Helically foldable diphenylureas as anion receptors: Modulation of the binding affinity by the chain length

Article abstract of DOI:10.1021/ol302266w

Using a series of diphenylureas capable of folding to helical conformations, the binding trends have been compared between two anions of different sizes, chloride and sulfate. The binding constant for the sulfate ion steadily increases from monomer to pen

Full text of DOI:10.1021/ol302266w

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5042–5045
Helically Foldable Diphenylureas as Anion
Receptors: Modulation of the Binding
Affinity by the Chain Length
Min Jung Kim,† Hye-Won Lee,† Dohyun Moon,*,‡ and Kyu-Sung Jeong*,†
Department of Chemistry, Yonsei University, Seoul 120-749, South Korea, and Pohang
Accelerator Laboratory, San 31 Hyoja-Dong, Nam-Gu, Pohang, KyungBuk 790-784,
South Korea
dmoon@postech.ac.kr; ksjeong@yonsei.ac.kr
Received August 15, 2012
ABSTRACT
Using a series of diphenylureas capable of folding to helical conformations, the binding trends have been compared between two anions of
different sizes, chloride and sulfate. The binding constant for the sulfate ion steadily increases from monomer to pentamer as the chain length
increases, but for the chloride ion it increases up until the trimer and then reaches a plateau.
Anion recognition chemistry has been an active area of
research for the past two decades, which includes the
synthesis and characterization of anion receptors, sensors,
transporters, and anion-induced assemblies.1 Anion recog-
nition was mostly based on H-bonding interactions, for
which amide and urea groups were frequently incorpo-
rated to synthetic anion receptors. Wilcox et al.2 and
Hamilton et al.3 demonstrated for the first time that
(thio)ureas could form strong H-bonds with oxoanions
such as carboxylates, sulfates, and phosphates. Since then,
a large number of urea-based anion receptors4,5 that
contain two or more urea groups to achieve multiple
H-bonds with target anions for the enhanced affinity and
selectivity has been reported.
(5) For selected recent examples of urea-based anion receptors, see:
ꢀ
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Yang, X.-J. Angew. Chem., Int. Ed. 2011, 50, 486–490. (e) Li, S.; Jia, C.;
Wu, B.; Luo, Q.; Huang, X.; Yang, Z.; Li, Q.-S.; Yang, X.-J. Angew.
Chem., Int. Ed. 2011, 50, 5721–5724. (f) Fremaux, J.; Fischer, L.;
Arbogast, T.; Kauffmann, B.; Guichard, G. Angew. Chem., Int. Ed.
2011, 50, 11382–11385. (g) Medda, A. K.; Park, C. M.; Jeon, A.; Kim,
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† Department of Chemistry, Yonsei University.
‡ Pohang Accelerator Laboratory.
(1) (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor
Chemistry; Royal Societyof Chemistry: Cambridge, U.K., 2006.
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r
10.1021/ol302266w
Published on Web 09/17/2012
2012 American Chemical Society

Herein, we have designed a synthetically more accessible
scaffold, a diphenylurea derivative 3, that possesses the same
H-bonding motif with two predecessors (Figure 1). Using this
new scaffold, we have prepared a series of diphenylureas 4ꢀ8
which consist of one to five diphenylurea moieties, together
with two hydroxyl groups at the ends. Diphenylureas 4ꢀ8
bind anions such as chloride and sulfate by multiple H-bonds,
and the affinity increases as the chain length increases. There
is however a noticeable difference in the increasing trend of
the binding affinity between anions. For the small chloride
ion, the association constant largely increases up until trimer
6 and then becomes nearly saturated, but for the large sulfate
ion it steadily increases up to pentamer 8.
The diphenylurea repeating units are linked through
rod-like ethynyl spacers to prevent intramolecular H-bonds
that often exist in oligourea-based anion receptors, thus
reducing the association constants. It should be noted that
the ethynyl spacer has been frequently used for the elonga-
tion of abiotic aryl foldamers because of the conformational
simplicity and low energy barrier for folding.6,7 The synth-
eses of diphenylureas 4ꢀ8 are summarized in Scheme 1.
4-tert-Butylaniline (1) was reacted with iodine in the pre-
sence of silver sulfate10 to give 4-tert-butyl-2-iodoaniline (2)
which was treated with triphosgene under basic conditions11
to afford N,N0-di(4-tert-butyl-2-iodophenyl)urea (3). Using
this new repeating scaffold, diphenylureas 4ꢀ8 were derived
by sequential Sonogashira reactions12 as described in the
Supporting Information (SI).
Figure 1. Comparison of hydrogen bonding patterns of (a)
biindole, (b) indolocarbazole, and (c) diphenylurea units.
Compared with cyclic analogues, acyclic receptors in
general show relatively weak binding affinities due to a
larger entropy penalty upon the complex formation. This
disadvantage could be in part mitigated if the acyclic
receptors can adopt a (semi)stable ordered conformation,
which in turn creates a binding cavity capable of accom-
modating a target guest. In this context, synthetic acyclic
oligomers which fold to ordered arrays such as helices have
been prepared and utilized as synthetic receptors.6,7 We were
Computer modeling studies have showed that, in the
presence of the sulfate ion, diphenylureas 5ꢀ8 adopt
Scheme 1. Synthesis of 4ꢀ8
(6) For recent reviews of foldamer, see: (a) Hill, D. J.; Mio, M. J.;
Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893–
4012. (b) Hecht, S., Huc, I., Eds. Foldamers: Structure, Properties, and
Applications; Wiley-VCH: Weinheim, Germany, 2007. (c) Li, Z.-T.; Hou,
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3977. (f) Juwarker, H.; Suk, J.-m.; Jeong, K.-S. Chem. Soc. Rev. 2009, 38,
3316–3325. (g) Juwarker, H.; Jeong, K.-S. Chem. Soc. Rev. 2010, 39,
3664–3674.
(7) For foldamer-based anion receptors, see: (a) Juwarker, H.;
Lenhardt, J. M.; Pham, D. M.; Craig, S. L. Angew. Chem. 2008, 120,
3800–3803. Angew. Chem., Int. Ed. 2008, 47, 3740–3743. (b) Meudtner,
R.; Hecht, S. Angew. Chem. 2008, 120, 5004–5008. Angew. Chem., Int.
Ed. 2008, 47, 4926–4930. (c) Xu, Y.-X.; Wang, G.-T.; Zhao, X.; Jiang,
X.-K.; Li, Z.-T. J. Org. Chem. 2009, 74, 7267–7273. (d) Zhao, X.; Li,
Z.-T. Chem. Commun. 2010, 46, 1601–1616. (e) Wang, Y.; Bie, F.; Jiang,
H. Org. Lett. 2010, 12, 3630–3633. (f) Hua, Y.; Flood, A. H. J. Am.
Chem. Soc. 2010, 132, 12838–12840. (g) Wang, Y.; Xiang, J.; Jiang, H.
Chem.;Eur. J. 2011, 17, 613–619. (h) McDonald, K. P.; Hua, Y.; Lee,
S.; Flood, A. H. Chem. Commun. 2012, 48, 5065–5075. (i) Haketa, Y.;
Bando, Y.; Takaishi, K.; Uchiyama, M.; Muranaka, A.; Naito, M.;
Shibaguchi, H.; Kawai, T.; Maeda, H. Angew. Chem., Int. Ed. 2012, 51,
7967–7971.
(8) (a) Chang, K.-J.; Kang, B.-N.; Lee, M. H.; Jeong, K.-S. J. Am.
Chem. Soc. 2005, 127, 12214–12215. (b) Kim, U.-I.; Suk, J.-m.; Naidu,
V. R.; Jeong, K.-S. Chem.;Eur. J. 2008, 14, 11406–11414.
(9) (a) Suk, J.-m.; Jeong, K.-S. J. Am. Chem. Soc. 2008, 130, 11868–
11869. (b) Kim, J.-i.; Juwarker, H.; Liu, X.; Lah, M. S.; Jeong, K.-S.
Chem. Commun. 2010, 46, 764–766. (c) Suk, J.-m.; Kim, J.-i.; Jeong,
K.-S. Chem.;Asian J. 2011, 6, 1992–1995.
(10) (a) Sy, W.-W. Synth. Commun. 1992, 22, 3215–3219. (b) Lindsay,
D. M.; Dohle, W.; Jensen, A. E.; Kopp, F.; Knochel, P. Org. Lett. 2002,
4, 1819–1822.
(11) Hiscock, J. R.; Caltagirone, C.; Light, M. E.; Hursthouse, M. B.;
Gale, P. A. Org. Biomol. Chem. 2009, 7, 1781–1783.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
also interested in the development of synthetic anion recep-
tors based on acyclic linear oligomers such as oligoindoles8
and oligoindolocarbazoles.9 These oligomers could fold to
helical conformations to form multiple H-bonds with an-
ions. An obstacle was the multistep synthesis of the repeating
units, a biindole and an indolocarbazole.
ꢀ
1975, 16, 4467–4470. (b) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,
874–922.
Org. Lett., Vol. 14, No. 19, 2012
5043

helically coiled structures by the rotation of CꢀC bonds
around ethynyl spacers (SI). For example, dimer 5 exists in
an extended S-shaped conformation but folds into a coiled
conformation upon binding a sulfate ion. Similarly, longer
oligomers 6ꢀ8 exist in extended random conformations in
the absence of an anion but adopt distorted helical struc-
tures wherein all of the existing NHs and OHs are simul-
taneously involved in H-bonding with a sulfate ion.
To find the binding mode in the solid state, we made
numerous attempts of crystallization with various combi-
nations of diphenylureas and anions. Fortunately, we
obtained single crystals of complex 5•(Bu4N)2SO4 by slow
diffusion of hexane to a CH2Cl2/hexane solution contain-
ing 5 (2.0 mM) and (Bu4N)2SO4 (1.2 equiv). As shown in
Figure 2, the sulfate ion is located in the middle of the
Table 1. Complexation-Induced Shifts (CIS, Δδ(ppm) =δcomplex
free) of 1H NMR signals for OHs and NHsa in 10% (v/v) CD3CN/
CD2Cl2 at 25 °C
ꢀ
δ
anion host OH NH(1) NH(2) NH(3) NH(4) NH(5)
Clꢀ
4
5
6
7
8
4
5
6
7
8
2.03
1.57
1.53
0.56
0.47
3.48
3.38
1.87
1.80
1.24
1.22
1.15
2.37
2.78
3.00
2.98
2.97
0.96
1.17
1.46
1.05
0.89
1.27
1.05
0.89
0.87
0.57
0.68
2ꢀ
SO4
2.12
1.84
2.82
2.55
b
ꢀ
1.73
b
b
b
ꢀ
ꢀ
ꢀ
b
ꢀ
2.51
1.15
cavity, forming two OH O (sulfate) and four NH
(sulfate) hydrogen bonds. Among them, two hydroxyl
O
a Numbering of NH signals in 4 to 8 was assigned from center NH(1)
3 3 3
3 3 3
to terminal NH(n). b 1H NMR signals were broaden out on the baseline.
groups and three urea protons form normal H-bonds with
˚
˚
distances of 2.67 and 2.69 A for O O and 2.72ꢀ2.84 A
3 3 3
middle of the helical strand and therefore the outer OH
and NH protons are distanced away from the entrapped
anion, forming relatively weak H-bonds in longer oligomers.
Third, the CIS values of NH protons in pentamer 8 by
chloride binding were smaller than those of the correspond-
ing NH protons in shorter ones, but they were comparable in
the case of the sulfate ion. A plausible explanation is that the
relative strength of the individual H-bond may decrease
when multiple H-bonds form with a small monatomic
anion, possibly due to electrostatic repulsions between
adjacent donor atoms. However, this effect could be much
smaller in the case of the larger polyatomic sulfate ion.
Finally, the chemical shift changes in the longer oligomers
6ꢀ8 were negligible when more than 1 equiv of chloride and
sulfate ions were added (Figure 3), clearly indicating that 1:1
complexes are formed even in the presence of excess anions.
for N O, but one urea proton is a little more distant
˚
(3.05 A), thus forming a weak H-bond.
3 3 3
Details of binding properties in solution were revealed
by 1H NMR spectroscopy. Tetrabutylammonium chloride
and bis(tetrabutylammonium) sulfate were chosen as a
representative anion for each of the small monatomic and
large polyatomic anions, respectively. The binding behav-
iors were first examined in a relatively nonpolar medium,
10% CD3CN/CD2Cl2, in order to find which protons are
involved in the H-bonding with anions based on the
complexation-induced shift (CIS, Δδ = δcomplex ꢀ δfree
)
of 1H NMR signals. The results are summarizedin Table 1.
Several trends are clearly noticeable.
First, signals for all the NH and OH protons in each
of the diphenylureas (4ꢀ8) were considerably shifted
Figure 2. Two views of the crystal structure for complex
5•(Bu4N)2SO4. H-bonds are marked by dashed lines. All the
CH H-atoms and tetrabutylammonium cations are omitted for
clarity.
downfield upon addition of either the chloride or sulfate
ion. In addition, the magnitudes of the CISs were larger in
the case of the sulfate ion compared to the chloride ion,
possibly due to the former forming stronger H-bonds than
the latter. Second, the CIS value ofthe OHsignal gradually
decreased with the increasing chain length of 4ꢀ8 for the
chloride ion. Inaddition, the most inner NH proton NH(1)
in each of the diphenylureas was the most downfield
shifted, and the most outer NH(n), the least shifted. This
result indicates that the bound anion is located in the
1
Figure 3. Partial H NMR spectra (250 MHz, 10% CD3CN/
CD2Cl2) of 8 in the presence of (a) no anions, (b) Bu4NCl
(1 equiv), (c) Bu4NCl (5 equiv), (d) (Bu4N)2SO4 (1 equiv), and
(e) (Bu4N)2SO4 (5 equiv).
5044
Org. Lett., Vol. 14, No. 19, 2012

Table 2. Association Constants (Ka ( 10%, Mꢀ1) between
Diphenylureas 4ꢀ8 and Anionsa (Clꢀ and SO42ꢀ) at 25 °C
2ꢀ a
Clꢀ a
SO4
15% CD3OH/
20% CD3OH/
40% CD3OH/
host
acetone-d6
DMSO-d6
DMSO-d6
b
4
5
6
7
8
85
17
ꢀ
b
210
390
ꢀ
1340
1350
1720
2230
270
>1.0 ꢁ 104
1690
16100
>1.0 ꢁ 104
Figure 4. Plots of the binding free energy (ꢀΔG, kcal/mol) of
4ꢀ8 with (a) chloride ion and (b) sulfate ion.
a Anions were used as the tetrabutylammonium salts. b Not determined.
Quantitative binding affinities were determined by the
1H NMR titrations in polar media containing a protic
solvent, MeOH. Under these conditions, 1H NMR spectra
of longer oligomers 6ꢀ8 are competely concentration-
independent in the range of 0.5ꢀ5.0 mM, suggesting that
the aggregation of ureas is negligible (SI). For accurate
comparison, the amount of methanol was chosen for the
The sulfate ion contains four oxygen atoms with a tetra-
hedral geometry as H-bond acceptors, each of which can
form two or three H-bonds. As a result, the sulfate ion can
accommodate multiple H-bonds,13 up to twelve in penta-
mer 8, without noticeably lessening the strength of indivi-
dual hydrogen bonds to enhance the net affinity.
In conclusion, using a series of helically foldable diphe-
nylureas, we have demonstrated that the affinity and
selectivity of an anion can be modulated by tuning the
chain length. Given that these helical foldamers possess an
internal cavity for anion binding, they could be further
modified to form a channel-like assembly, thus enabling
the transport of anions such as chloride in the lipid
membrane.
association constant to be in the range of 101 and 104 Mꢀ1
,
and the results are summarized in Table 2 and Figure 4.
First, the association constants of the chloride ion with
4ꢀ8 were evaluated in 15% (v/v) CD3OH/acetone-d6. The
association constants of 4, 5, and 6 increased by 3- to 7-fold
for an additional urea unit and then reached a plateau
(Figure 4a). It should be mentioned that all of the existing
NH protons of 7 and 8 showed downfield shifts during the
titrations, but the magnitudes of the CIS values were smaller
compared with those of 6. This result suggests that, relative to
6, more NH protons of 7 and 8 participate in H-bonding with
the chloride ion but the strength of individual H-bond may be
weakened as mentioned above, which is possibly responsible
for the comparable binding affinity of 6, 7, and 8.
Next, the association constants between 4ꢀ8 and the
sulfate ion were determined in much more H-bond-com-
petitive media 20% and 40% (v/v) CD3OH/DMSO-d6.
The binding affinity steadily increases from monomer 4 to
pentamer 8 by Gibbs free energy (ΔG) of 1.0ꢀ1.9 kcal/mol
for each increment of the diphenylurea unit (Figure 4b).
Acknowledgment. This work was supported by a
National Research Foundation of Korea (NRF) grant
funded by the Korea government (MEST) (2010-0011075).
M.J.K. acknowledges a fellowship from the BK21 program
from the Ministry of Education and Human Resources
Development. X-ray crystallography at the PLS-II
2D-SMC beamline was supported in part by MEST and
POSTECH.
Supporting Information Available. Synthesis and char-
acterization of new compounds, binding studies and Job’s
plot, X-ray details, and crystallographic data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(13) (a) Hay, B. P.; Firman, T. K.; Moyer, B. A. J. Am. Chem. Soc.
2005, 127, 1810–1819. (b) Bowman-James, K. Acc. Chem. Res. 2005, 38,
671–678. (c) Katayev, E. A.; Ustynyuk, Y. A.; Sessler, J. L. Coord. Chem.
Rev. 2006, 250, 3004–3037. (d) Ravikumar, I.; Ghosh, P. Chem. Soc. Rev.
2012, 41, 3077–3098.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5045