Fine tuning of receptor polarity for the development of selective naked eye anion receptor

Article abstract of DOI:10.1016/j.tetlet.2011.04.081

We designed and synthesized new anion receptors 1, 2, and 3, which have different N-H polarity. According to their N-H polarities, these receptors showed different selectivities for the anions they were interacting with. The difference of selectivity coul

Full text of DOI:10.1016/j.tetlet.2011.04.081

Tetrahedron Letters 52 (2011) 3361–3366
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fine tuning of receptor polarity for the development of selective naked
eye anion receptor
Jin Joo Park a, Young-Hee Kim a, Cheal Kim b, , Jongmin Kang a,
⇑
⇑
a Department of Chemistry, Sejong University, Seoul 143-747, Republic of Korea
b Department of Fine Chemistry, and Eco-Product and Materials Education Center, Seoul National University of Technology, Seoul 139-743, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We designed and synthesized new anion receptors 1, 2, and 3, which have different N–H polarity. Accord-
ing to their N–H polarities, these receptors showed different selectivities for the anions they were inter-
acting with. The difference of selectivity could be easily recognized from their color change during
recognition events. Therefore, fine tuning of receptor polarity could be a good strategy for the designing
of a selective anion receptor and made it possible to develop a selective naked eye anion receptor.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 March 2011
Revised 18 April 2011
Accepted 20 April 2011
Available online 27 April 2011
Keywords:
Naked eye anion receptor
Deprotonation
N–H polarity
The design and synthesis of receptors capable of binding and
sensing anions selectively have drawn considerable attention be-
cause anions play a major role in biological, medical, environmen-
tal, and chemical sciences.1 Many chemical sensors follow the
approach of the covalent attachment of signaling subunits and
binding sites.2 Chromogenic or fluorogenic groups that are cova-
lently linked to the receptor moiety as signaling subunits and mul-
tiple hydrogen-bonding interactions as binding sites have been
utilized in this regard. For binding sites, molecules containing
polarized N–H fragments are widely used as receptors for recogni-
tion and sensing purposes in aprotic solvents, such as CHCl3, MeCN,
and DMSO. Polarized N–H groups, behaving as H bond donors to
the anions, typically used in chromogenic or fluorogenic chemo-
sensors are ureas,3 thioureas,4 pyrroles,5 amines6 and amides.7
When designing an anion receptor, the N–H fragment of a
receptor can be further polarized through the insertion onto the
molecular framework of the electron-withdrawing substituent
and its H-bond donor tendencies increased. Furthermore, extreme
polarization may lead to deprotonation from the receptor. On
deprotonation, a substantial delocalization of negative charge usu-
ally leads to a large red shift, which results in drastic color changes
of solution. In consequence, naked detection of the anion becomes
possible.8 Therefore, fine tuning of polarity of the N–H fragment
could lead to development of selective naked eye anion receptor.
Previously, we reported on novel colorimetric receptor 1, which
had a nitrophenyl group and a quinoline group as chromogenic sig-
naling subunits.9 In this receptor, one amide and one amine group
is incorporated so that anions can make strong multiple hydrogen
bonding with the hydrogen atoms of these groups and we found
that the receptor 1 binds anions with a selectivity of FÀ > CNÀ
> CH3COÀ and proved to be an efficient naked-eye detector for
2
the fluoride and cyanide ion in acetonitrile.
As an extension of our work, we have designed new receptors 2
and 3. The new receptor 2 has only amide groups and the new
receptor 3 has only amine groups for hydrogen-bonding. Our
intention was to compare the anion detection abilities of the recep-
tors 1, 2, and 3, which have different N–H polarities, and we found
that these receptors detect anions through hydrogen bonding and
deprotonation.
The synthesis of the receptor 1 was previously reported.9
Receptor 2 was synthesized by the reaction of oxalyl chloride, 4-
nitroaniline, and 8-aminoquinoline. From the mixture of the com-
pounds 2, 4, and 5 the compounds 2 and 4 were precipitated as an
inseparable mixture while the compound 5 was soluble. After the
mixture of 2 and 4 was filtered, the mixture of 2 and 4 was treated
with di-tert-butyl dicarbonate to give BOC protected compounds
and the compound 6 could be separated through silica gel chroma-
tography. Removing BOC group with TFA gave the desired com-
pound 2 in 9.8% yield for the three step reactions. The receptor 3
was synthesized from the reduction of the compound 1 with bor-
ane dimethyl sulfide complex in 46% yield (Scheme 1).10
As the compound 2 was soluble only in DMSO, we compared the
binding abilities of three receptors 1, 2, and 3 in DMSO.
The receptors 1 and 2 displayed strong absorption bands at 333
and 334 nm in DMSO, respectively. Figure 1a and b show the fam-
ily of spectra obtained over the course of the titration of solutions 1
⇑
Corresponding authors. Tel: +82 2 970 6693; fax: +82 2 973 9149 (C.K.); fax:
+82 2 462 9954 (J.K.).
E-mail addresses: chealkim@snut.ac.kr (C. Kim), kangjm@sejong.ac.kr (J. Kang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.081

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J. J. Park et al. / Tetrahedron Letters 52 (2011) 3361–3366
NH2
N
oxalyl chloride
O2N
O
NH2
+
dichloromethane
O
O
O
O
O
+
NH HN
+
NO2
O2N
NH HN
NO2
NH HN
N
N
N
4
2
5
soluble in
dichloromethane
1. (BOC)2O/ DMAP/ dichloromethane
2. Chromatography
O
O
O
O
TFA/dichloromethane
NH HN
NO2
N
N
NO2
N
BOC
BOC
N
2
6
O
NH HN
NO2
(CH3)2S BH3/THF
reflux, 46%
NH HN
NO2
N
N
3
1
Scheme 1. The synthetic procedure for the anion receptor 2 and 3.
and 2 with tetrabutylammonium fluoride in DMSO. As fluoride
ions were added to the 20 M solutions of 1 and 2, kmax of 1 moved
to the fluoride only through hydrogen bonds.11 The deprotonation
of the compounds 1 and 2 were confirmed through the titration
experiments with tetrabutylammonium hydroxide ion.12 Assum-
ing 1:1 stoichiometry, a Benesi–Hildebrand plot13 by use of
absorption intensity change at 440 and 430 nm gave deprotonation
equilibrium constants for the receptors 1 and 2. In the case of the
receptor 3, absorption intensity change at 399 nm was used for the
calculation of hydrogen bonded association constant. From the
experiments, the deprotonation equilibrium constants of the
receptors 1 and 2 for fluoride were calculated as 5.5 Â 102 MÀ1
and 2.9 Â 103 MÀ1, respectively, and association constant of the
l
from 333 to 440 nm and kmax of 2 moved from 334 to 430 nm,
respectively. In addition, both spectra showed clear isosbestic
points at 375 and 367 nm, respectively. In the case of 3, at the same
solution and concentration, the intensity of the peak at 399 nm
was decreased as fluoride ions were added and the spectra showed
an isosbestic point at 420 nm (Fig. 1c). The presence of the sharp
isosbestic point for these compounds indicates that only two spe-
cies were present at equilibrium over the course of the titration
experiment. From the titration experiments with fluoride, it was
found that both compounds 1 and 2 showed drastic spectral
changes and development of new intense peaks, which indicates
the occurrence of N–H deprotonation while the compound 3 binds
receptor 3 for fluoride was calculated as 1.3 Â 103 MÀ1
.
This phenomenon could be confirmed by a 1H NMR titration.
For example, In DMSO-d6, one of the amide N–H hydrogen peaks
O
O
O
NH HN
NO2
NH HN
NO2
NH HN
NO2
N
N
N
3
2
1

J. J. Park et al. / Tetrahedron Letters 52 (2011) 3361–3366
3363
Figure 1. Familyofspectrarecorded overthecourseoftitrationof20 lMDMSOsolutions ofthereceptors1(a), 2(b) and 3(c)withthestandardsolutiontetrabutylammoniumfluoride.
Figure 2. 1H NMR spectra of 2 mM of 2 with increased amounts of tetrabutylammonium fluoride (0–4 equiv) in DMSO-d6.

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J. J. Park et al. / Tetrahedron Letters 52 (2011) 3361–3366
Figure 3. 1H NMR spectra of 2 mM of 1 with increased amounts of tetrabutylammonium fluoride (0–5 equiv) in DMSO-d6.
Figure 4. 1H NMR spectra of 2 mM of 3 with increased amounts of tetrabutylammonium fluoride (0–34 equiv) in DMSO-d6.
of receptor 2 became invisible upon addition of fluoride ion, which
indicated deprotonation of amide hydrogen. For example, two
amide peaks appeared at 11.59 and 11.54 ppm. One of amide peaks
disappeared completely with 1 equiv of fluoride ion (Fig. 2). In the

J. J. Park et al. / Tetrahedron Letters 52 (2011) 3361–3366
3365
Table 1
The association constants and the deprotonation equilibrium constants of the receptors 1, 2, and 3 with various anions in DMSO
Anion
1
2
3
UV
NMR
UV
NMR
UV
NMR
FÀ
5.5 Â 102
6.4 Â 102
2.9 Â 103
4.3 Â 103
1.3 Â 103
2.8 Â 102
1.1 Â 10
1.2 Â 10
1.8 Â 103
CH3COÀ2
C6H5COÀ2
H2POÀ4
4.2 Â 102
1.8 Â 102
4.1 Â 102
3.8 Â 102
4.7 Â 103
1.9 Â 102
2.1 Â 102
3.5 Â 103
1.1 Â 102
Deprotonation equilibrium constants are designated as
.
Figure 5. The color changes of the receptors 1, 2, and 3 when 100 lM DMSO solutions of receptors were treated with 4 equiv of various anions.
case of the receptor 1, only the amide peak appearing at 10.78 ppm
was deprotonated with 1 equiv of fluoride ion while the amine
peak appearing at 7.01 ppm moved downfield slightly ( Fig. 3).
However, amine peaks of the receptor 3 showed only downfield
shifts without deprotonation. The amine peaks of compound 3
appearing about 7.49 and 6.70 ppm showed a downfield shift until
7.85 and 6.73 ppm (Fig. 4). These results suggest that these com-
pounds interact with fluoride through hydrogen bonds and depro-
tonation. For titration, one of aromatic peaks was used for the
receptors 1, 2, and 3. In the case of receptors 1 and 2 the peak
appearing at 8.80 and 9.02 ppm was used to calculate the equilib-
rium constant. These peaks moved to 8.78 and 8.96 ppm, respec-
tively and no more shifts were observed. In the case of receptor
3, the peak appearing at 8.73 ppm was used and this peak moved
until 8.70 ppm. Although the peak shifts were small, analysis of
chemical shift utilizing EQNMR14 gave equilibrium constants
6.4 Â 102 MÀ1, 4.3 Â 103 MÀ1 and 1.8 Â 103 MÀ1 for the receptors
1, 2 and 3, respectively, which are similar values obtained from
UV–vis titration.
We also investigated association constants of other anions. The
results are summarized in Table 1. The receptors 1, 2, and 3 inter-
act with fluoride, acetate, benzoate, and dihydrogen phosphate in
DMSO. They did not bind chloride, bromide, iodide, hydrogen sul-
fate, perchlorate, and nitrate at all in the same solution. From the
experiments, the receptor 1 was deprotonated by only fluoride
and bound other anions only through hydrogen bonds. Therefore,
selective detection of the fluoride ion with naked eye was possible.
Figure 5 shows the color changes of the solutions of the receptor 1
upon additions of various anions in DMSO. It can be seen that the
color of solution of the receptor 1 changes from colorless to yellow
only in the presence of the fluoride ion. However, receptor 2 was
deprotonated by all the anions it was interacting with. The most
basic fluoride ion and less basic acetate ion have similar deproto-
nation equilibrium constants for receptor 2. Even benzoate and

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J. J. Park et al. / Tetrahedron Letters 52 (2011) 3361–3366
4545; (d) Bühlmann, P.; Nishizawa, S.; Xiao, K. P.; Umezawa, Y. Tetrahedron
1997, 53, 1647; (e) Benito, J. M.; Gómez-García, M.; Blanco, J. L. J.; Mellet, C. O.;
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Davis, A. P.; Joos, J.-B.; Roberts, E. P. L. Org. Biomol. Chem. 2004, 2, 2716; (g) Fan,
E.; Van Arman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 369.
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dihydrogenphosphate, which have low basicity, could deprotonate
receptor 2. High acidity of receptor 2 makes it impossible to
distinguish the anions it is interacting with just through naked
eye (Fig. 4b). In the case of receptor 3, it was interacting with the
anion only through hydrogen bonds. Therefore, naked detection
of anions was impossible with the receptor 3 (Fig. 5c).
6. Wichmann, K.; Antonioli, B.; Söhnel, T.; Wenzel, M.; Gloe, K.; Gloe, K.; Price, J.
R.; Lindoy, L. F.; Blake, A. J.; Schröder, M. Coord. Chem. Rev. 2006, 250, 2987.
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An, D.; Cho, W.-S.; Lynch, V.; Marquez, M. Chem. Eur. J. 2005, 11, 2001; (g)
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Ed. 2005, 44, 2899; (h) Nishiyabu, R.; Anzenbacher, P., Jr. J. Am. Chem. Soc. 2005,
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8. (a) Amedola, V.; Esteban-Gomez, D.; Fabbrizzi, L.; Licchelli, M. Acc. Chem. Res.
2006, 39, 343–353; (b) Dang, N. T.; Park, J. J.; Jang, S.; Kang, J. Bull. Korean Chem.
Soc. 2010, 31, 1204–1208; (c) Kang, J.; Lee, Y. J.; Lee, S. K.; Lee, J. H.; Park, J. J.;
Kim, Y.; Kim, S.-J.; Kim, C. Supramol. Chem. 2010, 22, 267.
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In summary, we designed and synthesized new anion receptors
1, 2, and 3 which have different N–H polarity. The receptor 1,
which has medium polarity, showed the most selective color
change for the fluoride ion. However, the most polar receptor 2
showed color changes for all the anions it was interacting with
and the least polar receptor 3 did not induce any color change
for any anions. Therefore, fine tuning of receptor polarity could
be a good strategy for the designing of selective anion receptor
and made it possible to develop a selective naked eye anion
receptor.
Acknowledgment
10. Synthesis of compound 6: To a solution of 4-nitroaniline (326 mg, 2.4 mmol), 8-
aminoquinoline (341 mg, 2.4 mmol), and diisopropylethylamine (0.81 mL,
4.8 mmol) in dichloromethane under nitrogen was added oxalyl chloride
(0.20 ml, 2.36 mmol) dropwise and stirred for 3 h. 246 mg of 2 and 4 were
This research was supported by a Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2010-0021333).
precipitated as
a mixture while the compound 5 was soluble in
dichloromethane. After the solid was filtered, the solid mixture was treated
with dibutyldicarbonate in dichloromethane (30 mL) to give BOC protected
compounds of 2 and 4. Silica gel chromatography on the silica gel (initially
hexane/ethyl acetate = 5:1 later hexane/ethyl acetate = 1:1) gave 134 mg of
BOC protected compounds 6. 1H NMR (CDCl3, 500 MHz): 8.9 (s, 1H), 8.3 (d,
J = 8.5 Hz, 2H), 8.2 (d, J = 8.0 Hz, 1H), 7.9 (d, J = 8.0 Hz, 2H), 7.6 (m, 3H), 7.4 (d,
J = 3.5 Hz, 1H), 1.4 (s, 9H). 1.3 (s, 9H). Synthesis of compound 2: To a solution of
the compound 6 (134 mg, 0.24 mmol) in dichloromethane (5 mL) was added
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.081.
trifluoroacetic acid (74 lL) and stirred for 6 h. Filtration of the solid and
References and notes
washing with acetone gave the compound 2 (78 mg) in 96% yield. 1H NMR
(DMSO-d6, 500 MHz) 11.6 (s, 1H), 11.5 (s, 1H), 9.0 (dd, J = 4 Hz, 1.5 Hz, 1H), 8.7
(dd, J = 7.5 Hz, 1 Hz, 1H), 8.5 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 8.3 (d, J = 9 Hz, 2H), 8.2
(d, J = 9 Hz, 2H), 7.8 (dd, J = 8.25 Hz, 1 Hz, 1H), 7.7 (m, 2H). 13C NMR (DMSO-d6,
500 MHz) 158.8, 156.8, 149.3, 143.4, 143.3, 137.9, 136.5, 132.3, 127.7, 126.6,
124.3, 123.2, 122.3, 120.6, 116.1. HR-MS (ESI): calcd for C17H12N4O4+H m/e
337.0938; found 337.0933. Synthesis of compound 3: To a solution of the
compound 1 (200 mg, 0.62 mmol) in dried THF (3 mL) under nitrogen at 0 °C
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was added borane dimethyl sulfide (118 lL, 1.24 mmol) and stirred for 30 min.
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1
(120 mg).
Chromatography on the silica gel (hexane/ethyl acetate = 1:1) gave the desire
compound 3 (35 mg) in 46% yield based on recovered starting material. 1H
NMR (DMSO-d6, 500 MHz) 8.7 (dd, J = 4 Hz, 1.5 Hz, 1H), 8.2 (dd, J = 8.5 Hz,
1.5 Hz, 1H), 8.0(d, J = 9.5 Hz, 2H), 7.5 (m, 2H), 7.4 (t, J = 8.0 Hz, 1H), 7.1 (d,
J = 8.0 Hz, 1H), 6.8 (d, J = 7.5 Hz, 1H), 6.7 (d+m, J = 9.5 Hz, 2H+1H from amine),
3.5 (m, 4H). 13C NMR (DMSO-d6, 500 MHz) 154.6, 146.9, 144.2, 137.5, 135.9,
135.7, 128.4, 127.8, 126.2, 121.7, 113.4, 104.2, 41.5, 41.3. HR-MS (ESI): calcd for
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