Fluorescent coumarinyldithiane as a selective chemodosimeter for mercury(II) ion in aqueous solution

Article abstract of DOI:10.1016/j.tetlet.2009.08.045

A coumarin-based dithiane (1) was synthesized for the selective detection of Hg²⁺ with respect to dual chromo- and fluorogenic changing events in an aqueous solution by the mercury-promoted transformation of a dithiane group into an aldehyde functional unit. The Hg²⁺-selective response of the chemodosimeter was clearly observed in aqueous buffer as well as in human blood plasma medium.

Full text of DOI:10.1016/j.tetlet.2009.08.045

Tetrahedron Letters 50 (2009) 5958–5961
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fluorescent coumarinyldithiane as a selective chemodosimeter
for mercury(II) ion in aqueous solution
Ja Hyung Kim , Hyun Jung Kim , Sang Hoon Kim , Jae Hong Lee , Jung Ho Do , Hae-Jo Kim b,*,
a
a
a
a
b
c
a,
*
Joung Hae Lee , Jong Seung Kim
a
Department of Chemistry, Korea University, Seoul 136-701, Republic of Korea
Department of Chemistry, Kyonggi University, Suwon 443-760, Republic of Korea
Korea Research Institute of Standards and Science, Taejon 305-600, Republic of Korea
b
c
a r t i c l e i n f o
a b s t r a c t
A coumarin-based dithiane (1) was synthesized for the selective detection of Hg2+ with respect to dual
Article history:
Received 29 June 2009
Revised 7 August 2009
Accepted 17 August 2009
Available online 20 August 2009
chromo- and fluorogenic changing events in an aqueous solution by the mercury-promoted transforma-
tion of a dithiane group into an aldehyde functional unit. The Hg -selective response of the chemodos-
imeter was clearly observed in aqueous buffer as well as in human blood plasma medium.
2+
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Chromogenic
Fluorogenic
Coumarin
Mercury ion
Chemical sensors for heavy metals such as mercury, cadmium,
and lead are of growing interest due to their bioaccumulation, bio-
magnification, and persistence in the environment.1 In particular,
mercury ion detection by optical probes is a rapidly growing area
owing to its strong toxicity within the human body.2a Mercuric
salts exist in many industrial materials such as electrical equip-
ment, catalysts, paints, and mining byproducts that produce high
concentrations of mercury pollutants. When ingested by humans,
methylmercury triggers several serious disorders stemming from
sensory, motor, and neurological damages.2b For example, when
ingested by a pregnant woman, methylmercury readily crosses
the placenta and targets the developing fetal brain and central ner-
vous system, potentially causing developmental delays in the
toward the Hg2+ ion, desulfurization of a thioacetal can be taken
into account. To date, a variety of desulfurization methods have
been devised by using heavy or transition metal salts with addi-
+
4
4d
5,6
tives, such as Ag /NBS or NCS, AgNO
3
/I
.8 Notably, desulfurization of the
thioacetal can also occur with HgCl /HgO/LiBF under reflux in
aqueous MeCN. Although these efforts have improved chemodos-
2
,
CuCl
2
/CuO,
HgO/
7
2 3 4 2 3
Et OÁBF , and Hg(ClO ) /CaCO
2
4
6
2
+
imetric functionality toward the Hg ion, their application toward
biological samples have been hampered by poor chemodosimeter
solubility in water and modest sensitivity, as well as their short
wavelength absorption and low quantum yield.
To further application in the environmental and biological
fields, we have focused on the synthesis of a new thioacetal deriv-
ative of thioacetalized coumarin (1) and investigated its chemod-
osimetric properties to provide sensitive detection of the Hg2+
ion in viewpoint of color and fluorescence changes in an aqueous
environment. In addition, to the best of our knowledge, the desul-
furization of a thioacetal was rarely successful under mild and
environment-friendly conditions (aqueous media and room tem-
perature), both prerequisites for a chemodosimetric sensing sys-
tem. Thus, herein the chemodosimetric behavior of 1 toward the
2
c,d
child.
Accordingly, it is exigent to provide analytical methods
for the sensitive and selective detection of the mercury ion.
Recently, a number of chemical sensors were developed as po-
tent luminescent probes. A particularly attractive alternative is the
use of chemodosimeter as a chemical sensor through a specific
chemical reaction between a dosimeter molecule and target spe-
3
cies, leading to the formation of a fluorescent or colored product.
One of the equally attractive approaches in this field involves the
use of highly selective reactions (usually irreversible) induced by
target analytes, in which an accumulative effect is directly related
to analyte concentration. As an approach of the chemodosimeters
2
+
Hg ion with respect to fluorescence and color changes, in addi-
tion to the mechanistic study of the transformation of coumarinyl
thioacetal (1) to coumarinaldehyde (2) under mild conditions and
without any catalyst is reported.
Compound 2 was synthesized from 4-(diethylamino)salicylal-
dehyde in two steps according to
*
Corresponding authors. Tel.: +82 2 3290 3143; fax: +82 2 3290 3121.
E-mail addresses: haejkim@kgu.ac.kr (H.-J. Kim), jongskim@korea.ac.kr (J.S. Kim).
a
literature procedure.9
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.045

J. H. Kim et al. / Tetrahedron Letters 50 (2009) 5958–5961
5959
Subsequently, 1 could be prepared from the reaction of 2 with 1,2-
ethanedithiol in the presence of Et in diethyl ether (Scheme
OÁBF
). The molecular structure of 1 was clearly characterized by its H-
and C NMR, mass spectra, infrared spectra, and X-ray single crys-
tal structure analysis (Fig. 1). All details concerning the crystal
structure are in Supplementary data.
tained a high Hg2+-selective chemodosimetric response, even
under polluted conditions containing heavy and transition metal
2
3
1
2+
2+
2+
2+
2+
2+
1
cations such as Mn , Co , Ni , Zn , Cd , and Pb (Fig. S3).
1
3
2+
0
The selectivity factor, defined as F /F, for the Hg ion was also cal-
culated to give 4.5, while the factors for other metals were less
than 1.1 (Fig. 4). Moreover, 1 can give a response to Hg2+ in the
Figure 2 shows that the absorption band of 1 in the UV–vis
4
À1
À1
spectrum originally appears at 393 nm (
in a solution of 30:70 MeOH/H O. As soon as the Hg ion was
added at room temperature, the absorption maximum of 1 at
e
= 3.6 Â 10
M cm )
2
+
2
3
93 nm decreases gradually whereas a new absorption maximum
4
À1
À1
at 443 nm (
e
= 5.1 Â 10 M cm ) increases with an isosbestic
point at 410 nm. The shift in the absorption band reached a maxi-
mum within 10 min, indicative of a rapid desulfurization of 1
(Fig. S1).
Excess metal ion salts (50 equiv, chlorides as counteranions) of
+
+
+
+
+
2+
2+
2+
2+
2+
2+
2+
2+
Li , Na , K , Ag , Cs , Mg , Ca , Mn , Co , Ni , Cu , Zn , Sr
,
2
+
2+
2+
2+
Cd , Ba , Hg , and Pb (total of 17) were tested to investigate
2+
selectivity. Only the Hg ion promoted a bathochromic shift in
the UV–vis absorbance from 393 to 443 nm, while other metal ions
did not cause any significant changes under identical conditions
(
1
Fig. 3a). Figure 3b shows the absorption spectra of 1, 2, and
2
+
2+
+ Hg , respectively. The absorption spectra of 2 and 1+Hg are
2
+
nearly identical, indicating that desulfurization of 1 by Hg ions
affords 2 with a short reaction time.
The selectivity of probe 1 for the Hg2 ion was also observed by
+
fluorescence measurements. The fluorescence intensity of 1 at kem
Figure 2. Absorption spectra of 1 (10.0
0:70 MeOH/H O.
l
M) at different concentrations of Hg2+ in
4
81 nm (kex 393 nm) decreased significantly upon the addition of
3
2
2
+
1
0 equiv of Hg ion to 1 (2.0 lM) in aqueous methanol (30:70 meth-
anol/water (v/v), 50 mM HEPES at pH 7.4), as shown in Figure S2.
The results of cation competitive experiments are also depicted
2
+
in Figure S3. The selectivity and sensitivity of 1 toward Hg were
not influenced by biologically active metal ions such as highly con-
+
+
2+
2+
centrated Na , K , Ca , and Mg (100 equiv). Compound 1 re-
Scheme 1. Synthetic scheme of 1.
+
+
+
Figure 3. (a) Absorption spectra of 1 (10.0 lM) upon the addition of Li , Na , K ,
+
+
2+
2+
2+
2+
2+
2+
2+
2+
2+
2+
2+
2+
Ag , Cs , Mg , Ca , Mn , Co , Ni , Cu , Zn , Sr , Cd , Ba , Hg , and Pb
50 equiv, respectively) in 30:70 MeOH/H O. (b) Normalized absorption spectra of 1
(red), 2 (black), and 1+30 equiv of Hg (blue).
(
2
2
+
Figure 1. Crystallographic representation of probe 1.

5
960
J. H. Kim et al. / Tetrahedron Letters 50 (2009) 5958–5961
Figure 4. Selectivity of 1 (2.0
l
M) with different metals (100 equiv, except 10 equiv
2+
2
Hg ) in 30:70 MeOH/H O (50 mM HEPES at pH 7.4), where F is an initial
0
fluorescence intensity of 1 at kem 481 nm (kex 393 nm) and F is the intensity after
the addition of each metal.
Figure 6. Mercuric ion sensitivity of 1 (2.0
at pH 7.4). kex 393 nm and kem 481 nm.
2
lM) in 30:70 MeOH/H O (50 mM HEPES
‘
naked-eye’ manner (inset of Fig. 3b). For the Hg2+-induced
chemodosimetric mechanism, the reactivity of 1 toward other
thiophilic metal cations (Cu2 and Ag ) was also investigated by
measuring fluorescence intensities centered at 481 nm; no fluores-
cence changes occurred in 1.
+
+
2+
the presence of Hg at room temperature. Upon the addition of
2
+
Hg (3.0 equiv) into 1 in a 50:50 CD CN:D O, the 1,3-dithiane
methine proton at d 5.92 ppm disappeared with a concomitant
appearance of a new peak at d 10.13 ppm, assignable to the corre-
3
2
The fluorescence responses of 1 to metal ions were also detect-
able by using a fluorescence microscope (kex band 330–385 nm,
1
2+
sponding aldehyde proton of 2. The H NMR spectrum of 1+Hg
k
em 400 nm). The obvious fluorescence decrease was prominently
was identical to that of the standard, 2 (Fig. S6). In addition, the
mass spectrum of the isolated product from the reaction was the
same as that of 2, demonstrating that 1 was, indeed, transformed
2+
observed exclusively for the Hg ion. Most other metal ions did
not induce the significant fluorescence change in 1 (Fig. 5).
2+
2+
To examine the sensitivity of 1 for Hg ion sensing, its fluores-
into 2 by Hg ions.
2+
cence intensity versus [Hg ] was plotted (Fig. 6). Upon variation of
the Hg ion concentration from 4.0 to 200
the addition of, at most, 10
the fluorescence of 1 (2.0
To address the possibility of interference from other chelating
2
+
2+
l
M, it was found that
M Hg2 ions, completely quenched
M) in buffered aqueous methanol
chemicals for the Hg ion-mediated desulfurization of 1, EDTA
+
2+
l
l
was added to the 1ÀHg solution. The resulting red-shifted
2
+
absorption bands of 1 caused by Hg showed no absorption
changes upon the addition of highly concentrated EDTA (10 mM),
demonstrating that unlike other chemosensors, chemodosimeter
1 proceeds by an irreversible chemical reaction upon the addition
(
30:70 methanol/water, 50 mM HEPES at pH 7.4) (Fig. 6). The sen-
2+
sitivity curve is indicative of less than 2.0 ppm of Hg ion detect-
able. This indicates that probe 1 can be utilized in the analysis of
micromolar concentrations of Hg2 ions present in water and en-
ables its application in fish assays and drinking water for safe hu-
man consumption.
To gain a deeper insight into the possible utility of 1 as a Hg
chemodosimeter, Hg was added to samples of deproteinized hu-
man blood plasma containing 1. Almost immediately, the UV–vis
absorbance of 1 bathochromically shifted and the fluorescence
intensity decreased, which is in good accordance with those tested
in the absence of blood plasma (Fig. S5).
+
2+
of Hg (Fig. S4).
From the results observed, the authors propose a Hg2+-pro-
1
0
moted desulfurization mechanism. The coordination of HgCl with
2
2
+
the sulfur atom, due to the thiophilicity of the mercuric ion, acti-
2
+
vates the carbon atom of the thioacetal that is then hydrolyzed
by water to afford the corresponding aldehyde unit (Scheme S1).
In summary, a water-soluble coumarin derivative (1) capable of
2
+
chemodosimetric Hg ion detection was synthesized. Not only col-
or changes and UV–vis changes, but also fluorescence changes of 1
1
2+
Changes in H NMR spectroscopic and mass spectrometric anal-
were eminently shown upon the addition of Hg , from which
2
+
yses also enabled confirmation of the transformation of 1 into 2 in
chemodosimeter 1 exclusively detected the Hg
ion with a
2
ppm detection limit within less than a reaction time of 1 min.
2
+
Compound 1 exhibited a high selectivity toward Hg that was
unimpeded by the presence of other metal ions. Chemodosimeter
2
+
1
and its selective and sensitive Hg detection in aqueous systems
give a potential guideline in biological and environmental applica-
tion-oriented chemodosimeter research.
Acknowledgments
This work was supported by the Creative Research Initiative
Program of the MEST, SRC (No. R11-2005-008-00000-0) and KRF
(
KRF-2008-313-C00501 and KRF-2008-313-C00508).
Supplementary data
Figure 5. Fluorescence microscopic images of 1 (30
the presence of various metals (each in 100 equiv). kex band 330–385 nm, kem
00 nm, scale bar 50 m.
lM, 50 mM HEPES at pH 7.4) in
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.045.
4
l

J. H. Kim et al. / Tetrahedron Letters 50 (2009) 5958–5961
5961
T.; Iwata, H.; Tanaka, R.; Lmajo, S.; Ishiguro, M. J. Chem. Soc., Chem. Commun.
991, 662.
References and notes
1
6
7
.
.
Weiying, L.; Lin, Y.; Wen, T.; Jianbo, F.; Lingliang, L. Chem. Eur. J. 2009, 15, 2305.
(a) Soderquist, J. A.; Miranda, E. I. J. Am. Chem. Soc. 1992, 114, 10078; (b) Vedejs,
E.; Fuchs, P. L. J. Org. Chem. 1971, 36, 366.
(a) Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron Lett. 1989, 30, 13; (b) Fujita,
E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull. 1978, 26, 3743; (c) Corey, E. J.; Boch,
M. G. Tetrahedron Lett. 1975, 16, 2643.
(a) Wu, J. S.; Liu, W. M.; Zhuang, X. Q.; Wang, F.; Wang, P. F.; Tao, S. L.; Zhang, X.
H.; Wu, S. K.; Lee, S. T. Org. Lett. 2007, 9, 33; (b) Kim, T.-K.; Lee, D.-N.; Kim, H.-J.
Tetrahedron Lett. 2008, 49, 4879.
1
.
(a) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J. M.;
McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997, 97, 1515; (b) Valeur,
B.; Leray, I. Coord. Chem. Rev. 2000, 205, 3; (c) Kim, S. K.; Lee, S. H.; Lee, J. Y.; Lee,
J. Y.; Bartsch, R. A.; Kim, J. S. J. Am. Chem. Soc. 2004, 126, 16499; (d) Kim, S. K.;
Bok, J. H.; Bartsch, R. A.; Lee, J. Y.; Kim, J. S. Org. Lett. 2005, 7, 4839; (e) Lee, J. W.;
Jung, H. S.; Kwon, P. S.; Kim, J. W.; Bartsch, R. A.; Kim, Y.; Kim, S.-J.; Kim, J. S.
Org. Lett. 2008, 10, 3801; (f) Kim, J. S.; Quang, D. T. Chem. Rev. 2007, 107, 3780;
8
9
.
.
(
g) Kim, H. N.; Lee, M. H.; Kim, H. J.; Kim, J. S.; Yoon, J. Chem. Soc. Rev. 2008, 37,
1
465; (h) Lee, M. H.; Lee, S. W.; Kim, S. H.; Kang, C.; Kim, J. S. Org. Lett. 2009, 11,
1
0. U.S. EPA, Regulatory Impact Analysis of the Clean Air Mercury Rule: EPA-452/R-
5-003, 2005.Preparation of (1): To a solution of 500 mg (3.0 mmol) of 2 in
.0 mL of ethyl ether were added dropwise 505 L (6.0 mmol) of ethanedithiol
and 184 (1.5 mmol) of boron trifluoride etherate for 24 h at room
temperature and then evaporated in vacuo. The resulting solid was dissolved
in CH Cl2, and the organic layer was washed three times with water, dried over
anhydrous MgSO , filtered, evaporated, and recrystallized from n-hexane to
give 250 mg (yellow solid, 38%) of 1. Mp: 116–118 °C. H NMR (300 MHz,
CDCl ): d 7.91 (s, 1H, ArH), 7.28 (s, 1H, ArH), 6.59–6.55 (dd, 1H, ArH, J = 2.53 Hz,
.78 Hz), 6.49–6.48 (d, 1H, ArH, J = 2.49 Hz), 5.73 (s, 1H, CH), 3.44–3.37 (q, 4H,
CH CH J = 7.09 Hz), 3.32 (s, 4H, SCH CH S), 1.22–1.17 (t, 6H, CH CH
J = 7.05 Hz). C NMR (100 MHz, CDCl ): 155.4, 139.3, 129.2, 121.7, 109.0,
7.2, 50.5, 45.0, 39.1, 12.6 ppm. FAB MS m/z (M ): calcd, 321.09; found, 321.38
2
101.
0
2
.
(a) Clarkson, T. W.; Magos, L.; Myers, G. J. Engl. J. Med. 2003, 349, 1731; (b)
Harada, M. Crit. Rev. Toxicol. 1995, 25, 1; (c) Grandjean, P.; Weihe, P.; White, R.
F.; Debes, F. Environ. Res. 1998, 77, 165; (d) Matsumoto, H.; Koya, G.; Takeuchi,
T. J. Neuropathol. Exp. Neurol. 1965, 24, 563.
(a) Chea, M.-Y.; Czarnik, A. W. J. Am. Chem. Soc. 1992, 114, 9704; (b) Yang, Y.-K.;
Yook, K.-J.; Tae, J. J. Am. Chem. Soc. 2005, 127, 16760; (c) Song, F.; Watanabe, S.;
Floreancig, P. E.; Koide, K. J. Am. Chem. Soc. 2008, 130, 16460.
5
l
l
L
2
3
.
.
4
1
3
4
(a) Corey, E. J.; Erikson, B. W. J. Org. Chem. 1971, 36, 3553; (b) Rama Rao, A. V.;
Venkatswamy, G.; Javeed, S. M.; Deshpande, V. H.; Rao, B. R. J. Org. Chem. 1983,
8
2
3
,
2
2
2
3
,
4
8, 1552; (c) Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891; (d) Nishide, K.;
13
3
Yokota, K.; Nakamura, D.; Sumiya, T.; Node, M. Tetrahedron Lett. 1993, 34, 3425.
(a) Narasaka, K.; Sakashita, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1972, 45,
+
9
5
.
+
(
1), 322.39 (1+H ). IR
m
= 2969, 2926, 2356, 1706, 1606, 1528, 1421, 1363,
3
724; (b) Stütz, P.; Stadler, P. A. Org. Synth. Colloid 1988, 6, 109; (c) Nakatsuka,
À1
1
271, 1235, 1185, 1135, 792 cm
.