Halide-guided oligo(aryl-triazole-amide)s foldamers: Receptors for multiple halide ions

Article abstract of DOI:10.1002/chem.201001560

We synthesized and characterized a series of oligo(phenyl-amide-triazole)s that can fold into a helical conformation guided by halide ions. Their binding models and affinities are highly dependent on the length of the foldamer, media and the inducing capa

Full text of DOI:10.1002/chem.201001560

FULL PAPER
DOI: 10.1002/chem.201001560
Halide-Guided Oligo(aryl-triazole-amide)s Foldamers:
Receptors for Multiple Halide Ions
Ying Wang,[a, b] Junfeng Xiang,[a] and Hua Jiang*[a]
Abstract: We synthesized and charac-
with one helical turn shows a 1:1 bind-
ing stoichiometry to all halides, while
the longer foldamer with two or three
helical turns in principle can form 1:2
terized a series of oligo(phenyl-amide-
triazole)s that can fold into a helical
conformation guided by halide ions.
Their binding models and affinities are
highly dependent on the length of the
foldamer, media and the inducing capa-
bility of halide ions. The short foldamer
complexes with chloride anions even
bromide anions with an enhancement
on binding affinities. A result of quan-
titative NOE calculations imply that
the longer foldamer should increase its
helical pitch so as to release the elec-
trostatic repulsion between halide ions.
Keywords: amides · binding stoichi-
ometry · foldamers · halide ions ·
triazoles
Introduction
ent.[12–15] The scarcity is mainly due to the lack of suitable
anion receptors that could be easily engineered as foldam-
ers. In this aspect, the prominent examples are the oligoin-
dole[13] and oligotriazole-based[14] foldamers, which induced
by indole N-H···ClÀ and C-H···ClÀ hydrogen bonds, respec-
tively. Both of which were found to form 1:1 complex with
chloride ions. A plausible explanation for this behavior is
due to the strong static repulsion between two chloride
anions binding to the cavities of foldamers.[15] However,
little is known about the influence of the static repulsion on
the foldamers and the binding stoichiometry between the
foldamer and anions, which lead to that the rational design
of foldamers able to host multiple anions remains a very dif-
ficult problem to resolve. Herein, we report on a new type
of oligomers 1–3 (Scheme 1) based on aryl-triazole-amides
which can form a stable helical conformation as binding one
halide ion. The longer foldamers 2 and 3 are able to host
more than one chloride anion even bromide anion. Impor-
tantly, to host two halide ions, the foldamer was found to in-
crease its helical pitch so as to release the electrostatic re-
pulsion between the two halide ions.
Recently, several groups reported that shape-persistent
macrocycles[17] or quasifoldamers[14] containing triazole moi-
eties provide strong affinity for chloride ions with C-H···ClÀ
hydrogen bonds. In our previous work,[15] we also found that
oligo(phenylene-1,2,3-triazole)s composed of alternating
meta-phenyl groups bearing water-soluble side-chains fold
and aggregate in aqueous solution. Furthermore, these olig-
omers are able to recognize fluoride and chloride ions, con-
sequently preventing the aggregation of oligo(phenylene-
1,2,3-triazole)s in aqueous solution. On the other hand, the
Ions display an essential physiological role to the living
cell.[1] In nature, peptides have been discovered to orient
parallel to the surface of the membrane to recognize ions
and subsequently function as ion channels.[2] Effort on de-
veloping artificial ions receptors can help us to gain deeper
insight into the ion-binding mechanism in nature and to find
a new strategy for treating ion-related diseases, such as
cystic fibrosis which caused by chloride channel malfunc-
tions.[3] Accordingly, a number of artificial ions receptors
have been developed.[4] Among them, synthetic oligomers
that can adopt specific folding patterns to mimic the struc-
ture of proteins and DNA, so-called foldamers,[5–6] provide a
simple and efficient approach for investigating the ions-
binding properties of their natural counterparts. In the past
decade, a few foldamers capable of hosting guest molecules
with stable yet dynamic conformation have been report-
ed,[7–16] but only a few, which can bind anions, exist at pres-
[a] Y. Wang, Dr. J. Xiang, 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] Y. Wang
Graduate University of Chinese Academy of Sciences
Beijing 100049 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001560.
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hydroxy-5-nitrobenzoic acid (15), which could be converted
to azide 17 by reduction using ammonium ferrous sulfate in
concentrated ammonia and subsequently diazotized in the
presence of NaN3. Protecting the acid group in 17 to give
ester 18, which was alkylated to yield 19. Thus, through the
“click” coupling[20] of the two essential precursors men-
tioned above, monomer bearing 1,2,3-triazole group in the
middle of two phenyl groups and two function groups of
BocNH and ester at both ends can be obtained. A segment
doubling strategy involving selective deprotections and cou-
plings via acid chlorides was then adopted to generate oligo-
mers 1, 2 and 3. Note that to protect the Boc group, the acid
was activated to the corresponding acid chloride under mild
conditions using the Ghosez reagent (1-chloro-N,N,2-trime-
thylpropenylamine).[21] Compound 4 was obtained after cou-
pling the monomer acid chloride 20c with 9.
Scheme 1. Oligomers studied herein.
amide N-H group is widely used as hydrogen-bond donor to
construct anion receptors.[4f–i] These facts inspired us to
design oligo(phenyl-amide-triazole)s 1–4, which possess two
phenyl rings, a triazole and an amide group in the repeat
unit that is supposed to provide moderate affinities for
halide ions. According to molecular modelling (Figure S1 in
the Supporting Information), oligomer 1 exists as a helical
conformation in one turn in the presence of halide ions. The
longer oligomers such as 2 and 3, in principle, were designed
to yield two and three helical turns, respectively. We hy-
pothesized that longer oligomers could bind more than one
anion like chloride ions. Short oligomer 4 was designed to
assess the affinity between phenyl-amide-triazole motif and
halide ions and also to study the conformation of their com-
plex in the solid state.
Binding properties: The folding behaviors of oligomers 1–4
1
1
were investigated by H NMR spectroscopy. H NMR spec-
tra of 1 and 4 initially recorded in CDCl3 show one set of
sharp signals indicative of nonaggregation taking place. Un-
expectedly, the longer oligomers 2 and 3 were found to ag-
gregate under the identical conditions. This aggregation of 2
can clearly be detected by concentration-dependent
1H NMR spectra and 2D DOSY experiments (Figures S2, S3
and S4). To avoid this aggregation, several other commer-
cially available deuterated solvents were tested, and
[D5]Pyridine ([D5]Pyr) and the mixture of [D6]DMSO/
[D5]Pyr were chosen for investigations as indicated (see
below and Figures S5 and S6).
The 1H NMR spectrum of 4 in [D5]Pyr shows considerable
changes in the chemical shift upon addition of halide ions,
indicative of strong interactions between the phenyl-amide-
triazole motif and halide ions. In details, upon addition of
Bu4N+ClÀ, the chemical shifts of the triazole and amide pro-
tons shifted downfield up to Dd=1.8 and 1.1 ppm, respec-
tively, as a result of the formation of hydrogen bonding (Fig-
ure S7). The titrations of bromide also produced a large
change in the chemical shift of the protons at triazole and
amide moieties but less than that of chloride ions, and the ti-
trations of iodide ions gave the smallest change in chemical
shift (Figures S10 and S13). The fitting analyses of binding
data[22] yield the association constants (K) of 540, 83 and
11mÀ1 in a 1:1 binding model for chloride, bromide and
iodide ions, respectively (Table 1), suggesting the binding is
highly dependent on the inducing capability of halide ions.
Although an attempt to co-crystallize 4 and chloride ion
failed, the results mentioned above still unambiguously sug-
gest the interaction between the phenyl-amide-triazole motif
and halide ions is directional and sufficiently strong so as to
induce the longer oligomer to fold into a helical conforma-
tion.
Results and Discussion
Synthesis: The preparations of the proposed oligomers 1–4
consisting of two functional group in the repeated units, that
is, amide and 1,2,3-triazole, are depicted in Scheme 2. The
key issue in this approach is to obtain two essential precur-
sors, that is, N-Boc-3-ethynyl-5-isobutoxyaniline and methyl
3-azido-5-isobutoxybenzoate. Initially, 3,5-dibromophenol
(6), which was prepared from the comercially available pen-
tabromophenol (5) according to the method reported by
Tour,[18] was alkylated under an alkaline condition to pro-
duce 3,5-dibromo isobutoxybenzene (7). By treating with
nBuLi and TsN3, one of the bromo groups in 7 was convert-
ed to azide to yield 8 at À788C in an acetone bath. Com-
pound 8 was reduced by NaBH4 to generate amine com-
pound 9, which was protected by tert-butoxycarbonyl (Boc)
group via (Boc)2O to provide 10. Then, Sonogashira reac-
tion[19] of 10 with excess 2-methylbut-3-yn-2-ol at 788C yield-
ed 11. In this reaction, we selected 2-methylbut-3-yn-2-ol in-
stead of trimethylsilylacetylene to avoid the tube-sealing op-
eration due to the fact that the boiling point of trimethyl-
silylacetylene (538C) is lower than the reaction temperature.
Treatment of 11 with NaH in anhydrous toluene produced
12. On the other hand, 14 can be prepared from 3,5-dinitro-
benzoic acid as previously reported.[15] The amine group in
14 went through diazotation and then hydrolyzed to yield 3-
The folding of oligomer 1 in the presence of chloride ions
1
were first demonstrated by H NMR titration experiments.
The marked signals of 1 were assigned on the basis of
COSY, HSQC, TOCSY and 2D NOESY experiments (see
1
Supporting Information). It can be found that the H NMR
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Receptors for Multiple Halide Ions
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Scheme 2. Preparation of 1–4. a)AlCl3, toluene; b) 1-iodo-2-methylpropane, K2CO3, DMF; c) nBuLi, TsN3, THF; d) NaBH4, MeOH; e) (Boc)2O, diox-
ane; f) 2-methyl-3-butyn-2-ol, Pd(PPh3)4, CuI, (iPr)2NH; g) NaH, toluene; h) Fe, HOAc; i) H2SO4, NaNO2, H2O; j) Cu(NO3)2, Cu2O; k) conc. NH4OH,
(NH4)2Fe(SO4)2, H2O; l) NaN3, H2O; m) H2SO4, MeOH; n) sodium ascorbate, CuSO4, tBuOH, H2O; o) TFA, CH2Cl2; p) NaOH, THF, H2O; q) 1-chloro-
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
N,N,2-trimethylpropenylamine, CH2Cl2; r) CH2Cl2.
Titrations of 1 with chloride ions gave 1:1 binding stoichi-
ometry, which was confirmed by a Jobꢁs plot. The best fit to
the binding data yields an association constant of 350mÀ1,
slightly smaller than that of 4. It is presumably due to the
steric hindrance of the extra phenyl-triazole group.[23] The ti-
trations with bromide and iodide ions showed similar pat-
terns to those observed in the case of chloride ions (Fig-
ure S28-35), and give an atom-radius-dependent sequence of
K values (ClÀ >BrÀ >IÀ) as a result of electrostatic nature
of hydrogen-bonding interactions (Table 1).
To address the formation of a helical conformation of 1
induced by halide ions (Figure 1B), we performed NOESY
experiments. In the absence of halides, NOE correlations
were observed between triazole protons H5 and H13 and
four adjacent protons at the consecutive phenyl rings. The
similar NOE correlations also apply to proton H9 (Fig-
ure 2A). The NOE data indicate oligomer 1 prevailed as a
random-coiled conformation in solution. However, the NOE
correlations displayed totally different patterns in the pres-
ence of halides, for example, of chlorides, triazole proton H5
only exhibits strong NOE correlation with H4 and H6 which
are supposed to be located at the inner cavity (Figure 1B).
Similarly, the amide proton H9 also shows significant contact
with H6 and H10. Besides, the triazole proton H13 has a
Table 1. Association constants [mÀ1] of oligomers 1, 2, 3 and 4 for halide
ions ClÀ, BrÀ and IÀ at ambient temperature.[a]
Anion
ClÀ
1
2
3
4
350
4900 (13)
250 (1.2)[b]
590 (3.2)
76
540
490 (38)[b]
BrÀ
IÀ
80
15
83
11
[c]
[c]
[a] All titrations were carried out in [D5]pyridine unless otherwise speci-
fied. The association constants were calculated by the software WinE-
QNMR.[22a] All relative errors for the values are less than 10%. The
values of K2 are listed in parentheses. [b] In 20:80 (v/v) [D6]DMSO/
[D5]Pyr. [c] Not determined.
spectra of 1 in [D5]Pyr showed significant changes in the
chemical shifts upon titration of chloride ions (Figure 1A
and C). The triazole proton H5 and amide proton H9 largely
downshifted from d = 9.30 and 11.44 ppm to 10.88 and
12.32 ppm (Dd=1.58 and 0.88 ppm, respectively) upon addi-
tion of five equivalents Bu4N+ClÀ, as expected for the for-
mation of strong hydrogen bonds between the binding motif
and chloride ions. Similar downfield shifts were observed for
the aryl protons H4, H6 and H10. However, other protons
such as H1, H3, H7 and H12, showed little change in chemical
shift.
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H. Jiang et al.
partly due to the formation of
hydrogen bindings between fol-
damers with the second ClÀ,
and partly due to the decrease
of the p-stacking effect which
results from the increase of the
helical pitch (see below). As ex-
pected, the binding isotherms
of the amide protons fit well to
a 1:2 complex model to yield
the association constants for
each step being the values of K1
at 4.9ꢂ103 mÀ1 and K2 at 13mÀ1
(Figure S38) suggesting that the
folding process is not coopera-
tive, which is sharply different
from a cooperative process in-
duced by cations in meta-phe-
nylacetylene oligomer as de-
scribed by Moore et al.[16b]Alth-
ough K2 is far lower than K1,
the findings give an obvious
proof for the presence of the
electrostatic repulsion between
Figure 1. A) Partial 1H NMR spectra changes of 1 upon addition of chloride ions: a) 1, b) 1 + 5 equiv ClÀ. two chloride anions binding in
B) Representation of the folding of 1 with the help of chloride ions. C) Changes in chemical shift for protons
of 1 at variable concentrations of chloride ions. All measurements were carried out in [D5]Pyr at ambient tem-
perature; [1]=5 mm.
helical cavity.
The titrations of 2 with bro-
mide ions lead to a similar but
weaker inversion on chemical
strong correlation with H10 rather than H12 (Figure 2B).
These results present unequivocal evidence that 1 folded
into a stable helical conformation upon complexation with
chloride ions. Additionally, it is interesting to note that H5
has a stronger contact with H4 than H3, indicating the
BocNH group keeps away from the interior cavity due to its
strong steric hindrance.
shift in comparison with that of chloride ions, indicating 2
also form 1:2 complexes in the presence of bromide with as-
sociation constants K1 at 590mÀ1 and K2 at 3.2mÀ1 (Figur-
es S43–S45). However, the titrations of 2 with iodide ions
show a homologous binding behavior as that of 1 in which
all amide protons keep upshift upon addition of iodide ions
due to the largest size and the lowest charge density of
iodide (Figures S46–48). The fitting of binding profile yields
a K value to be 76mÀ1 in a 1:1 binding stoichiometry that
was confirmed by the Jobꢁs Plot.
NOESY measurements provide additional information
about the conformation of 2 upon interaction with chloride
ions. Expectedly, 2 exits in Pyr as a random-coiled confor-
mation in the absence of halide ions. However, oligomer 2 is
supposed to host one chloride ion in the helical cavity in the
presence of 1.6 equivalent chlorides. At such a condition,
the NOE cross-peaks (Hb–Hc, Hc–Hd, Hd–He, He–Hf, Hf–Hg,
Hg–Hh) as shown in Figure 4 are strongly indicative of the
existence of a helical conformation of 2 while complexing
with one chloride ion (1:1 complexes). Besides, the NOE
correlations can also be observed between the protons locat-
ed at the adjacent helical turns, such as Hb–Hf and Hd–Hh,
providing another direct evidence for the folding.[24] To fur-
ther address the conformation of oligomer 2 binding two
chloride ions (1:2 complexes), we repeated the NOESY
measurements of 2 in the presence of 20 equivalents chlo-
ride ions. Under such conditions, the NOE correlations of
Hb–Hc, Hc–Hd, Hd–He, He–Hf, Hf–Hg and Hg–Hh were still
With these data at hand, we next explore the folding
properties of longer oligomer 2, which are expected to fold
into helical conformation with two turns, in principle, in the
presence of halide ions. The NMR titrations of 2 with chlo-
ride and bromide ions displayed totally different binding be-
haviors from those of 1. That is, the chemical shifts of amide
protons initially upshift upon titration of chloride ions up to
1.6 equivalence and then downshift while chloride ions
beyond 1.6 equivalence (Figure 3A and B). The inversion on
the chemical shift is indicative of two equilibria involved in
which oligomer 2 presumably first folded into a helical con-
formation in the assistance of one chloride ion, and then the
resulting foldamer is able to bind another chloride ion (Fig-
ure 3C). The similar inversions on the chemical shifts were
observed in an anion-macrocycle system by Hamilton.[22b,c]
In details, in the first process, the proton Hg upshift from
d = 11.41 to 10.91 ppm with a large Dd=À0.5 ppm (Fig-
ure 3B). The upfield shifts of amide protons are ascribed to
the ring-current effects arising from p-stacking within intra-
molecular aggregate. However, in the second process, all
protons of amide and triazole shift downfield dramatically,
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Receptors for Multiple Halide Ions
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sequently yield a ratio of the
average
hydromechanical
radius of 2 in the presence of
20 equivalents ClÀ to that in the
presence of 1.6 equivalent ClÀ
to be 1.34.[26] These results sug-
gest the foldamer
2 has to
extend its helical pitch to cer-
tain extent so as to release the
electrostatic repulsion originat-
ing from the two chloride ac-
commodated within the cavity.
Unfortunately, we did not
obtain the X-ray structure of 2
upon binding two chlorides, so
the detailed conformation of
1:2 complexes is unknown.
Therefore, we speculated
2
might adopt a loose helical or
an S-shape conformation, even
a dynamic equilibrium between
the helical and the S-shape con-
formation, to hold two chloride
ions.
The findings presented above
demonstrate that oligomer 2 is
able to host two chloride or
bromide ions. But K2 is too
small in comparison with K1 in
both cases. For example, K2 is
377 times lower than K1 in the
case of chloride ions. We antici-
pated that binding constants
could be enhanced while the
length of oligomer was in-
creased and the enhancement
would be more favorable for
K2. To test our hypothesis, the
longer oligomer 3, which theo-
retically bears three helical
turns, was designed and synthe-
sized. The binding behaviors
Figure 2. Partial 1H–1H NOESY spectra (600 MHz, [D5]Pyr, 298 K) of 1 in the absence of chloride ions (A)
and in the presence of 1.2 equivalent chloride ions (B). [1]=5 mm.
1
observed (Figure S58), providing a possibility that 2 still
exists in a helical conformation while complexing two chlo-
ride ions. However, the result of fitting analysis to the titra-
tion curve shows that, in the presence of 20 equivalents
chloride ions, the 1:2 complexes only take up 50 rather than
100% (Figure S39). Therefore, the observed NOE correla-
tions cannot guarantee 2 to adopt a helical conformation
upon complexing two chlorides because these NOE correla-
tions may also come from the 1:1 complexes. In order to ex-
tract detailed information from the NOE experiments, quan-
titative NOE calculation was conducted on 2 in the presence
of 1.6 and 20 equivalents chloride ions using the intensity
ratio method.[25,26] The molecular correlation times of 2 in
the presence of 1.6 and 20 equivalents ClÀ were calculated
to be 6.1ꢂ10À11 and 1.47ꢂ10À10 sÀ1, respectively, which sub-
were first investigated by H NMR in [D5]Pyr. Unexpected-
ly, 3 shows slight aggregation in [D5]Pyr (Figure S6). To cir-
cumvent this problem, NMR titrations of 3 were carried out
in 20:80 (v/v) [D6]DMSO/[D5]Pyr at ambient temperature.
The variations of chemical shifts of 3 upon titration of chlo-
ride ions also demonstrate an inversion (Figure 5 and S59)
similar to that of 2 in pure pyridine. That is, all of the amide
protons except BocNH undergo an upshift up to 5 equiva-
lents chloride ions, and then shift downfield beyond 5 equiv-
alents chloride ions. The overall titration data once again
fits well to a 1:2 binding model and the association constants
were determined to be 490mÀ1 for K1 and 38mÀ1 for K2. For
comparison, NMR titration experiments of 2 with chloride
ions were repeated under the condition of 20:80 (v/v)
[D6]DMSO/[D5]Pyr. The fitting analysis of the titration
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H. Jiang et al.
Figure 4. Partial 1H–1H NOESY spectra (600 MHz, [D5]Pyr, 298 K) of 2
(5 mm) in the presence of 1.6 equiv chloride ions.
Figure 3. A) Partial 1H NMR spectra changes of 2 in [D5]Pyr upon addi-
tion of chloride ions: a) 2, b) 2 + 1.6 equiv ClÀ, c) 2 + 40 equiv ClÀ.
1
B) Changes in the amide and triazole H chemical shift of 2 with increas-
ing chloride ions at ambient temperature. The data were curve-fitted to a
1:2 binding equilibrium model.[26] [2]=5 mm. C) Schematic representation
of the complexation process of 2 with chloride ions, involving oligomer 2
folded into a helical conformation upon complex with chloride and the
resulting foldamer further binds another chloride with folded but dynam-
ic structure.
Figure 5. Partial changes of 1H NMR of 3 in 20:80 (v/v) [D6]DMSO/
[D5]Pyr upon addition of chloride ions: a) 3, b) 3 + 5 equiv ClÀ, c) 3 +
40 equiv ClÀ. Measurements were taken at ambient temperature; [3]=
2 mm.
curves of 2 yields the values of K1 at 250mÀ1 and K2 at only
1.2mÀ1 (Figures S40–S42), which are much smaller than
those in pure pyridine (Table 1). This shrinkage of the bind-
ing constants originates from the overwhelming competition
of DMSO. On the other hand, we realized that the binding
constants of 3 are greater than those of 2 in the mixed sol-
vents supporting our hypothesis that the elongation on the
length of oligomers consequently lead to the enhancement
of binding constants at least in the present case, presumably
because of the presence of more available hydrogen binding
receptors for chloride ions. Additionally, it is worthy of note
that the ratio of K1/K2 for 3 to be 12.9 is 16 folded lower
than that of 2 to be 208. This means that increasing the
chain length of oligomer is more favourable for K2. An at-
tempt to interpret the conformation of oligomer 3 in the
presence of halide ions from NOESY experiments is unprof-
itable because of extensive overlaps of protons.
tween foldamers and the halide ions have not been investi-
gated in great details due to the lack of foldamer which
could complex halide ions in multiple binding models. In
this paper, we prepared a series of halide-induced oligo-
(phenyl-1,2,3-triazole-amide)s foldamers, the binding model
and affinity of which are dependent on the chain length and
media. The short oligomer 1 shows a 1:1 binding stoichiome-
try to the chloride, bromide and iodide ions. However, the
longer oligomers 2 and 3 were found to bind two chloride or
bromide ions. Quantitative NOE calculation results suggest
that, to accommodate the second halide ions, the foldamers
have to increase their helical pitch to release the electrostat-
ic repulsion between the halide ions bind to the foldamers.
Increasing the chain length of the oligomer can improve its
binding affinity for the chloride ions, especially for the
second one. We expect that these findings may help us to
design foldamers with a stable tube-like structure to bind
multiple halide ions in their cavity, thus serving as an artifi-
cial halide transmembrane channels.[27]
Conclusion
In the past decades, although foldamer-based molecular rec-
ognition has received extensive attention, the interaction be-
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Acknowledgements
We thank the Chinese Academy of Sciences “Hundred talents program”,
the National Natural Sciences Foundation of China (20772127 and
20972164) and the National Basic Research 973 Program of China
(Grant No. 2009CB930802) for financial support.
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Received: June 3, 2010
Published online: November 16, 2010
Chem. Eur. J. 2011, 17, 613 – 619
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
619