2-Thiohydantoin containing OH and NH recognition subunits: A fluoride ion selective colorimetric sensor

Article abstract of DOI:10.1039/c3nj41134f

A novel anion receptor based on 2-thiohydantoin, containing different hydrogen bonding donors such as OH and NH groups, was synthesized. This receptor showed a colorimetric response to fluoride ions. ¹H NMR titration confirmed the deprontonation of the phenol OH group and hydrogen bonding interaction between NH group and F^-.

Full text of DOI:10.1039/c3nj41134f

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2-Thiohydantoin containing OH and NH recognition
subunits: a fluoride ion selective colorimetric sensor†
Cite this: DOI: 10.1039/c3nj41134f
Xue Yong,a Mingjian Su,a Wen Wan,a Wenwei You,b Xinwei Lu,b Jinqing Qu*a and
Ruiyuan Liu*b
Received (in Montpellier, France)
13th December 2012,
Accepted 1st March 2013
A novel anion receptor based on 2-thiohydantoin, containing different hydrogen bonding donors such
as OH and NH groups, was synthesized. This receptor showed a colorimetric response to fluoride ions.
1H NMR titration confirmed the deprontonation of the phenol OH group and hydrogen bonding
interaction between NH group and Fꢀ.
DOI: 10.1039/c3nj41134f
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bonding can be formed, which means that 2-thiohydantoin
ring can act as an anion recognition motif to detect anions.
Introduction
Anion recognition and sensing has attracted much attention
due to the fundamental roles of anions in many chemical
and biological processes.1 For example, fluoride ions exhibit
beneficial effects on dental health and the treatment of
osteoporosis,2 however, it is accused of causing several human
pathologies.3 A series of receptors that are able to detect
fluoride ions have been reported.4 Of particular interest in this
regard are colorimetric anion sensors that would allow the
naked-eye detection of fluoride ion.5 The anion sensors com-
monly contain recognition subunits such as amides,6 urea and
thioureas,7 amidoureas,8 azophenol,9 pyrrole,10 imidazolium,11
and indoles.12 In these sensors, N–Hꢁ ꢁ ꢁXꢀ or O–Hꢁ ꢁꢁXꢀ hydrogen
bonding play very important roles for anion recognition. The
phenolic OH group is a strong donor unit, which undergoes
deprotonation in the presence of Fꢀ.13 The amide NH group is
less susceptible to deprotonation compared to the phenolic
OH group, and it is able to form strong N–Hꢁ ꢁ ꢁXꢀ hydrogen
bonding.
Herein, we designed receptor 1 including a 2-thiohydantoin
ring, which contains different types of hydrogen bonding
donors such as OH and NH. The colorimetric response of this
receptor towards fluoride ions was also investigated.
Results and discussion
Receptor 1 was synthesized starting from 30,50-diiodo-N-a-tert-
butoxycarbonyl-L-tyrosine methyl ester,17 which was converted
to 30,50-diiodo-L-tyrosine methyl ester using TFA. Reaction
between 30,50-diiodo-L-tyrosine methyl ester with butyl isothio-
cyanate gave receptor 1 in 73% yield (Scheme 1). The structure of
receptor 1 was confirmed from its spectroscopic and analytical
data (see ESI,† S1–S3).
To examine the anion sensing ability of receptor 1, a series
of tetra-n-butylammonium (TBA) salts were added to the
solution of receptor 1 in CH3CN. The photograph in Fig. 1
shows the color changes after addition of anions (NO3ꢀ, Brꢀ,
Clꢀ, HSO4ꢀ, C6H5COOꢀ, CH3COOꢀ, and Fꢀ) to the CH3CN
solution of receptor 1. Upon the addition of Fꢀ, the colorless
solution immediately tuned to yellow, while the color of the
solution hardly changed with addition of NO3ꢀ, Clꢀ, Brꢀ,
HSO4ꢀ, CH3COOꢀ, and C6H5COOꢀ. It seems that the color
change occurred only when fluoride ion was added, other anions
There has been considerable interest in 2-thiohydantoins,
mainly because of their use for medical purposes as anti-
convulsant, antimutagenic, anticarcinogenic, antiandrogen
and antiviral agents,14 but also recently as polymerization
catalysts,15 as corrosion inhibitors and as analytical reagents.16
Due to the presence of hydrogen bonding donors and acceptors
in the 2-thiohydantoin rings, N–H–O intermolecular hydrogen
a School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China. E-mail: cejqqu@scut.edu.cn;
Fax: +8602087111344; Tel: +8602087111344
b School of Pharmaceutical Science, Southern Medical University,
Guangzhou 510515, P. R. China. E-mail: ruiyliu@smu.edu.cn;
Fax: +8602061648196; Tel: +8602061648196
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3nj41134f
Scheme 1 Synthesis of receptor 1.
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Fig. 1 Visible color changes of receptor 1 in CH3CN after the addition of TBA
salts of a series of anions ([1] = 1.0 mM, [anion]/[1] = 10).
failed to cause any significant color change. Considering the
high selectivity for Fꢀ over other anions and the convenience of
not needing to resorting to using any spectrometers, the
receptor 1 provided a great advantage for detecting fluoride
ions. We also measured the naked-eye detection limit of
receptor 1 toward Fꢀ (see ESI,† S4). Upon addition of 1 mM of
Fꢀ, the colorless CH3CN solution ([1] = 1 mM) changed to light
yellow. On the other hand, exposure to 0.1 mM Fꢀ did not lead
to any obvious change in color of the solution. It seems that the
naked-eye detection limit of receptor 1 toward Fꢀ is 1 mM.
For more detail, UV-vis spectra of receptor 1 were measured in
the presence of these anions (Fig. 2). The UV-vis spectrum of
receptor 1 exhibited a strong absorption band at around 277 nm.
With addition of Fꢀ, two new red-shifted absorption bands at 327
and 423 nm were observed. Upon addition of CH3COOꢀ and
C6H5COOꢀ, only a new absorption band at 327 nm was observed
in the absorption spectrum of receptor 1, while the absorption
spectrum changed slightly upon addition of Clꢀ, Brꢀ, NO3ꢀ, and
HSO4ꢀ. Thus, the system only caused a distinct host–guest
interaction for Fꢀ. It is suggested that the high selectivity might
be attributed to the high charge density and small size of fluoride
anion, which enables Fꢀ to be a strong hydrogen bonding
acceptor that shows interaction with phenol and/or amide groups.
The interaction of receptor 1 with Fꢀ was investigated in detail.
Fig. 3 showed the absorption spectral changes of receptor 1 with
increase of the TBAF concentration in CH3CN. The UV-vis
Fig. 3 UV absorption changes of receptor 1 in CH3CN upon addition of Fꢀ ([1] =
100 mM, [Fꢀ]/[1] = 0–60).
spectrum of receptor 1 exhibited one absorption band in
CH3CN. Upon addition of Fꢀ, two new strong absorption bands
at 327 nm and 423 nm increase continuously, which is asso-
ciated with the drastic color change from colorless to yellow.
It seems that the interaction between receptor 1 and fluoride
ion induced the UV-vis spectra change which exhibited a red-
shifted charge-transfer (CT) band.
To provide an insight into the interaction between receptor 1
1
and anions, we carried out H NMR titrations of receptor 1 in
the presence of Fꢀ (see Fig. 4 and ESI† Fig. S5). As shown in
Fig. 4, the phenol OH proton signal (5.84 ppm) was broadened
with increasing Fꢀ concentration from 0 to 0.5 equiv., then
completely disappeared upon addition of 1.0 equivalent of
fluoride ion. The NH proton signal was downfield shifted with
increasing Fꢀ concentration from 0 to 1.0 equiv., then under-
went a continuous downfield shift with decrease of peak area.
At the same time, upon addition of 4 equiv. of Fꢀ, a proton
signal (16.44 ppm) was found, which was ascribed to FHFꢀ.10d
These observations confirmed the deprotonation of the phenol
OH group which increases the electron density on the phenyl
ring, enhanced the internal charge transfer (ICT) and resulted in
colorimetric changes.10d It seems that the interaction between
receptor 1 and Fꢀ involves the deprotonation of phenol OH
groups and hydrogen bonding interaction of 2-thiohydantoin
Fig. 4 1H NMR spectra of receptor 1 in the presence of (a) 0, (b) 0.5, (c) 1.0,
(d) 2.0, (e) 4.0, (f) 8.0, and (g) 16.0 equiv. of TBAF in CDCl3. * means NH proton.
** means OH proton.
Fig. 2 UV-vis spectra of receptor 1 in CH3CN after the addition of TBA salts of a
series of anions ([1] = 1.0 mM, [anion]/[1] = 10).
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hydrogen sulfate (TBAHSO4) were purchased from Tokyo Kasei
Kogyo Co., Ltd. (TCI, Tokyo, Japan), and used without further
purification.
30,50-Diiodo-N-a-tert-butoxycarbonyl-L-tyrosine methyl ester
was prepared as reported.17
Measurements
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded
on a Bruker Avance/DMX 400-MHz NMR spectrometer with
CDCl3 as solvent and tetramethylsilane as an internal reference.
IR spectra were measured using a Shimadzu FTIR-8100 spectro-
photometer. Melting point (mp) was measured on a Yanaco
micro-melting point apparatus. Elemental analysis was per-
formed on an Eager 300 elemental microanalyzer. UV-vis spectra
were recorded in a quartz cell (thickness: 1 cm) at room tem-
perature using a JASCO J-820 spectropolarimeter.
Fig. 5 Job’s plot for receptor 1–Fꢀ interaction. The total [Fꢀ] + [1] = 200 mM.
Typical experimental procedure for UV-vis absorption
measurements
NH moieties with Fꢀ. The reason for the different interactions
lies in the difference between the acidity and hydrogen bond
formation ability in phenol OH and 2-thiohydantoin NH group.13b
The acidity and high hydrogen bonding donor ability of the phenol
OH group have made it preferable to undergo deprotonation,
while NH group prefers to form hydrogen bonding.
All UV-vis absorption measurements were performed in dry
solvent. The concentration of receptor 1 was 100 mM for all the
measurements.
A typical experimental procedure is described as follows:
stock solutions of receptor 1 (53.0 mg/10 mL) and tetra-n-
butylammonium fluoride (TBAF) (10 mM) in CH3CN were
prepared in flasks equipped with stopcocks, respectively. The
receptor 1 solution (0.1 mL) and the TBAF solution (1 mL) were
transferred to a vial, and then the resulting mixture was diluted
to 10 mL with dry CH3CN to give the sample solution, of which
[1] and [TBAF]/[1] were adjusted to be 100 mM and 10, respec-
tively. The UV-vis absorption spectrum of the resulting sample
solution was measured in a quartz cell with a 10 mm path
length at 25 1C.
Continuous-variation plots (Job’s plots) was carried out to
confirm the stoichiometry of the receptor 1–Fꢀ interaction.
Fig. 5 shows the variation of the absorbance at 423 nm which
was plotted against the molar fraction of the Fꢀ(w). As shown in
Fig. 5, the maximum value was clearly observed at 0.7 of w,
which indicated that receptor 1 and fluoride ion formed the
1 : 2 complex. The binding constant of receptor 1 to Fꢀ was then
calculated with the help of the nonlinear least-squares curve-
fitting program Reactlab EQULIBRIA by fitting the titration data
to a 1 : 2 binding model over the entire spectral range.18 The
apparent binding constant of receptor 1 to Fꢀ was 1028 Mꢀ1
.
Job’s plot
CH3CN solutions of receptor 1 and TBAF were mixed to prepare
sample solution with varying molar fractions of the receptor 1
(w) from 0 to 1. The total concentration of receptor 1 and Fꢀ was
kept constant at 200 mM. UV-vis measurement of each sample
was performed. Absorbance at 423 nm was normalized to the
variation of absorbance (DA423) with the following equation:
DA423 = Aobs ꢀ (1 ꢀ w)A0, where A0 is absorbance of receptor 1 in
CH3CN at 200 mM (w = 0). Job’s plot was obtained by plotting
DA423 values against w.
Conclusions
In conclusion, we have reported one novel anion receptor based
on 2-thiohydantoin containing different hydrogen bonding
donors such as OH and NH groups. The binding properties
were confirmed by absorption and 1H NMR techniques. This
receptor showed colorimetric response to Fꢀ. 1H NMR titra-
tions confirmed the deprotonation of the phenol OH group and
hydrogen bonding interaction between NH group and Fꢀ. This
receptor formed a 1 : 2 complex with fluoride ions.
Synthesis of receptor 1
10.94 g, 20 mmol of 30,50-diiodo-N-a-tert-butoxycarbonyl-L-
tyrosine methyl ester in 20 mL of CH2Cl2 was added to a 100 mL
flask. 20 mL CF3COOH was then added to the flask at 0 1C, and
then the resulting mixture was stirred at room temperature for
Experimental section
Materials
Butyl isothiocyanate, tetra-n butylammonium nitrate (TBAN), 1 h. The reaction mixture was concentrated by rotary evapora-
tetra-n-butylammonium fluoride (TBAF), tetra-n-butylammonium tion and dried in vacuo. The residual compound was dissolved
benzoate (TBAB), tetra-n-butylammonium acetate (TBAA), and in THF (30 mL), then butyl isothiocyanate (2.30 g, 20 mmol)
tetra-n-butylammonium bromide (TBABr), were purchased from and triethylamine (10 mL) were added to the solution. The
Sigma-Aldrich Chemical Co., Inc., and used as received. tetra-n- reaction mixture was stirred at room temperature overnight.
Butylammonium chloride (TBACl), and tetra-n-butylammonium The filtrate was concentrated by a rotary evaporator and the
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7 Selected recent reviews: (a) Y. Takemoto, Org. Biomol. Chem.,
2005, 3, 4299; (b) V. Amendola, L. Fabbrizzi and L. Mosca,
Chem. Soc. Rev., 2010, 39, 3889; (c) A. Li, J.-H. Wang, F. Wang
and Y.-B. Jiang, Chem. Soc. Rev., 2010, 39, 3729, and reference
therein; (d) S. Zhang and L. Echegoyen, J. Am. Chem. Soc., 2005,
127, 2006; (e) C. Li, N. Munenori, T. Masayuki and S. Shinkai,
Angew. Chem., Int. Ed., 2005, 44, 6371; ( f ) D. R. Turner,
M. J. Paterson and J. W Steed, J. Org. Chem., 2006, 71, 1598.
8 (a) F. Y. Wu, Z. Li, L. Guo, X. Wang, M. H. Lin, Y. F. Zhao and
Y. B. Jiang, Org. Biomol. Chem., 2006, 4, 624; (b) W.-X. Liu
and Y.-B. Jiang, Org. Biomol. Chem., 2007, 5, 1771;
(c) R. Yang, W.-X. Liu, H. Shen, H.-H. Huang and
Y.-B. Jiang, J. Phys. Chem. B, 2008, 112, 5105.
residue was extracted with 100 mL of CH2Cl2. The organic
phase was with 1 M HCl, saturated aq. NaHCO3 aqueous and
brine. The organic layer was dried over anhydrous MgSO4 and
evaporated to dryness. After filtration and solvent evaporation,
the crude product was purified using a silica gel column using
hexane/ethyl acetate mixture (2 : 1 by volume) as eluent. White
solid was obtained in 73% yield (7.74 g). Mp: 223–224 1C.
1H NMR (400 MHz, CDCl3): d 0.92–0.96 (m, 3H, CH3), 1.23–1.28
(m, 2H, CH2), 1.46–1.52 (m, 2H, CH2), 2.86–2.92(m, 1H, CH),
3.12–3.16 (m, 1H, CH), 3.71–3.75 (m, 2H, CH2), 5.84(s, 1H, OH),
7.56 (s, 2H, Ar), 7.94(s, 1H, NH). 13C NMR (100 MHz, CDCl3):
d 13.82, 19.94, 29.63, 35.27, 41.16, 60.03, 82.66, 130.3, 142.01,
153.28, 173.02, 184.06. IR (cmꢀ1, KBr): 3370, 3124, 2957, 2793,
1647, 1521, 1487, 1322, 1172, 1124, 925, 810, 774, 642. Elemental
analysis: Anal. Calcd for C14H16I2N2O2S: C, 31.72; H, 3.04; I, 47.87;
N, 5.28; O, 6.04; S, 6.05. Found: C, 31.56; H, 3.08; N, 5.30.
9 (a) D. H. Lee, H. Y. Lee, K. H. Lee and J. I. Hong, Chem.
Commun., 2001, 1188; (b) X. Zhang, L. Guo, F. Y. Wu and
Y. B. Jiang, Org. Lett., 2003, 5, 2667.
10 (a) J. L. Sessler, E. Katayev, G. D. Pantos, P. Scherbakov, M. D.
Reshetova, V. N. Khrustalev, V. M. Lynch and Y. A. Ustynyuk,
J. Am. Chem. Soc., 2005, 127, 11442; (b) K. A. Nielsen, W.-S. Cho,
J. Lyskawa, E. Levillain, V. M. Lynch, J. L. Sessler and J. O.
Jeppesen, J. Am. Chem. Soc., 2006, 128, 2444; (c) S. O. Kang,
D. Powell, V. W. Day and K. Bowman-James, Angew. Chem., Int.
Ed., 2006, 45, 1921; (d) Q. Wang, Y. Xie, Y. Ding, X. Li and
W. Zhu, Chem. Commun., 2010, 46, 3669.
11 (a) B. G. Zhang, P. Cai, C. Y. Duan, R. Miao, L. G. Zhu,
T. Niitsu and H. Inoue, Chem. Commun., 2004, 2206;
(b) J. Yoon, S. K. Kim, N. J. Singh and K. S. Kim, Chem.
Soc. Rev., 2006, 35, 355; (c) Z. Xu, S. K. Kim and J. Yoon,
Chem. Soc. Rev., 2010, 39, 1457.
Acknowledgements
We gratefully thank the ‘‘National Natural Science Foundation
of China’’ (21074073, 51173050, and 21244007) for financial
support of this work.
Notes and references
1 Selected recent reviews: (a) R. Martinez-Manez and
F. Sancenon, Chem. Rev., 2003, 103, 4419; (b) C. Bowman-
James, Acc. Chem. Res., 2005, 38, 671; (c) C. Suksai and
T. Tuntulani, Top. Curr. Chem., 2005, 255, 163; (d) P. A. Gale,
Acc. Chem. Res., 2006, 39, 465; (e) P. A. Gale, Chem. Commun., 12 (a) D. Curiel, A. Cowley and P. D. Beer, Chem. Commun.,
2011, 47, 82.
2005, 236; (b) K.-J. Chang, M. D. Dohyun, M. S. Lah and
K. S. Jeong, Angew. Chem., Int. Ed., 2005, 44, 7926.
2 (a) K. L. Kirk, Biochemistry of the Halogens and Inorganic
Halides, Plenum Press, New York, 1991, p. 58; 13 (a) D. H. Lee, K. H. Lee and J. I. Hong, Org. Lett., 2000, 3, 5;
(b) M. Kleerekoper, Endocrinol. Metab. Clin. North Am.,
1998, 27, 441.
(b) L. Xu, Y. Li, Y. Yu, T. Liu, S. Cheng, H. Liu and Y. Li,
Org. Biomol. Chem., 2012, 10, 4375.
3 M. Cametti and K. Rissanen, Chem. Commun., 2009, 2809.
4 (a) H. Lu, W. Xu, D. Zhang and D. Zhu, Chem. Commun.,
2005, 4777; (b) M. Melaimi and F. Gabbai, J. Am. Chem. Soc.,
2005, 127, 9680; (c) A. M. Costero, C. Manuel, G. Pablo and
G. Salvador, Chem. Commun., 2006, 761.
5 (a) C. Suksai and T. Tuntulani, Chem. Soc. Rev., 2003,
32, 192; (b) E. J. Cho, B. J. Ryu, Y. J. Lee and K. C. Nam,
Org. Lett., 2005, 7, 2607; (c) S. E. Louise, P. A. Gale,
M. E. Light and R. Quesada, Chem. Commun., 2006, 965;
(d) Z.-H. Lin, S.-J. Ou, C.-Y. Duan, B.-G. Zhang and Z.-P. Bai,
Chem. Commun., 2006, 624; (e) F. M. Pfeffer, P. E. Kruger and
T. Gunnlaugsson, Org. Biomol. Chem., 2007, 5, 1894;
( f ) R. M. Duke, E. B. Veale, F. M. Pfeffer, P. E. Kruger and
T. Gunnlaugsson, Chem. Soc. Rev., 2010, 39, 3936.
14 (a) C. Carmi, A. Cavazzoni, V. Zuliani, A. Lodola, F. Bordi,
P. V. Plazzi, R. R. Alfieri, P. G. Petronini and M. Mor, Bioorg.
Med. Chem. Lett., 2006, 16, 4021; (b) A. Cavazzoni,
R. R. Alfieri, C. Carmi, V. Zuliani, M. Galetti, C. Fumarola,
R. Frazzi, M. Bonelli, F. Bordi, A. Lodola, M. Mor and
P. G. Petronini, Mol. Cancer Ther., 2008, 7, 361;
(c) M. Mudit, M. Khanfar, A. Muralidharan, S. Thomas,
G. V. Shah, R. W. M. van Soest and K. A. El Sayed, Bioorg.
Med. Chem., 2009, 17, 1731; (d) C. Harrison, Nat. Rev. Drug
Discovery, 2009, 8, 452; (e) H. C. Shen and S. P. Balk, Cancer
Cell, 2009, 15, 461; ( f ) Q. F. Zhu, Y. H. Pan, Z. X. Xu,
R. M. Li, G. G. Qiu, W. J. Xu, X. B. Ke, L. M. Wu and
X. M. Hu, Eur. J. Med. Chem., 2009, 44, 296.
15 (a) S. S. Kandil, G. B. El-Hefnawy and E. A. Baker,
Thermochim. Acta, 2004, 414, 105; (b) A. O. Yu¨ce and
G. Kardas-, Corros. Sci., 2012, 58, 86.
6 Selected recent reviews: (a) J. L. Sessler and J. M. Davis, Acc.
Chem. Res., 2001, 34, 989; (b) J. L. Sessler, S. Camiolo and
P. A. Gale, Coord. Chem. Rev., 2003, 240, 17; (c) P. Dydio, 16 (a) L. D. Cromwellt and G. R. Stark, Biochemistry, 1969, 8, 4735;
D. Lichosyt and J. Jurczak, Chem. Soc. Rev., 2011, 40, 2971, (b) B. Mo, J. Li and S. Liang, Anal. Biochem., 1997, 249, 207.
and reference therein; (d) P. A. Gale, Chem. Commun., 2005, 17 R. Liu, F. Sanda and T. Masuda, Polymer, 2010, 48, 6510.
3761.
18 G. Pizzoli and M. G. Lobello, Dalton Trans., 2012, 41, 11841.
c
New J. Chem.
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