Anion Recognition by Aliphatic Helical Oligoureas

Article abstract of DOI:10.1002/chem.201602481

Anion binding properties of neutral helical foldamers consisting of urea type units in their backbone have been investigated.¹H NMR titration studies in various organic solvents including DMSO suggest that the interaction between aliphatic oligoureas and anions (CH₃COO^?, H₂PO₄^?, Cl^?) is site-specific, as it largely involves the urea NHs located at the terminal end of the helix (positive pole of the helix), which do not participate to the helical intramolecular hydrogen-bonding network. This mode of binding parallels that found in proteins in which anion-binding sites are frequently found at the N-terminus of an α-helix.¹H NMR studies suggest that the helix of oligoureas remains largely folded upon anion binding, even in the presence of a large excess of the anion. This study points to potentially useful applications of oligourea helices for the selective recognition of small guest molecules.

Full text of DOI:10.1002/chem.201602481

DOI: 10.1002/chem.201602481
Full Paper
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Oligourea Foldamers |Hot Paper|
Anion Recognition by Aliphatic Helical Oligoureas
Vincent Diemer+,[a, b, d] Lucile Fischer+,[a, b] Brice Kauffmann,[c] and Gilles Guichard*[a, b]
Abstract: Anion binding properties of neutral helical foldam-
ers consisting of urea type units in their backbone have
been investigated. 1H NMR titration studies in various or-
gen-bonding network. This mode of binding parallels that
found in proteins in which anion-binding sites are frequently
1
found at the N-terminus of an a-helix. H NMR studies sug-
ganic solvents including DMSO suggest that the interaction
gest that the helix of oligoureas remains largely folded upon
anion binding, even in the presence of a large excess of the
anion. This study points to potentially useful applications of
oligourea helices for the selective recognition of small guest
molecules.
À
between aliphatic oligoureas and anions (CH3COOÀ, H2PO4
,
ClÀ) is site-specific, as it largely involves the urea NHs located
at the terminal end of the helix (positive pole of the helix),
which do not participate to the helical intramolecular hydro-
Introduction
cules of various size and shapes also represent a remarkable
achievement.[4]
Helices in proteins and a-peptides are highly modular
secondary-structure elements that contribute to a wide range
of molecular-recognition events critical to biological functions.
Preorganization of a recognition motif through helical folding
to achieve selective interactions with target molecules is, how-
ever, not restricted to natural biopolymers. Foldamers have re-
cently made their way through to the field of molecular recog-
nition. Helical systems highly diverse in terms of backbones,
shapes, and appended functionalities can be created from
a large repertoire of monomers, thus opening new opportuni-
ties for receptor design and guest recognition.[1] Some recent
developments include the design of helical foldamers that in-
teract with protein surfaces and inhibit protein–protein interac-
tions[2] as well as the structural characterization of several fol-
damer–protein complexes at atomic resolution.[3] The design
and chemical evolution of helical foldamers with an internal
cavity or hollow interior for selective binding of small mole-
The development of foldamer-based receptors and channels
for anions is another area of active research.[5] This interest
stems from the importance of anion recognition and
transmembrane anion transport in living systems but also from
possible applications as stimuli-responsive materials. Anion-
binding properties have been demonstrated for a number of
aromatic oligomers equipped with hydrogen-bond donor
groups (e.g., oligoguanidiniums,[6] oligoindoles and oligoindo-
locarbazoles,[7] aromatic oligoureas,[8] and oligotriazoles[9]). In
most of these systems in which the main chain of the oligomer
is wrapped around the anion, the helical folding and anion rec-
ognition are coupled processes, that is to say, folding is largely
induced by the binding of the oligomer to the anion. In con-
trast, oligomers that adopt a stable helical secondary structure
on their own may provide anion-binding sites with a high level
of preorganization. In proteins for example, anion-binding sites
are often located at the amino terminus of an a-helix in which
the interaction with the positive pole of the helix dipole may
contribute to the anion stabilization in addition to contacts
with main chain amide NHs and some polar side chains (e.g.,
hydroxyl groups of Tyr and Ser).[10] In the case of anion chan-
nels (e.g., CLC chloride channels) this mode of anion recogni-
tion based on partial positive charges prevents the anion from
binding too tightly, and thus permits a high conduction rate.[11]
Anion–macrodipole interactions (as well as other less
common noncovalent interactions like halogen bonds and
anion–p interactions) are equally useful for the design of
synthetic ion transporters and other functional systems (e.g.,
catalysts).[12] Fine tuning of the anion-binding properties at the
positive end of a helix dipole can be achieved by using helical
backbones different from a-peptides in terms of helix parame-
ters and hydrogen-bond donor groups. Here, we have investi-
gated for the first time the anion-binding properties of a series
of helical urea foldamers by focusing on the effects of the
[a] Dr. V. Diemer,+ Dr. L. Fischer,+ Dr. G. Guichard
Universitꢀ de Bordeaux, UMR 5248 CBMN
Institut Europꢀen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac (France)
E-mail: g.guichard@iecb.u-bordeaux.fr
[b] Dr. V. Diemer,+ Dr. L. Fischer,+ Dr. G. Guichard
CNRS, UMR 5248 CBMN, 33607 Pessac (France)
[c] Dr. B. Kauffmann
Universitꢀ de Bordeaux, CNRS, UMS 3033, INSERM US001
Institut Europꢀen de Chimie et de Biologie
2 rue Robert Escarpit, 33607 Pessac (France)
[d] Dr. V. Diemer+
Present Address : UMR CNRS 8161, Pasteur Institute of Lille
Univ Lille, 1 rue du Professeur Calmette, 59021 Lille (France)
[+] Both authors contributed equally to the work.
Supporting information and ORCID(s) for the author(s) of this article can be
found under http://dx.doi.org/10.1002/chem.201602481.
Chem. Eur. J. 2016, 22, 1 – 10
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chain length and termination variations as well as on the
nature of the solvent (Scheme 1).
Scheme 1. Schematic principle of the backbone-mediated anionic guest
recognition by aliphatic oligourea helices.
The 2.5-helical structure formed by aliphatic N,N’-linked oli-
goureas[13] displays several features that make it suitable for
anion recognition as illustrated in Scheme 1: 1) Ureas and thio-
ureas have proven to be very effective hydrogen-bond donor
groups for the construction of very diverse synthetic anion re-
ceptors and transport systems ranging from a relatively simple
design,[14] to cyclohexane-based scaffolds,[15] macrocycles,[16]
capsules, and cages.[17] 2) The four urea NHs at the positive
end of the helix dipole do not participate in any intramolecular
H-bond interactions and are therefore available for the anion
recognition. 3) The geometry of the helix is well defined, thus
providing significant preorganization for anion recognition.
Scheme 2. Formulae of the N,N’-linked oligoureas O1–O5 used in this work.
Results and Discussion
Design and synthesis of oligourea helices
Five oligourea sequences (O1–O5) have been investigated in
this study, all containing residues with side chains of the pro-
teinogenic amino acids valine (Valu), alanine (Alau), and leucine
(Leuu, Scheme 2).
Scheme 3. Stepwise synthetic approach leading to oligoureas O1–O5
(DIEA=diisopropylethylamine).
They differ from one another either by the number of resi-
dues (O1, n=6; O2, n=9) or by their terminations (tert-butyl
carbamate, 4-bromophenyl-urea or (1H-indol-7-yl)urea at the
positive pole of the helix, and NHMe or 2-(azidomethyl)pyrroli-
dine (B) at the negative pole of the helix macrodipole). The
synthesis of O1 has been previously reported.[13b] All oligomers
were synthesized in solution according to the iterative method
shown in Scheme 3 using N-Boc protected activated mono-
mers A, C, and D.[13c,18] The synthetic pathway that involves
successive deprotection/coupling sequences allowed the intro-
duction of each residue of the oligomer in a stepwise and se-
quence-controlled manner. Final capping of the amino group
of the chain with either 4-bromophenylisocyanate or prop-1-
en-2-yl 1H-indol-7-ylcarbamate E[19] provided compounds O1,
O2, O4 and O5.[20]
The helical conformation of O1 was further confirmed in the
solid state by X-ray diffraction (XRD) analysis of crystals grown
in a mixture of nitromethane and DMSO (Figure 1).[20,21] The
structure shows a regular and complete network of intramolec-
ular 12- and 14-membered H bonds and compares well with
the crystal structure of the N-Boc protected precursor, the
structure of which was previously solved[18b] (Figure 1b).
Evidence for the chloride recognition at the positive pole of
the helix of O1
We first investigated the anionic recognition properties of the
2.5-oligourea helix in solution by using O1 as a representative
compound in the series and chloride as anion. The ability of
All oligomers were found to display spectroscopic features
1
1
(by H NMR and also by CD spectroscopy for O1 and O2) char-
O1 to bind anions was investigated by H NMR spectroscopy
acteristic of a helical conformation in solution (vide infra)[20]
.
in
a
mixture of [D6]DMSO/CD3CN 5:95 (v/v) as solvent.
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Figure 1. a) X-ray crystal structure of O1 (crystals grown in a 1:1 mixture of
nitromethane and DMSO) and b) overlay of the structures of O1 (carbon
atoms colored in light blue) and of the corresponding N-Boc protected pre-
cursor (CCDC 1026125,[18b] carbon atoms colored in beige). The RMSD (root-
mean-square deviation of atomic positions) for this alignment performed by
fitting the six pairs of b-carbons (CH(R) in the canonical units) is 0.246 ꢁ.
[D6]DMSO was added to overcome the low solubility of the
molecule in pure acetonitrile. Note that DMSO is also expected
to decrease the interaction with the anion, thus minimizing
a possible error when calculating the binding constants from
the experimental data. The sterically hindered and chemically
inert tetrabutylammonium countercation was selected to limit
possible interactions of the positive charge with the helix and
for solubility reasons.
The addition of increasing concentrations (up to 5.1 equiv)
of the anion to a solution of O1 was found to cause a signifi-
cant downfield shift of some but not all of the NMR signals of
the 14 urea NHs present in the molecule (Figure 2a). This
chemical shift variation is reflecting both a fast equilibrium be-
tween the free and bound forms of O1, and the magnitude of
the interaction for each urea NH. Homonuclear COSY, TOCSY,
and ROESY NMR experiments were required to unambiguously
assign all urea NHs at each step of the titration. Chemical shift
variations extracted from these NMR spectra are reported for
each NH proton in Figure 2b.
1
Figure 2. a) Part of the H NMR spectra (aromatic and NH protons) of O1
(2 mm) in the absence and in the presence of increasing concentrations of
tetrabutylammonium chloride. Data were recorded at 258C in a mixture of
[D6]DMSO/CD3CN (5:95, v/v). b) Chemical shift variations (Dd) of O1 NH pro-
tons upon addition of increasing amounts of tetrabutylammonium chloride.
NH protons are colored per urea function according to their position in the
sequence.
and NH3) were found to exhibit a shift upon chloride addition
similar to that of NH1’ and NH2 (Dd=0.28 and 0.31 ppm, re-
spectively). This observation is not necessarily in conflict with
an anion-binding mode involving only the first two ureas of
the oligomer as proposed. NH2’ and NH3 are H bonded to the
first urea moiety, which exhibits the highest affinity for the
chloride ion. The spectroscopic behavior of NH2’ and NH3
could, thus, rather result from the massive electronic changes
affecting this neighboring urea moiety.
It is noteworthy that the resonances of the NH protons
along the backbone are differentially affected by the presence
of the chloride guest. Marked downfield shifts (Dd) of 1.11 and
0.75 ppm were observed for the NH0 and NH1 protons (corre-
sponding to the terminal urea close to the positive pole of the
helix), respectively. This variation was less important in the
case of NH1’ and NH2 (Dd=0.28 and 0.31 ppm, respectively).
Although all four protons are in principle available to partici-
pate to the anion-recognition process, the data qualitatively
suggest that the interaction of chloride with the diurea recog-
nition site of O1 is unsymmetrical and the binding event ap-
pears to be more centered on the first urea function. Chemical
shifts of the protons of the ureas 4–7 (i.e., NH3’, NH4, NH4’,
NH5, NH5’, NH6, NH6’, and NH7) did not shift significantly
(Dd<0.08 ppm) upon chloride addition in agreement with the
binding mode we proposed. When the oligomer is folded, the
protons of the ureas 3–7 are expected to be engaged in a net-
work of ten C=O···HN bonds that maintain the overall foldamer
helical conformation, thus precluding interactions with the
anionic guest. However, the signals of the NHs of urea 3 (NH2’
Examination of the 1H NMR spectra also showed that the
aromatic signals of O1 are similarly affected by the addition of
chloride (Figure 3). There is an inversion of the AB system de-
1
tected by H NMR spectroscopy around 7.37 ppm at low chlo-
ride concentrations, and an increase of the splitting between
the two signals of the AB system at higher concentrations. This
splitting reflects the different electronic properties of the sub-
stituents in the 1 and 4 positions of the aromatic ring, namely
the first urea function of the helix and the bromine atom. As
previously discussed, anion binding to the helix substantially
modifies the electronic properties of the terminal urea func-
tion. It is noteworthy that the experimental splitting variation
of the AB system and the downfield shift of NH0 with chang-
ing concentrations of the anion are nearly superimposable.[20]
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Table 1. Binding constants (Ka) of anionic guests to O1 in [D6]DMSO/
CD3CN (5:95, v/v) measured by 1H NMR titrations at 258C for NH0, NH1,
and the aromatic protons ArÀH.[a]
[b]
Protons
monitored
Ka of anions [mÀ1
]
CH3COOÀ
À
ClÀ
H2PO4
NH0
2400
3700
3500
3300
log(b1)=5.7[d]
log(b2)=9.8
log(b1)=5.0[d]
log(b2)=8.5
log(b1)=5.9[d]
log(b2)=9.9
NH1
2900
1700
ArÀH[c]
[a] Errors are estimated to be <10%. [b] Anions added as tetrabutylam-
monium salts. [c] Splitting between the two signals of the AB system was
monitored during the titration. [d] Chemical shift data were fitted to a 1:2
binding model. b1 =K11 (binding constant of one anionic guest), b2 =
K11K12 (binding constant of two anionic guests).
1
Figure 3. Overlay of the aromatic region of the H NMR spectra of O1 in the
absence and in the presence of increasing concentrations of tetrabutyl-
ammonium chloride. Data were recorded at 208C in a [D6]DMSO/CD3CN mix-
ture (5:95, v/v).
concentrations. Additional information about the extent of the
helical perturbation or stabilization induced by the presence of
1
These complex-induced shifts can be interchangeably used as
a reporter to monitor the anionic recognition process taking
place exclusively at the helix terminus.
anions was gained from further analyses of the H NMR spec-
tra. When placed in a helical environment, the main-chain
methylene protons of a given residue exhibit a high degree of
anisochronicity, which can be used as an empirical parameter
to locally interrogate the helicity of the oligomer. The aniso-
chronicity values were extracted for each residue from the
1H NMR spectra of O1 measured at increasing anion concentra-
tions and compared to the corresponding values for anion-free
O1 (Table 2). These values are only slightly affected by the ad-
Job plot analysis reveals a maximum at an equimolar ratio
of O1 and tetrabutylammonium chloride, confirming the 1:1
binding stoichiometry of the interaction (Figure 4). The stability
of the complex was, thus, determined by fitting the titration
data for NH0, NH1, and the aromatic protons to a 1:1 binding
Table 2. Anisochronicity of the backbone geminal aCH2 protons in O1
(Res 1–6) with increasing concentrations of tetrabutylammonium
chloride.
Anion [equiv]
Dd [ppm][a]
Res 3 Res 4
Res 1
Res 2
Res 5
Res 6
0
1.04
0.92
0.99
–
1.26
1.21
1.24
1.22
1.31
1.26
1.32
1.30
1.25
1.23
1.24
1.22
1.35
1.33
1.33
1.33
1.12
1.12
1.08
–
0.7
2.0
5.5
[a] Determined by 1H NMR spectroscopy at 208C in
a mixture of
[D6]DMSO/CD3CN (5:95, v/v).
1
Figure 4. Job plot for the binding of O1 with NBu4Cl determined by H NMR
in a mixture of [D6]DMSO/CD3CN 5:95 at 208C ([anion]+[oligourea]=5 mm).
The results are given based on the chemical shift variation Dd of NH0, NH1,
NH1’, and NH2.
dition of chloride (up to 5.5 equivalents), suggesting that the
organization of the binding site and the 2.5-helical conforma-
tion are largely maintained during the anion-recognition pro-
cess.
model using the WinEQNMR2 program.[22] The resulting Ka
values in the range 1700–2900mÀ1 (Table 1) support a predomi-
nant interaction of the chloride with the first urea moiety in
O1. Corresponding binding constants calculated from NH1’
and NH2 are reduced by a factor of 17.[20]
Overall, these NMR data are consistent with an interaction
between the oligomer and the chloride anion taking place at
the end of the main chain, in which the four free NHs corre-
sponding to the first two urea linkages are located. The dis-
symmetry of the binding site that seems to be rather centered
on the first urea group is likely to reflect the intrinsically lower
pKa value of the aryl-substituted urea moiety.[23]
As already mentioned, the signals of the protons corre-
sponding to those urea functions involved in the helical
H-bond network are hardly influenced by the presence of tet-
rabutylammonium chloride, which suggests that the helical
conformation is only weakly modified upon increasing anion
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Anion recognition properties of O1
We next screened a variety of other anions for binding to O1
to evaluate how the affinity and the binding mode are affected
by the nature of the anion. Figure 5 shows an overlay of the
1
Figure 5. Part of the H NMR spectra (NH region) of oligomer O1 (2 mm) in
the presence of 1 equiv of different tetrabutylammonium salts NBu4X
(X=ClO4À, NO3À, BrÀ, ClÀ, H2PO4À,AcOÀ, and PhCOOÀ). H NMR data were
1
recorded at 208C in a mixture of [D6]DMSO/CD3CN (5:95, v/v).
Figure 6. Chemical shift variations (Dd) of O1 NH protons upon addition of
increasing amounts of tetrabutylammonium salts with a) AcOÀ and
b) H2PO4À as anions. Data were recorded at 258C in a [D6]DMSO/CD3CN mix-
ture (5:95, v/v). NH protons are colored per urea function according to their
position in the sequence.
1H NMR (NH region) spectra recorded for a solution of O1 in
[D6]DMSO/CD3CN (5:95, v/v) in the absence and in the pres-
ence of one equivalent of the TBA salts of ClO4À, NO3À, BrÀ,
ClÀ, H2PO4À, AcOÀ, and PhCOOÀ. The complexation-induced
downfield shift of the NH0 resonance that is easily identified
on all spectra (dꢀ8.5 ppm in the absence of an anion) was
found to be strongly dependent on the nature of the anion
and was used to examine the general anion-binding behavior
The binding mode appears to be more complex in the case
of H2PO4À, which shows a marked downfield shift of the NH1’
and NH2 resonances (Dd=1.33 and 1.28 ppm, respectively) in
addition to strong shifts of the NH0 and NH1 signals (Dd=
2.05 and 1.64 ppm, respectively), revealed by NMR titration
curves (Figure 6b).
of O1.
À
The anions can be classified in two groups. Those like ClO4
,
NO3À, and BrÀ that induce no or only a weak downfield shift of
the NH0 signal (and all other urea resonances in the oligomer)
are likely to be poor anionic guests. The complexation-induced
shift of the NH0 signal (and some other NH resonances) upon
Job plot analysis[20] suggests the formation of a 1:2 complex
with two phosphate molecules bound to O1, which confirms
that the first two ureas in the sequence are both involved in
the binding process. The stability constants of each equilibrium
step, expressed as log(K11) and log(K12), were estimated by fit-
ting the titration curves of NH0, NH1, NH1’, and the aromatic
protons to a 1:2 model with WinEQNMR2. The best fit was ob-
tained by using the splitting variation of the AB system, which
gave log(K11)=5.9 and log(K11K12)=9.9 for the binding of one
and two anions, respectively. The log(K12) for the second
the addition of chloride, phosphate, acetate, and benzoate
À
salts is much more pronounced in the order C6H5CO2
>
CH3CO2À >H2PO4À >ClÀ. The NMR titration curves upon addi-
tion of the acetate salt (Figure 6a) were reminiscent of those
obtained for chloride (Figure 2b) with a strong downfield shift
of both NH0 and NH1 resonances (d=2.28 and 2.16 ppm, re-
spectively) and moderate complexation-induced shifts of the
NH1’ and NH2 resonances (d=0.46 and 0.39 ppm, respective-
ly), which suggests a mode of binding centered on the first
urea. The binding constant Ka (ꢀ3300–3700mÀ1) that is calcu-
lated by fitting the experimental titration data for NH0, NH1,
and the aromatic protons to a 1:1 binding model indicated
that the terminal urea function of the oligomer O1 has a slight-
ly higher affinity for AcOÀ than for ClÀ (Table 1). A CD analysis
of O1 in MeCN and in the presence of increasing amounts of
tetrabutylammonium acetate (up to 8 equiv) confirmed that
the oligomer remains largely folded upon anion binding.[20]
À
H2PO4 therefore equals log(K11K12)Àlog(K11)=4.
Chain-length effect on anion recognition
The length of the main chain is an important parameter that
may influence the ability of the terminal end of the helix to
bind anions. The folding propensity of oligoureas is known to
increase with their chain length,[13c,24] yet it is not clear whether
this is accompanied by a local rearrangement of the anion-
binding site. In addition, the helix dipole is expected to in-
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crease with the length of the helix, which would suggest
a more favorable contribution to the anion binding of longer
oligomers. To evaluate this effect, we have prepared O2, a non-
amer with one additional ValuAlauLeuu repeat for direct com-
parison with O1. The lower solubility of O2 precluded the use
of CD3CN/[D6]DMSO (95:5, v/v) and we decided to use
[D6]DMSO to compare the two sequences. Because conforma-
tional variations imposed by the solvent may affect the anion-
binding site of O1 and the recognition process, we have first
evaluated whether the ability of O1 to fold and to bind chlo-
ride was maintained in a more competitive solvent such as
DMSO. Previous studies have shown that the 2.5-helix folding
propensity of oligoureas, though more populated in apolar or
weakly polar solvents, is largely maintained in more polar
ones.[24b] The anisochronicity values measured for the diaste-
reotopic protons within O1 in [D6]DMSO are reported in
Table 3 and were found to be significantly smaller than those
measured in CD3CN/[D6]DMSO (95:5), indicating some pertur-
bation of the helical conformation. Helix fraying appears to be
more pronounced at the helix terminus in which the anion-
binding site is located.
Table 4. Binding constants (Ka) of anionic guests to O1, O2, and O5
1
measured by H NMR titrations at 258C.[a]
[c]
Compound
Anion[b]
Ka [mÀ1
]
CD3CN/[D6]DMSO[d]
[D6]DMSO
O1 (6-mer)
O2 (9-mer)
O5 (6-mer)
O5 (6-mer)
ClÀ
2400 (2900)
89[h]
[e]
ClÀ
–
140[i]
ClÀ
AcOÀ
>10000[f]
212 (222)[j]
3800 (4200)[k]
[g]
–
[a] Errors are estimated to be <10%. [b] Anions added as tetrabutylam-
monium salts. [c] Ka was calculated by fitting the titration data (NH0) to
a 1:1 binding model (binding constant calculated from NH1 data in
brackets). [d] [D6]DMSO/CD3CN (5:95, v/v). [e] Not soluble. [f] Ka value has
to be considered with caution as it is above the upper determination
limit. [g] The titration data (NH0 and NH1) gave a sigmoidal curve that
could not be fitted to a suitable binding model. [h] Ka calculated from the
variation of the aromatic proton splitting is 49mÀ1. [i] Ka calculated from
the variation of the aromatic proton splitting is 107mÀ1. [j] Ka calculated
by fitting of the titration data for the indole NH is 217mÀ1. [k] Error are
estimated to be ꢀ15%.
second urea linkage of O1 to the anion-binding process, we
analyzed oligomer O3 in which the 4-bromophenyl-urea group
has been replaced by a tert-butyl carbamate. To maximize the
anion-binding properties of O3 we performed titrations in
CD3CN. The 2-(azidomethyl)pyrrolidine residue at the other
helix end was introduced to increase the solubility in CD3CN
and facilitate the determination of a binding constant. This
structural change has no significant effect on the helicity at
the recognition site.[20,25] The signals of the urea NHs between
residues 1 and 2 (i.e., NH1’ and NH2) were strongly downfield
shifted upon titration of O3 with tetrabutylammonium acetate
(Dd=2.21 ppm for NH1’ and Dd=2.06 ppm for NH2), thus in-
dicating a site for anion binding at the helix end. The NH1
(Boc protected) protons were only moderately involved in the
recognition process (Dd=0.64 ppm). The titration curves of
NH1’ and NH2 were nicely fitted to a 1:1 binding model[20] and
gave a binding constant Ka of roughly 830mÀ1. For a direct
comparison, we titrated O4 under the same conditions. As ex-
pected, the signals of NH0 and NH1 were downfield shifted to
a higher extent than those of NH1’ and NH2, and the affinity
constants calculated by fitting these curves to a 1:1 binding
model (Ka =22000mÀ1 from the NH0 and NH1 data) were
higher than those calculated for O3 by more than one order of
magnitude.[20] This increased affinity of acetate for O4 com-
pared to O3 is also evident when comparing the binding con-
stants calculated for the second urea (Ka =11000mÀ1 and
4500mÀ1 from NH1’ and NH2 in O4, respectively). Overall,
The hexaurea O1 was then titrated with increasing amounts
of tetrabutylammonium chloride in [D6]DMSO.[20] Although the
chemical shift variations of the NH protons are much smaller
than in CD3CN containing 5% [D6]DMSO, the observed trend
was the same; the NH0 and NH1 protons show a more pro-
nounced downfield shift, which suggests that the anion-bind-
ing mode is conserved. As expected, the binding constant cal-
culated from the NMR-chemical-shift data using NH0 (Ka =
89mÀ1) was significantly smaller in DMSO (Table 4). The aniso-
chronicities measured in residues 1–5 of O2 (Table 3) match
those in O1, which indicates that the binding site at the helix
end is unlikely to be modified (i.e., rigidified) upon chain
lengthening. Titration curves were similar to those of O1,[20]
which suggests that the anion-binding mode is also conserved.
The binding affinity of O2 for chloride was also calculated by
fitting the titration curves using NH0 and was found to be
more than 1.5 fold higher (Ka =140mÀ1), consistent with a role
of the helix dipole in the anion-recognition process (Table 4).
Influence of the end group on anion recognition
Studies with O1 and O2 revealed a key role of the first urea
group in the binding of anions, with NH0 and NH1 signals
showing the most pronounced downfield shifts upon anion ti-
tration. To more specifically investigate the contribution of the
Table 3. Anisochronicity of the backbone geminal aCH2 protons in O1 and O2.
Compound
Solvent
Dd [ppm][a]
Res 1
Res 2
Res 3
Res 4
Res 5
Res 6
Res 7
Res 8
Res 9
O1
O1
O2
[D6]DMSO/CD3CN[b]
[D6]DMSO
1.04
0.59
0.60
1.26
0.92
0.88
1.31
1.19
1.18
1.25
1.19
1.28
1.35
1.20
1.26
1.12
0.88
1.37
–
–
1.20
–
–
1.23
–
–
0.82
[D6]DMSO
1
[a] Determined by H NMR spectroscopy at 208C. [b] [D6]DMSO/CD3CN (5:95, v/v).
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these data show that the more acidic protons of the first urea
group largely dictate the recognition process and confirm the
dissymmetry of the anion-binding site in O1.
We next sought to further modify the anion-binding site of
the oligoureas by replacing the terminal 4-bromophenyl-urea
moiety by a capping group that could directly participate to
the anion-binding process. We selected 1H-indol-7-yl-urea
based on earlier work from Gale and coworkers, which showed
that such derivatives have excellent anion-binding properties
including an enhanced ability to bind oxo anions,[14b,26] and
therefore prepared oligomer O5. The anion-binding properties
of O5 were first studied by NMR spectroscopy in CD3CN/
[D6]DMSO (95:5, v/v). The examination of the titration curves
with tetrabutylammonium chloride shows that the NH signals
of the first three ureas (i.e., NH0, NH1, NH2’, and NH3;
NH1’and NH2 to a lesser extent) and the indole NH all shift
downfield and reach a plateau upon addition of 1 equiv of
chloride, thus suggesting a contribution of all these NHs in the
binding process. Fitting the titration data for these NHs to
a 1:1 binding mode revealed that O5 binds chloride strongly
with a stability constant (Ka >104 mÀ1) about 4–5 fold higher
than O1 in the same solvent mixture (Table 4). The increased
binding of O5 to chloride compared to O1 was also confirmed
in [D6]DMSO (see Figure 7a for the titration data) with a calcu-
lated constant of Ka =212mÀ1 (NH0). Similarly, O5 was found to
tightly bind to tetrabutylammonium acetate (see Figure 7b for
the titration data) with an estimated binding constant of Ka =
3800mÀ1 (NH0) in [D6]DMSO (Table 4).
Figure 7. Chemical shift variations (Dd) of O5 NH protons upon addition of
increasing amounts of tetrabutylammonium salts with a) ClÀ and b) AcOÀ as
anions. Data were recorded at 258C in [D6]DMSO. NH protons are colored
per urea function according to their position in the sequence.
Structural insight into the recognition properties of the
oligoureas
Attempts to grow crystals of the anion complexes of the oli-
goureas and elucidate their structure by XRD have failed thus
far. The engagement of the first two ureas in the anion binding
as well as the presence of the counter ion are believed to pre-
vent the ability of oligourea helices to pack axially by H bonds
as usually observed in the crystals of oligoureas grown in or-
ganic solvents. However, single crystals of O1 and O5 suitable
for XRD were grown from CH3CN/DMSO and DMSO solutions.
The structures determined by XRD analysis (Figure 8) reveal
that one solvent molecule is bound to the anion-binding site
at the terminus of the fully folded helical structure.[20,21] In the
case of the O1·DMSO solvate (Figure 8a), the DMSO molecule
is hydrogen bonded to NH0 and NH1 (N···O distances of 2.878
and 3.078 ꢁ, respectively) whilst NH1’ and NH2 of the second
urea group are each intermolecular H bonded to one of the
last two carbonyl groups of a second helix (Figure 8c). The
structure of O5 shows that the binding site at the end of the
helix is significantly remodeled by the indole group, the nitro-
gen of which points towards the helix interior (Figure 8b). The
sulfoxide oxygen in the solvate of O5 is engaged in three hy-
drogen bonds with the NHs (NH1’ and NH2) of the second
urea (N···O distances of 3.089 ꢁ and 2.973 ꢁ, respectively) and
of the indole (N···O distance of 2.893 ꢁ). The NHs of the first
urea are now engaged in intermolecular bonds with the penul-
timate carbonyl group of a neighboring helix. Altogether,
Figure 8. (a,b) X-ray crystal structures of a) O1·DMSO and b) O5·DMSO sol-
vates. (c,d) Details of the intermolecular H bonds formed between c) two
helices of O1 and d) two helices of O5. The C atoms defining the anion-
binding site at the positive pole of the helix dipole are shown in green.
these two structures give some useful information about possi-
ble ways to modulate the geometry of the binding site as well
as some molecular insight into host–guest interactions at the
helix terminus. However, the structures of the DMSO solvates
in the solid state reported herein only imperfectly account for
host–guest interactions in solution, because half of the binding
sites are used to pack and align the helices in the crystal.
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ous conditions, thus, expanding the range of possible applica-
tions of these foldamers. In particular, the tight binding of
phosphate to O1 may suggest a complementary mechanism
to account for the remarkable interaction properties of anti-
microbial oligourea helices with negatively charged model
phospholipid membranes as well as bacterial membranes.[28a,32]
Conclusion
The recognition properties of aliphatic N,N’-linked oligoureas,
like other peptidomimetic foldamers,[2a,b,27] can be easily tuned
by projection of requested side chains at the surface of the
helix in a sequence-dependent manner.[28] In this work, we
have shown that the 2.5-helical oligourea backbone possesses
intrinsic features that make it useful as a receptor for small
guest molecules. The NMR titration studies in solvents ranging Acknowledgements
from the moderately polar CD3CN to the more competitive
DMSO reported herein, reveal for the first time the ability of
N,N’-linked oligourea foldamers to interact with various anions
(oxyanions and halides) as well as some details about possible
binding modes. The proton signals corresponding to the termi-
nal urea moieties located at the positive pole of the helical
macrodipole experience marked downfield shifts upon titration
with the different anions (as their tetrabutylammonium salt).
This trend confirms the hypothesis of a preorganized anion-
binding site at the terminal end of the helix. Indeed, the struc-
tures at atomic resolution of the 2.5-helix of oligoureas shows
that the four NHs of the first and second urea groups are not
involved in intramolecular H bonding and are, thus, free to in-
teract with guest molecules (see Figure 1). Calculations from
the titration curves suggest that the selectivity, the affinity, and
the anion-binding mode can be finely tuned by varying the
nature of the capping group and through further differentia-
tion of the two urea moieties forming the binding site (e.g., by
increasing the acidic strength). These findings pave the way
for new developments of aliphatic oligourea helices in areas
such as chiral ion recognition, sensing, anion transport, and
catalysis.[12a,16d,29] One noteworthy example in this direction is
the recent finding that a screw-sense preference may be in-
duced in achiral meso-oligourea helices by selective formation
of a 1:1 hydrogen-bonded complex with a chiral carboxylate
anion.[30]
This work was supported by the CNRS, the University of Bor-
deaux (UB), the Conseil Regional d’Aquitaine (Project
#20091102003), the Agence Nationale de la Recherche (ANR-
10-RPDOC-016), and UREkA Sarl. The crystallographic data
have been collected at the IECB X-ray facility (UMS3033, CNRS
and UB, US001 INSERM). We thank Axelle Grꢂlard and Estelle
Morvan for their assistance with all NMR measurements.
Keywords: anions · foldamers · helical structures · oligourea ·
X-ray diffraction
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Received: May 24, 2016
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FULL PAPER
&
Oligourea Foldamers
V. Diemer, L. Fischer, B. Kauffmann,
G. Guichard*
&& – &&
Anion Recognition by Aliphatic Helical
Oligoureas
Free to interact! The four backbone
urea NHs located at the positive pole of
homo-oligourea helices are ideally
preorganized to interact with anionic
guests. 1H NMR titration studies with
various anions reveal that binding to
oligoureas is site-selective and does not
cause a helix unfolding. This anion-
binding mode is reminiscent of that
observed in proteins in which anion-
binding sites are frequently found at
the N-terminus of an a-helix.
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