.94 g,
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G. Li, Y. Ju et al.
3.9 mmol) were stirred at 608C for 4 h. After cooling to room tempera-
ture, the excess iodine was destroyed with an aqueous sodium sulfite so-
lution (10%), and the reaction mixture was poured into ice water
(300 mL). The aqueous phase was extracted with diethyl ether (3ꢂ
30 mL), and the solvent of the combined organic layers was evaporated.
Purification of the residue by means of column chromatography (silica
gel, hexane/EtOAc 50:1) resulted in a colorless solid (3.1 g, 6 mmol,
0.68 (s, 3H; 18-CH3), 0.78–2.39 (m, 39H), 3.52–3.69 (brs, 1H; 3-CH),
3.90 (brs, 3H; OCH3), 3.90–4.10 (m, 3H; OCH2, 12-CH), 4.08–4.20 (d,
2H; OCH2), 7.00–6.93 (m, 2H; Ar-H), 7.52 ppm (brs, 4H; Ar-H); ele-
mental analysis calcd (%) for (C45H56O6)n: C 78.00, H 8.15; found: C
77.58, H 9.30.
Synthesis of the model polymer (P3): Compound 4 (544 mg, 1 mmol),
1,4-diethynylbenzene (126 mg, 1 mmol), [PdACHTNURTGNE(UNG PPh3)4] (10 mg), and CuI
1
80%). M.p: 50–518C; H NMR (CDCl3, 300 MHz): d=1.90–2.00 (m, 2H;
(3 mg) were dissolved in a mixture of (iPr)2NH (1.5 mL) and THF
(3.5 mL). The solution was stirred under an N2 atmosphere at 508C for
24 h. The reaction mixture was extracted with CHCl3 (50 mL) and
washed with 10% HCl (50 mL), saturated aqueous NaHCO3, and brine
(2ꢂ50 mL). The organic layer was dried over MgSO4 and concentrated
under reduced pressure. The remaining residue in CHCl3 (5 mL) was
poured into a large amount of methanol (150 mL) to precipitate the
yellow solid P3 (0.331 g, 80%). Mn was measured by GPC (eluent:
THF): Mn =12750; PDI=1.72; IR: n˜ =2920, 2860, 1520, 1380, 1210,
CH2), 2.06–2.17 (m, 2H; CH2), 3.52 (t, 2H; CH2Br), 3.81 (s, 3H; OCH3),
3.96 (t, 2H; OCH2), 7.17 ppm (s, 2H; Ar-H); 13C NMR (CDCl3,
75 MHz): d=27.88, 29.61, 33.74, 57.34, 63.35, 85.65, 86.48, 121.54, 123.00,
152.70, 153.51 ppm.
1-[4-(3a,7a,12a-Trihydroxy-5b-cholan)butoxy]-2,5-diiodo-4-methoxyben-
zene (4): Sodium cholate (1 mmol, 0.449 mmol) was added to a solution
of 3 (511 mg, 1 mmol) and NaI (0.75 mmol, 100 mg) in DMF (20 mL),
and the reaction mixture was stirred at 658C for 4 h. The mixture was
then cooled, poured into water (100 mL), and extracted with EtOAc
(30 mL) twice. The organic layer was washed with H2O (30 mL) and
aqueous NaHCO3 solution (30 mL). The crude product obtained after re-
moval of the solvent was purified by chromatography on silica gel with
4% MeOH/CH2Cl2 as eluent to give 4 (0.50 g, 51%) as a white solid.
831 cmÀ1 1H NMR (CDCl3, 300 MHz): d=0.89 (brs, 3H), 1.29 (brs,
;
16H), 1.50–1.60 (m, 2H), 1.80–1.95 (m, 2H), 3.89 (brs, 3H; OCH3), 3.98–
4.20 (m, 2H), 6.92–7.04 (m, 2H), 7.53 ppm (brs, 4H); elemental analysis
calcd (%) for (C29H34O2)n: C 84.02, H 8.27; found: C 83.71, H 8.50.
M.p: 96–978C; IR: n˜ =3450, 2940, 2860, 1740, 1650, 1470 cmÀ1 1H NMR
;
(CDCl3, 300 MHz): d=0.68 (s, 3H; 18-CH3), 0.89 (s, 3H; 19-CH3), 0.98
(d, 3H; 21-CH3), 1.10–2.40 (m, 31H; aliphatic H), 3.43–3.49 (m, 1H; 3a-
CH), 3.82–3.86 (m, 4H; OCH3, 7a-CH), 3.93–4.02 (m, 3H; OCH2, 12a-
CH), 4.16 (t, 2H; -COOCH2), 7.18 ppm (d, 2H; Ar-H); 13C NMR
(CDCl3, 300 MHz): d=12.64, 17.46, 22.60, 23.33, 25.58, 26.01, 28.33,
30.56, 31.03, 31.43, 34.71, 34.82, 27.60, 35.29, 35.35, 39.64, 39.74, 41.56,
41.88, 46.57, 47.18, 57.28, 64.00, 68.55, 69.75, 72.03, 73.11, 85.52, 86.43,
121.59, 123.04, 152.82, 153.50, 174.44 ppm; HRMS (ESI): m/z: calcd for
[C35H52I2O7 +Na]+: 861.1700; found: 861.1688.
Acknowledgements
We wish to thank Dr. C. Zhao, Beijing Normal University, for the bioac-
tivity test. The work was financially supported by the National Science
Foundation of China (20533050, 20772071, and 50673048) and the
973 Program (2006CB806200).
[1] T. A. Skotheim, J. Reynolds in Handbook of Conducting Polymers,
3rd ed., CRC Press, Boca Raton, 2007.
1-(4-(3a,12a-Dihydroxy-5b-deoxycholan)butoxy)-2,5-diiodo-4-methoxy-
benzene (5): This compound was synthesized by using the same proce-
dure as described for 4, with deoxycholic acid instead of cholic acid. M.p:
[2] D. E. Discher, A. Eisenberg, Science 2002, 297, 967–973.
[3] P. Leclꢃre, A. Calderone, D. Marsitzky, V. Francke, Y. Geerts, K.
Mꢄllen, J. Brꢅdas, R. Lazzaroni, Adv. Mater. 2000, 12, 1042–1046.
[4] J. W. Y. Lam, B. Z. Tang, Acc. Chem. Res. 2005, 38, 745–754.
[5] J. Sjçvall, Lipids 2004, 39, 703–722.
[6] D. B. Salunke, B. G. Hazra, V. S. Pore, Curr. Med. Chem. 2006, 13,
813–847.
[7] a) E. Virtanen, E. Kolehmainen, Eur. J. Org. Chem. 2004, 3385–
3399; b) P. Babu, N. M. Sangeetha, U. Maitra, Macromol. Symp.
2006, 241, 60–67.
[8] P. Bandyopadhyay, V. Janout, L. H. Zhang, S. L. Regen, J. Am.
Chem. Soc. 2001, 123, 7691–7696.
[9] S. Ghosh, U. Maitra, Org. Lett. 2006, 8, 399–402.
[10] Y. Zhao, Z. Zhong, J. Am. Chem. Soc. 2005, 127, 17894–17901.
[11] L. Ahlheim, M. L. Hallensleben, Makromol. Chem. Rapid Commun.
1988, 9, 299–302.
[12] a) X. X. Zhu, M. Nichifor, Acc. Chem. Res. 2002, 35, 539–546;
b) J. E. Gautrot, X. X. Zhu, Angew. Chem. 2006, 118, 7026–7028;
Angew. Chem. Int. Ed. 2006, 45, 6872–6874.
[13] Y. Li, W. Zhang, G. Li, Y. Ju, Polymer 2008, 49, 225–233.
[14] a) F. Brustolin, F. Goldoni, E. W. Meijer, N. A. J. M. Sommerdijk,
Macromolecules 2002, 35, 1054–1059; b) J. Bouchard, M. Belletete,
G. Durocher, M. Leclerc, Macromolecules 2003, 36, 4624–4630.
[15] E. Ryu, J. Yan, Z. Zhong, Y. Zhao, J. Org. Chem. 2006, 71, 7205–
7213.
[16] a) T. Miteva, L. Palmer, L. Kloppenburg, D. Neher, U. H. F. Bunz,
Macromolecules 2000, 33, 652–654; b) U. H. F. Bunz, J. M. Imhof,
R. K. Bly, C. G. Bangcuyo, L. Rozanski, D. A. Vanden Bout, Macro-
molecules 2005, 38, 5892–5896.
[17] H. Shen, A. Eisenberg, J. Phys. Chem. B 1999, 103, 9473–9487.
[18] J. H. Fuhrhop, H. H. David, J. Mathieu, U. Liman, H. J. Winter, E.
Boekema, J. Am. Chem. Soc. 1986, 108, 1785–1791.
[19] M. Berthelot, C. Laurence, M. Lucon, C. Rossignol, R. W. Taft, J.
Phys. Org. Chem. 1996, 9, 626–630.
[20] a) X. B. Yuan, H. Li, X. X. Zhu, H. G. Woo, J. Chem. Technol. Bio-
technol. 2006, 81, 746–754; b) V. H. S. Tellini, A. Jover, F. Meijide,
78–798C; IR: n˜ =3450, 2930, 2860, 1730, 1660, 1490 cmÀ1 1H NMR
;
(CDCl3, 300 MHz): d=0.67 (s, 3H; 18-CH3), 0.91 (s, 3H; 19-CH3), 0.98
(d, 3H; 21-CH3), 1.10–1.95 (m, 31H; aliphatic H), 2.17–2.52 (m, 2H; 23-
CH2), 3.52–3.63 (m, 1H; 3a-CH), 3.82 (m, 3H; OCH3), 3.97 (brs, 4H;
À
OCH2, 12a-CH), 4.16 (t, 2H; COOCH2), 7.18 ppm (d, 2H; Ar-H);
13C NMR (CDCl3, 300 MHz): d=12.87, 17.43, 23.26, 23.58, 25.75, 26.00,
26.21, 27.21, 27.56, 28.76, 30.59, 31.01, 33.76, 34.20, 35.17, 35.30, 36.12,
36.52, 42.17, 46.59, 47.42, 48.35, 57.28, 63.98, 69.75, 71.90, 73.23, 85.51,
86.42, 121.58, 123.04, 152.81, 153.50, 174.36; HRMS (ESI): m/z: calcd for
[C35H52I2O6 +Na]+: 845.1751; found: 845.1745.
Cholic acid decorated PPE (P1): Compound 4 (822 mg, 0.8 mmol), 1,4-
diethynylbenzene (101 mg, 0.8 mmol), [PdACHTNURTGNEUNG(PPh3)4] (10 mg), and CuI
(3 mg) were dissolved in a mixture of (iPr)2NH (1.5 mL) and THF
(3.5 mL). The solution was stirred under an N2 atmosphere at 508C for
24 h. After cooling the reaction mixture to room temperature, the salts
were filtered, the filtrate was poured into acetone (100 mL), and the pre-
cipitated solid was collected by filtration. The resulting solid was redis-
solved and precipitated into a large amount of methanol (200 mL). A
bright-yellow polymer P1 (0.394 g, 69%) was obtained. The product was
dried under vacuum for 24 h before characterization. The number-aver-
age molecular weight (Mn) was measured by gel-permeation chromatog-
raphy (GPC; eluent: THF). Weight-average molecular weight Mw =
30422, Mn =20927; polydispersity index (PDI)=1.45; IR: n˜ =3493, 2910,
2809, 1725, 1430 cmÀ1 1H NMR ([D6]DMSO, 300 MHz): d=0.71 (s, 3H;
;
18-CH3), 0.85 (s, 3H; 19-CH3), 0.99–2.20 (m, 36H), 3.39 (m, 1H; overlaps
with the peak of the water signal, 3-CH), 3.82–3.91 (m, 4H; OCH3, 7-
CH), 4.05 (m, 3H; OCH2, 12-CH), 4.36 (d, 2H; OCH2), 6.97–7.06 (m,
2H; Ar-H), 7.52 ppm (brs, 4H; Ar-H); elemental analysis calcd (%) for
(C45H56O7)n: C 76.24, H 7.96; found: C 76.15, H 8.81.
Deoxycholic acid decorated PPE (P2): This compound was synthesized
by using the same procedure as that described for P1. Note that P2 has
much better solubility in CHCl3 than P1. The Mn was measured by GPC
(eluent: THF): Mw =32901, Mn =21138; PDI=1.56; yield: 73%; IR: n˜ =
3508, 2908, 2790, 1708, 1480 cmÀ1 1H NMR (CDCl3, 300 MHz): d=0.64–
;
10338
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Chem. Eur. J. 2008, 14, 10331 – 10339

Conjugated Polymers with Bile Acid Groups
FULL PAPER
J. V. Tato, L. Galantini, N. V. Pavel, Adv. Mater. 2007, 19, 1752–
1756; c) T. Kaneko, A. Ichikawa, J. P. Gong, Y. Osada, Macromol.
Rapid Commun. 2003, 24, 789–792; d) B. Jean, L. Oss-Ronen, P.
Terech, Y. Talmon, Adv. Mater. 2005, 17, 728–731; e) X. Wang, Y.
Lu, Y. Duan, L. Meng, C. Li, Adv. Mater. 2008, 20, 462–465.
[21] M. Shibakami, M. Tamura, A. Sekiya, J. Am. Chem. Soc. 1995, 117,
4499–4505.
[25] N. S. S. Kumar, S. Varghese, G. Narayan, S. Das, Angew. Chem.
2006, 118, 6465–6469; Angew. Chem. Int. Ed. 2006, 45, 6317–6321.
[26] S. Kawano, N. Fujita, S. Shinkai, Chem. Eur. J. 2005, 11, 4735–4742.
[27] Y. Jiang, D. Perahia, Y. Wang, U. H. F. Bunz, Macromolecules 2006,
39, 4941–4944.
[28] J. E. Gautrot, X. X. Zhu, J. Biomater. Sci. Polym. Ed. 2006, 17,
1123–1139.
[22] Y. Wang, B. Erdogan, J. N. Wilson, U. H. F. Bunz, Chem. Commun.
2003, 1624–1625.
[29] M. J. Plater, J. P. Sinclair, S. Aiken, T. Gelbrich, M. B. Hursthouse,
Tetrahedron 2004, 60, 6385–6394.
[23] For a comprehensive review on the properties of PPE derivatives,
see: a) U. H. F. Bunz, Chem. Rev. 2000, 100, 1605–1644; b) T. A.
Skotheim, J. Reynolds, Handbook of Conducting Polymers, Vol. 6,
3rd ed., CRC Press, Boca Raton, 2007.
[30] R. R. Nambiar, G. L. Brizius, D. M. Collard, Adv. Mater. 2007, 19,
1234–1238.
[24] H. M. Willemen, T. A. Vermonden, T. M. Marcelis, E. J. R. Sudhçlt-
er, Eur. J. Org. Chem. 2001, 2329–2335.
Received: May 22, 2008
Published online: September 24, 2008
Chem. Eur. J. 2008, 14, 10331 – 10339
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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