Folding and aggregation of cationic oligo(aryl-triazole)s in aqueous solution

Article abstract of DOI:10.1002/chem.200900546

Cationic aryl triazole oligomers have been synthesized through "click chemistry". The results show that cationic aryl triazole oligomers adopt a helical conformation in water or in a mixture of water and methanol, but prevail as a random-coiled conformati

Full text of DOI:10.1002/chem.200900546

DOI: 10.1002/chem.200900546
Folding and Aggregation of Cationic Oligo(aryl-triazole)s in Aqueous
Solution
Ying Wang,[a] Fei Li,[b] Yumiao Han,[a] Fuyi Wang,[a] and Hua Jiang*[a]
Abstract: Cationic aryl triazole oligo-
mers have been synthesized through
“click chemistry”. The results show
that cationic aryl triazole oligomers
adopt a helical conformation in water
or in a mixture of water and methanol,
but prevail as a random-coiled confor-
mation in methanol. Importantly, circu-
lar dichroism spectroscopy and dynam-
ic light scattering experiments revealed
that cationic oligomers aggregated in-
termolecularly to form higher order ar-
chitectures with a helical sense oppo-
site to that of the individual helix,
which eventually led to the formation
of aggregates with sizes in the range
100–500 nm. The aggregation of cation-
ic oligomers was governed by the con-
centration and polarity of the environ-
ment. More interestingly, cationic fol-
damers were able to recognize chloride
and fluoride anions in aqueous solu-
tion. The recognition consequently de-
stabilized intermolecular aggregation.
Keywords: aggregation
chemistry halides
recognition · triazoles
·
click
·
· molecular
Introduction
fined conformations, termed as foldamers, represent a new
family of self-assembled supramolecular architectures in the
past decade.[8] Up to now, much effort has been placed on
the development of novel oligomers and their secondary
structure, especially, on the helical conformations.[9] As a
result, considerable advancement has been achieved not
only in secondary structures, but also in intrinsic properties
such as recognition, chiral amplification, catalysis, and mo-
lecular machines triggered by acid/base, light, and the envi-
ronment.[10] In view of the fact that the tertiary structures
are widely adopted by biomacromolecules like proteins, in
which multiple helices associate reciprocally to create a plat-
form to perform various functions such as catalysis and rec-
ognition, chemists are motivated to assemble these available
foldamers into higher-order structures, that is, tertiary struc-
tures.[11] For example, Huc et al.,[11d] reported that the abiotic
proteomorphous foldamer exhibited a tertiary structure like
a small protein. Gellman and co-workers[11e] demonstrated
that b-peptides self-assembled into a 14-helix bundle quater-
nary structure in aqueous solution that is reminiscent of ter-
tiary structures in globular proteins. Recently, Li et al.[12] re-
ported that a new family of foldamers formed organogels
both in the absence and presence of chiral glucoses. A hier-
archical self-assembly mechanism was proposed to account
for the assembling process of the foldamers, in which the
helix elongate through an “end-to-end” adhesion accompa-
nied by a transverse aggregation of helical columns.[11a–c,12]
However, little is known about foldamersꢀ ability to assem-
ble into higher order structures, and the assembling process
The intriguing chemical self-assembly in biomacromolecules
such as DNA and proteins[1–3] has inspired the development
of a number of synthetic molecules that are able to self-as-
semble into supramolecular architectures of different sizes
and shapes, such as supramolecular polymers,[4] organogels,[5]
nanofibers,[6] vesicles,[7] and so on; these complexes are held
together by weak interactions such as hydrogen bonding, p-
stacking, and van der Waals forces. In most cases, the hier-
archical process, one of the typical characters of self-assem-
bly, has been involved. For example, oligo(p-phenylene-vi-
nylene)-based derivatives are able to assemble into organo-
gels.[5e] On the other hand, artificial oligomers with well-de-
[a] Y. Wang, Y. Han, F. Wang, Prof. H. Jiang
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Photochemistry
Institute of Chemistry, Chinese Academy of Science
Beijing 100190 (P. R. China)
Fax : (+86)10-82617315
E-mail: hjiang@iccas.ac.cn
[b] F. Li
Faculty of Science
Beijing University of Chemical Technology
Beisanhuan East Road 15, Chaoyang District
Beijing 100029 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900546.
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FULL PAPER
as well as the properties of the aggregates have not yet been
investigated in as great a detail as that for discotic or some
claviform molecules.[13]
ical conformation in aqueous solutions in the absence of
chloride ion. The helical conformation induced by solvopho-
bic interactions is largely dependent on the chain lengths of
oligomers and the polarity of the solvents. More important-
ly, it was found that oligo(phenylene-1,2,3-triazole)s pro-
duced aggregates, the formation of which is highly depen-
dent on the concentration of the individual oligomer in
water. The aggregated foldamer exhibits an inverse helical
sense in comparison with the individual helix. A “sergeant
and soldiers” effect was also observed in the self-assembly
process. Furthermore, oligo(phenylene-1,2,3-triazole)s are
able to recognize fluoride and chloride ions in mixtures of
water and methanol, which consequently prevents the aggre-
gation of the foldamers in the presence of halides.
Since the independent discovery of the copper(I)-cata-
lyzed 1,3-cycloaddition of azides and terminal alkyne by the
Meldal[14] and Sharpless[15] groups, “click chemistry” has
widely been used in a broad range of fields including materi-
al science, organic chemistry, medicinal chemistry, and bio-
chemistry, because of its unique advantages such as the
benign reaction conditions, tolerance for other functional
groups, and high yield. The key product of click chemistry is
a 1,2,3-triazole compound, which is remarkably stable under
harsh conditions such as oxidation and hydrolysis. One of
the most appealing features of the 1,2,3-triazole moiety is
that the triazole bears a large dipole moment in the ring
(5 D).[16] Recently, Arora and co-workers reported on a pep-
tidotriazole oligomer obtained by swapping amide bonds in
the peptide with triazole moieties and was found to bear a
defined conformation that was induced through a dipole–
dipole interaction.[17] Intrigued by these advantages and fea-
tures of triazole, we designed and synthesized oligomers 1–
6, which are composed of alternating meta-phenyl groups
bearing water-soluble side-chains and linked by triazole moi-
eties (Scheme 1); quaternary ammonium salt groups were
Results and Discussion
Synthesis: To study the effect of chain length on the forma-
tion of helical conformation and aggregation behavior, olig-
omers with different chain lengths, that is, compounds 1–4,
were synthesized (Scheme 2). Compound 5, which bears one
chiral side-chain at the terminal and four achiral water-solu-
ble chains was designed and synthesized to investigate the
chirality transfer in the folding and self-assembly processes
through circular dichroism (CD) spectroscopy. Achiral coun-
terpart 6 was also synthesized as a control to study the chir-
ality amplification effect in the self-assembly processes.
A key issue in the synthesis of these oligomers was to
design and synthesize monomers with two potential func-
tional groups that could easily be converted into an azide
and terminal alkyne, respectively. Consequently, elongation
of the oligomer chain lengths can be achieved by click
chemistry. In this study, the amino group and TMS-protect-
ed acetylene have been selected as functional groups. The
syntheses of monomer 15 and oligomers are shown in
Scheme 2. The starting material, 3,5-dinitrobenzoic acid was
partially reduced by iron powder in glacial acetic acid solu-
tion to give nitroaniline 8. The generated amino group went
through diazotation and then reacted with KI to yield com-
pound 9, which was further reduced by ammonium ferrous
sulfate in concentrated ammonia to produce aminobenzoic
acid 10. Subsequently, compound 10 was directly coupled
with N-Boc-propylenediamine with the aid of the coupling
reagent benzotriazol-1-yl- oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP) in DMF to produce com-
pound 11. On the other hand, compound 10 could also be
converted to azide 12 through diazotization and a nucleo-
philic substitution reaction in the presence of sodium azide.
A peptide coupling condition was also applied to the reac-
tion of N-Boc-propylenediamine with azide 12 to generate
compound 13. The Sonagashira reaction[22] of 11 and 13 with
excess (trimethylsilyl)acetylene yielded 15 and 14, respec-
tively. Note that 14 could also be obtained from 15 under
similar conditions as were used to generate 12. Compound
15 was deprotected by tetrabutylammonium fluoride in the
presence of a drop of acetic acid to give 16, which was cou-
Scheme 1. Oligomers studied herein.
chosen as water-soluble side-chains in view of ubiquity of
cationic groups in biomacromolecules and their important
roles in nature.[18–20] We hypothesized that a well-defined
conformation like a helical structure would be obtained in
aqueous solution through non-covalent interactions such as
a solvophobic interactions and van der Waals forces.
We demonstrate the folding and aggregation of oligo(phe-
nylene-1,2,3-triazole)s 1–6 with cationic side-chains in the
phenyl moieties. During our investigation, similar motifs
were reported in which the symmetric oligomer or the poly-
mer can fold into a helical conformation with the assistance
of chloride ion or through solvophobic interactions.[21] We
were prompted to disclose our discoveries because our
system is distinctly different in its asymmetric sequence,
folding, and aggregating properties in aqueous solution. Our
findings show that oligo(phenylene-1,2,3-triazole)s prevail as
a random-coiled conformation in methanol, but adopt a hel-
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H. Jiang et al.
Scheme 2. Preparation of 1–4. a) Fe, HOAc; b) NaNO2, concd HCl, H2O; c) KI, H2O; d) concd NH4OH, (NH4)2FeACHTNUGTRENNNUG
diamine, PyBOP, iPr2EtN, DMF; f) NaN3, H2O; g) (trimethylsilyl)acetylene, [PdACHTNUGTRENNUNG
sodium ascorbate, CuSO4; j) TFA, CH2Cl2.
pled with compound 14 through the copper-catalyzed 1,3-di-
polar cycloaddition reaction to yield triazole 17. Experience
in our group has shown that keeping the click chemistry re-
action in an oxygen-free atmosphere can effectively reduce
the dosage of sodium ascorbate. Compounds 20, 22, and 23
were prepared from the corresponding reactant as shown in
Scheme 2 through a convergent segment-doubling strategy
that involved iterative reactions consisting of conversion of
the amine to azide, deprotecting trimethylsilyl group, and
click chemistry. It has been reported that the preparation of
azides from the corresponding amino-triazolamers was diffi-
cult and of low yield;[17b] however, it is worth noting that in
our synthetic procedure, azide compounds were easily ob-
tained from the corresponding amino compounds through
diazotization and nucleophilic substitution under weakly
acidic conditions, which are mild and tolerable for the pres-
ence of tert-butoxycarbonyl (Boc) groups. It was found that
the use of hydrochloric acid gave better yields than sulfuric
acid. The water-soluble compounds 1–4 were produced by
deprotection of the Boc groups on compounds 17, 20, 22,
and 23, respectively, in the presence of trifluoroacetic acid
(TFA). Chiral oligomer 5 and achiral oligomer 6 were also
obtained by the coupling the corresponding monomer with
21 under similar click chemistry conditions as mentioned
previously (Scheme S1 in the Supporting Information).
Folding of the oligomers in aqueous solution: We envisaged
that the oligomers would adopt a helical conformation in
water, but should prevail as a random-coiled conformation
in less polar solvents such as methanol. The folding confor-
1
mations of 1–5 were first monitored by H NMR spectrosco-
py in a mixture of methanol and water. In pure methanol,
1
the H NMR spectra of 2 are sharp and spread over a large
range of chemical shifts, indicating no folding (Figure 1).
When the fraction of water increased from 0 to 50%, the
spectra of 2 remained sharp with significant upshifts of the
protons of triazoles and aromatic rings as well as TMS; this
suggests that a helical conformation was initially formed.[24]
With the continuous increase of water until the fraction of
water was up to 80%, all the signals shifted further to the
high field and broadened. During this process, the signal of
terminal TMS group dramatically shifted from d=0.28 ppm
in methanol to À0.21 ppm in 80% water, an upshift of Dd=
À0.49 ppm. The singlet signals of aromatic rings appeared
between d=8.8 and 7.1 ppm in methanol, but between d=
8.1 and 6.6 ppm in 80% water. Similarly, the singlets as-
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Oligo(aryl-triazole) Foldamers
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Figure 1. Part of the 1H NMR spectra of 2 upon changing the fraction of
H2O in MeOH at ambient temperature. [2]=2 mm; MeCN in D2O was
used as the internal standard for the chemical shift.[23]
signed to the protons of triazoles were also found between
d=9.4 and 9.0 ppm in methanol, but between d=9.1 and
8.9 ppm in 80% water. The large extent of the shift suggests
that 2 folded into a stable helical conformation. On the
other hand, the broadening behavior indicates that aggrega-
tion of 2 might be taking place (vide infra). A non-helical
aggregate could be ruled out because although a non-helical
aggregate would cause the similar upshift effect, the very
small extent of shift relative to a helical conformation was
expected due to no or weak shielding/deshielding arising
from stacking of aromatic rings in the case of a non-helical
aggregate. In addition, the clickamers that have been de-
scribed by Hecht and co-workers displayed similar behavior
in aqueous solution.[21c] It is worth noting that all the signals
undergo a slight downshift when the amount of water is
varied from 80 to 100%, which is likely to come from the
change to a highly polar environment as the solvent was
swapped from methanol to water. For 3–5, the signal of ter-
minal TMS group appears at approximately d=0.21 ppm in
methanol, but at À0.16–0.26 ppm in water (Figure S3B, S4,
and S5 in the Supporting Information), suggesting that 3–5
also fold and aggregate in water. However, it is difficult to
assign particular signals of 3–5 in water owing to more dras-
tic aggregation in comparison with that of 2. As expected,
Figure 2. A) The UV/Vis absorption spectra of 4 in varying percentages
of H2O in MeOH at ambient temperature; [4]=5 mm, light-path length
was 10 mm. B) The ratios of the intensity of the UV absorption at
238 nm and 264 nm (A238/A264) versus fraction of H2O in MeOH at ambi-
ent temperature for oligomers 2–5. [2]=[3]=[4]=5 mm, [5]=20 mm.
erative phenomena and conformational transition from a
random coiled state to a folded conformation.[25,26] Similarly,
oligomers 3 and 5 also undergo a conformational transition
as the solvent was switched from methanol to water (Fig-
ure 2B, Figures S8 and S9A in the Supporting Information).
In the case of 2, the curve exhibits approximately linear be-
havior (Figure 2B), indicative of weak intramolecular p–p
stacking, and is supported by the fact that 2 forms only one
helical turn as shown by molecular modeling (Figure S1 in
the Supporting Information). However, the UV/Vis spec-
trum of 1 in methanol was almost identical to that in water;
this indicates that the folding process does not occur for the
shortest oligomer (Figure S6 in the Supporting Information).
To obtain detailed information on conformational transi-
tion, CD spectroscopy measurements were carried out on
chiral oligomer 5 at 20 mm in a mixture of methanol and
water at ambient temperature. It is known that introduction
of a chiral group to a helix causes a bias in the helical
sense.[27] The CD measurements were first taken immediate-
ly after the samples were prepared. In methanol, the CD
signal of 5 is silent, as is expected for a random-coiled con-
formation (Figure 3A). The onset of the Cotton effect is ini-
tiated when the fraction of water is about 30%. The signals
at 272 nm increase significantly with increasing the amount
of water from 30% to 80% (Figure 3B), which is evidence
that 5 folds into a helical conformation with a bias for the
one-handed helical sense, and that the addition of more
1
however, the H NMR spectrum of 1 showed little variation
upon increasing the amount of water (Figure S3A in the
Supporting Information).
UV/Vis spectroscopic measurements provided additional
information about the folding conformation. To reduce the
effect of aggregation, dilute solutions of the oligomers were
used. In methanol, the UV spectrum of 4 at 20 mm shows a
peak at 238 nm with a shoulder at 264 nm (Figure 2A). The
absorbance at 238 nm shows a sharp descent accompanied
by a slight blue shift with increasing amounts of water. A
similar shrinkage of absorbance at 264 nm was also observed
upon increasing the amount of water. The hypochromicity is
suggestive of intramolecular p–p stacking. The ratios of ab-
sorbance at 238 nm to that at 264 nm (A238/A264) were plot-
ted as a function of the amount of water (Figure 2B). The
curve exhibits a typical sigmoid pattern, which hints at coop-
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H. Jiang et al.
helices, as observed in ortho-phenylene–ethynylene folda-
mer by Tew et al,[28a] and in abiotic metallofoldamers by Fox
and co-workers.[28b] Surprisingly, no clear isodichroic point
was observed when the solvent was changed from methanol
to water. The lack of an isodichroic point is probably due to
a change in the structure of the helix, leading to a change in
the strength of the exciton couple, as observed in ortho-
phenylene–ethynylene systems.[29]
Aggregation of the foldamers in solution: It has been men-
tioned above that at high concentrations in D2O, the
1H NMR spectra peaks for 2–5 are all somewhat broadened,
which is indicative of the possible presence of intermolecu-
lar aggregation. Additionally, it was found the oligomers can
aggregate in aqueous solution, as indicated by TOF-ESI
mass spectrometry (Figure S10–S14 in the Supporting Infor-
mation). These phenomena triggered our interest to study
the aggregation behavior of oligo(phenylene-1,2,3-triazole)s
in aqueous solution.
Aggregation of 2, 4, and 5 were first investigated in pure
1
water by variable concentration H NMR spectroscopy after
the samples were stored for 5 h. At low concentration
(1 mm), the aromatic signals of 2 spread over wide region,
and some aromatic signals overlap in the range of d=7.6–
8.0 ppm. The signals of the triazole appear to be broad in
the range of d=8.7–9.0 ppm (Figure 4). Upon increasing the
Figure 3. A) Change of CD spectra of 5 upon changing of the ratio of
H2O in MeOH; the spectra were obtained after the samples were stand
for 24 h, [5]=20 mm, light-path length was 10 mm. B) Corresponding in-
tensity at 272 nm of CD spectra upon changes of solvents when tested in
less than 5 min (dashed line) and after 24 h (solid line) the samples were
prepared.
water allows it to form a more stable helix. Surprisingly, a
decrease in the CD intensity is observed when the fraction
of water varied from 80 to 100% (Figure 3B). We hypothe-
sized that the decrease is caused by the twist sense bias of
the helix lagging behind the initial folding event in such a
highly polar environment.[11a] To clarify this, an identical ex-
periment was repeated after the samples had been allowed
to stand for 24 h. The CD spectra showed that all signals
were further enhanced (Figure 3B), which is undoubtedly
suggestive of the presence of the bias lags. Unexpectedly,
however, the decrease in the CD intensity was still observed
when increasing the fraction of water from 80 to 100%,
even though the solution was equilibrated for a few days. It
is clear that the decrease on the CD intensity could not be
mainly ascribed to the twist-sense bias lag. On the other
hand, because variable-concentration CD spectroscopy and
dynamic light scattering (DLS) ruled out the aggregation of
5 at 20 mm (vide infra), we therefore speculated that this de-
crease was partially ascribed to the “horizontal flipping” of
the terminal groups, and in particular the terminal phenyl
groups with a chiral side-chain around the benzene–triazole
linkages, while the interaction of solute with environment
was changed. An attempt to confirm this flipping by NMR
spectral analysis was unsuccessful due to drastic aggregation
of oligomers at the millimolar range (vide infra). In fact,
“horizontal flipping” of the terminals is a dynamic nature of
Figure 4. Part of variable concentration 1H NMR spectra of 2 in D2O at
ambient temperature. Measurements were taken after the samples were
stored at RT for 5 h.
concentration from 1 to 10 mm, all protons shifted upfield,
and this was accompanied by evident broadening; no indi-
vidual signal could be designated at 10 mm. Such upshifts
and broadening behavior indicate that aggregation of 2
takes place in water. Similar phenomena could also be ob-
served for the longer oligomers 4 and 5 (Figure S17 and S18
in the Supporting Information).
To address the aggregation of the oligomers in water, dy-
namic light scattering (DLS) measurements were carried
out. All samples were stored for 5 h before measurements.
We first investigated the aggregation of oligomer 4 in pure
water. DLS experiments showed that 4 formed aggregates
with the average diameter in the range of 100–400 nm over
a wide concentration range (5–200 mm; Figure 5). Similar ag-
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might originate from an interaction of the foldamers either
in a column stacking[11a] or in a side-by-side intertwining.[30]
Such an inversion of the observed CD spectrum has also
been observed in many other self-assembly cases in which
the initially formed 1D aggregates with a helical bias twist
to form higher-order architectures with an opposite helical
sense.[31]
Time-dependent CD spectroscopy experiments were de-
signed to investigate the formation of superstructure. A so-
lution of 5 at 200 mm was prepared and subjected to CD
measurements immediately. Initially, the CD spectrum
showed a negative peak at 265 nm and a positive peak at
289 nm. Interestingly, the original peak at 265 nm disap-
peared gradually, but the peak at 289 nm was enhanced pro-
gressively and accompanied by a blue shift as the equilibri-
um was established (Figure 6A). A plot of CD intensity at
278 nm as a function of time shows that the intensity
strengthens fleetingly at the beginning, but weakens gradual-
ly and reaches a steady state within 2 h (Figure 6B).
Figure 5. Average diameter of the aggregates of 4 in pure H2O upon
changing concentration. Measurements were taken after the samples
were stored at RT for 5 h.
gregation behavior was also observed for 3 under identical
experiment conditions (Figure S20). However, oligomer 2
acts differently from 3 and 4. Variable concentration DLS
data show that no detectable aggregates were observed
when the concentration was below 150 mm. The aggregates
50 nm in size were detected only when the concentration
was beyond 150 mm (Figure S19). Under identical conditions,
chiral 5 formed particles with sizes in the range of 200–
400 nm as its concentration rose above 100 mm (Figure S21
in the Supporting Information).
To monitor the generation and growth process of the
nanoparticles, a 60 mm solution of 5 in water was prepared
by rapidly dissolving 5 within 5 min, and the average size of
the aggregates was monitored by DLS at fixed intervals at
room temperature. The results show that aggregates were
detected after the sample was stored as long as 10 h. The
size of aggregates increases significantly with increasing stor-
age time and reaches about 140 nm after 15 h (Figure S22).
This implies that the generation of aggregates appears to be
very slow at the early stage and the large aggregates form
from the small ones. Furthermore, the scanning electron mi-
croscopy (SEM) examination also revealed the formation of
irregular aggregates for 2–5 in water solution (Figure S23 in
the Supporting Information).
We next investigated the intermolecular aggregate by CD
spectroscopy measurements through chiral 5. All samples
were equilibrated for 5 h in water solutions before each
measurement. The CD spectrum shows that at 20 mm, 5 ex-
hibits negative signal in the range 250–350 nm with a peak
at 272 nm and a shoulder at 320 nm. However, the CD spec-
trum of 5 at 200 mm shows a distinct, positive signal between
250–350 nm with a peak at 278 nm accompanying two weak
shoulders at 258 and 318 nm, respectively (Figure S24 in the
Supporting Information). Combined with previous DLS re-
sults, it can be concluded that the negative Cotton effect of
5 originates from its helical conformation with a helical bias
at the low concentration, whereas the positive Cotton effect
of 5 at high concentration can be ascribed to the formation
of a superstructure, which eventually leads to formation of
aggregates. The findings indicate that the superstructure of
aggregated foldamers has a helical sense opposite to that of
original helix. The inversed chirality in the helical sense
Figure 6. A) Changes of CD spectra of 5 with concentration of 200 mm
upon time in pure H2O and B) corresponding intensity at 278 nm of CD
spectra versus time; light-path length was 1 mm.
To further elucidate the effects of concentration and sol-
vents on the self-assembly, the concentration-dependent be-
havior of 5 in water were examined by CD spectroscopy.
The CD spectra of 5 with different concentrations in pure
water were collected after the samples were stored for 5 h.
A plot of the CD intensity at 278 nm versus concentrations
shows that, below 50 mm, the CD signal of 5 is almost linear-
ly dependent on the concentration of 5 (Figure 7A), indicat-
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H. Jiang et al.
plot of CD intensities at 272 nm as a function of mole per-
centage of chiral 5 is linear. No deviation from linearity in-
dicates that no “sergeant and soldiers” effect occurred. The
similar results were also obtained over a broad range of con-
centrations (5–200 mm) and even when the samples were
heated to 708C, then cooled slowly to room temperature
(Figure 8A and Figure S29 in the Supporting Informa-
Figure 7. A) The intensity at 278 nm of CD spectra of 5 versus concen-
tration in pure H2O and B) that of 272 nm in mixture of H2O/MeOH
(75:25 vol%) solution. Measurements were taken after the samples were
stored at RT for 5 h; light path length was 1 mm. The insert chart in B) is
the intensity at 272 nm of CD spectra of 5 versus concentration below
120 mm and their linearity.
ing there was no self-assembly or weak self-assembly in this
range of concentrations. However, as the concentration in-
creased further, the CD signal decreased and finally showed
a positive signal, indicative of a dominant self-assembly in
these solutions. When the solvent was changed from pure
water to 75% water in methanol, the CD intensities of 5 at
272 nm keep a good linear relationship with concentration
in the range of 0–120 mm (Figure 7B, inset). However, the
CD intensities show negative deviation with increasing the
concentration of 5 from 120 to 300 mm (Figure 7B), which
indicates that a dominant self-assembly process occurred.
Once the concentration is over 300 mm, the CD signals de-
crease sharply, indicating that a distinct self-assembly pro-
cess becomes dominant. However, no positive signals could
be observed even at the concentration up to 400 mm. The
data strongly suggest that the folding and aggregation of
oligomers are controlled not only by its concentrations, but
also by its environment.
The control of the conformational properties of large
numbers of cooperative achiral molecules by a few chiral
molecules, which is called the “sergeant and soldiers” princi-
ple[32] has been widely used to validate the presence of self-
assembly.[11a,33] This principle predicates that a small number
of chiral helices direct the conformation properties of a
large number of achiral helices. To examine the intermolec-
ular stacking of oligomers, the aggregation behavior of the
mixture of chiral 5 and achiral 6 were first studied in pure
water with a total concentration of 200 mm. Surprisingly, a
Figure 8. Plot of the intensity at 278 nm (or 272 nm) versus molar fraction
of the chiral 5 in a 5/6 mixture which kept the total concentration con-
stant as 200 mm in A) pure H2O and B) 25:75 (v/v) MeOH/H2O. All the
samples were dissolved and stored at RT for 5 h prior to the measure-
ments; light-path length was 1 mm.
tion).[34] One possible explanation is due to compact aggre-
gate conformation in pure water. To verify this deduction,
the similar experiments were repeated in the mixture of
methanol/water (25:75 v/v). The intensities of the Cotton
effect at 272 nm were plotted as a function of mole percent
of sergeant 5. The curve shows a nonlinear behavior (Fig-
ure 8B). The positive deviation indicates that chiral 5 can
impart its chirality to achiral one in helical columns. Howev-
er, it required more than 50% of the chiral foldamer to ach-
ieve full bias of the chirality. This weak “sergeant and sol-
dier” effect, in sharp contrast to a strong “sergeant and sol-
dier” effect for discotic molecules, is also observed in other
oligomer foldamers that are induced by solvent–solute inter-
actions[11a] and some helical polymers such as poly(cis-acety-
lenes)[35] and polythiophene.[36,37]
Combined with DLS and CD results together, a hierarchi-
cal assembly mechanism was proposed to address the self-
assembly process (Figure 9). Firstly, the formation of a heli-
cal conformation is induced through weak forces such as sol-
vophobic interactions and van der Waals forces as the sol-
vents were switched from methanol to water. The foldamers
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Oligo(aryl-triazole) Foldamers
FULL PAPER
clude that oligo(aryl/triazole)s
are able to recognize chloride
anion in aqueous solution,
which consequently prevents
the aggregation of the foldam-
ers. The findings are sharply
different from cation-promoted
hierarchical formation of self-
organized foldamers, as ob-
served by Lehn and co-work-
Figure 9. Proposed schematic representation of the folding and aggregation process of cationic oligo(phenyl
1,2,3-triazole)s in aqueous solutions.
thus stack intermolecularly to form the stacked columns of
helices. Finally, the helical columns twist reciprocally to
form helix bundles, which eventually result in the formation
of aggregates.
Effect of halide anion on the aggregation of foldamers: As
mentioned at the beginning, aryl triazole macrocycle or fol-
damers displayed a high affinity for halide ions through
À
À
pure C H···X hydrogen bonds in organic solvents such as
dichloromethane or acetone.[21] We wonder whether pure
C H···X hydrogen bonds still work in aqueous solution. If
so, how do the cationic foldamer behave in the presence of
halide?
À
À
To address this question, we first investigated interaction
between oligomer 5 and halides, that is, chloride and fluo-
ride ions, by UV/Vis spectroscopy in a water/methanol
(75:25) mixture. All solutions of 5 were stored at room tem-
perature for 5 h prior to the titration. The results showed
that the absorbance of 5 at 20 mm decreased upon increasing
concentration of chloride (Figure S30). The hypochromic ef-
fects, which result from the p-stacking interactions and con-
formational transformations, suggest that 5 is able to host
chloride ion through its internal helical cavity even in aque-
ous solution. A similar phenomenon was also observed
upon the titration of fluoride in aqueous solution. However,
it seems that oligomer 5 exhibits stronger affinity for chlo-
ride than for fluoride. This is likely due to the fact that the
cavity of foldamer fits chloride well.
Figure 10. A) Changes of CD spectra of 5 upon concentration in the pres-
ence of KCl in 75 vol% H2O in MeOH at RT and B) corresponding in-
tensity at 272 nm as a function of concentration. One equivalent of KCl
was added to all fresh solutions of 5, then the solutions were stored for
5 h at RT before being tested; light-path length was 1 mm.
To further investigate the effect of halide anions on the
self-assembly behavior of the foldamers, a series of different
concentrations of 5 containing equimolar amounts of chlo-
ride were prepared in 25 vol% methanol in water. CD spec-
tra of 5 at different concentrations were recorded after the
samples had been allowed to stand at room temperature for
5 h. All CD spectra display similar pattern and an isodichro-
ic point at 247 nm (Figure 10). The presence of the isodi-
chroic point suggests that 5 adopts a similar folded confor-
mation in a broad range of concentrations. A plot of CD in-
tensities at 272 nm against concentrations shows that the
CD signal is linearly dependent on the concentration of 5,
which is evidently different from the results in the absence
of chloride (Figure 7B). On the other hand, when monitor-
ing the same solutions by DLS, there are no aggregates ob-
served at any concentration (data not shown). In combina-
tion with UV/Vis and CD spectroscopic data, one can con-
ers.[38] A possible explanation for this behavior is due to the
static repulsion between the chloride anions binding to the
foldamers.
Conclusions
Cationic oligo(m-phenylene-1,2,3-triazole)s have been de-
signed and synthesized by click chemistry. Cationic oligo-
mers can fold into a helical conformation in mixtures of
water and methanol. The foldamers show a concentration-
dependent self-assembly behavior in both water/methanol
mixtures and pure water. “Sergeant and soldiers” experi-
ments revealed that a “chirality amplification” effect of
oligo(m-phenylene-1,2,3-triazole)s is more easily realized in
Chem. Eur. J. 2009, 15, 9424 – 9433
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9431

H. Jiang et al.
2007, 46, 4442; e) W. Cai, G. Wang, Y. Xu, X. Jiang, Z. Li, J. Am.
Chem. Soc. 2008, 130, 6936.
the mixture of water/methanol (75:25 v/v) in which foldam-
ers bear a looser conformation than in pure water. By moni-
toring the self-assembling process through circular dichroism
spectroscopy and dynamic light scattering experiments, it
was found that oligo(m-phenylene-1,2,3-triazole)s formed
aggregates with sizes in the range from 100 to 500 nm. Ap-
parently, the foldamers stack intermolecularly to form the
stacked columns of helices, which thus entwined to form
higher-order architectures. Compared with the chirality of
the foldamers, the higher order architectures have an oppo-
site bias in the screw sense to the individual helix. Finally,
the foldamers can bind halide ions through the internal
cavity in the mixture of water/methanol (75:25 v/v) and the
binding of which is effective to prevent the aggregation of
the foldamers.
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Details of the experimental procedures can be found in the Supporting
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Acknowledgements
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We thank the Chinese Academy of Sciences ꢂHundred talents programꢀ,
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National Basic Research 973 Program of China (Grant No.
2009CB930802) for financial support.
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Received: February 27, 2009
Published online: August 5, 2009
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9433