An anthracene-based Cd2+ fluorescent chemosensor with a 4,7-bis(2-hydroxyethyl)-9-hydroxy-1,4,7-triazanonyl group as a highly selective chelator to Cd2+ over Zn2+

Article abstract of DOI:10.1016/j.tetlet.2013.08.055

We have developed a Cd²⁺ fluorescent chemosensor with high selectivity as well as sensitivity by tethering a 4,7-bis(2-hydroxyethyl)-9- hydroxy-1,4,7-triazanonyl chelator to anthracene. This sensor features the ability to discriminate Cd²⁺ from Zn²⁺ to a high degree (K_dZn/K_dCd = 560) in a pH 7.2 buffer.

Full text of DOI:10.1016/j.tetlet.2013.08.055

Tetrahedron Letters 54 (2013) 5971–5973
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An anthracene-based Cd2+ fluorescent chemosensor
with a 4,7-bis(2-hydroxyethyl)-9-hydroxy-1,4,7-triazanonyl
group as a highly selective chelator to Cd2+ over Zn2+
⇑
Koji Tsukamoto , Shogo Iwasaki, Mari Isaji, Hatsuo Maeda
School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe 650-8530, Japan
a r t i c l e i n f o
a b s t r a c t
We have developed a Cd2+ fluorescent chemosensor with high selectivity as well as sensitivity by tether-
ing a 4,7-bis(2-hydroxyethyl)-9-hydroxy-1,4,7-triazanonyl chelator to anthracene. This sensor features
the ability to discriminate Cd2+ from Zn2+ to a high degree (KdZn/KdCd = 560) in a pH 7.2 buffer.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 28 June 2013
Revised 9 August 2013
Accepted 16 August 2013
Available online 28 August 2013
Keywords:
Fluorescence
Chemosensor
Cadmium
Zinc
Anthracene
Although cadmium (Cd) has been recognized as a highly toxic
heavy metal,1 human and environmental health is still threatened
by Cd discharged through production activity such as industry and
agriculture.2 Therefore, much effort has been made on designing
high sensitive and selective fluorescent sensors for Cd2+ based on
coordination chemistry, leading to recent development of the sen-
sors.3 However, in aqueous solutions, most of them can provide re-
sponse toward Zn2+ as well. This is because both Cd2+ and Zn2+
have similar chemical and physical properties, making it difficult
to distinguish between them.3,4 One of the highest Cd2+-selective
sensors reported so far is the BODIPY derivative with a tetraamide
is because the differences in dissociation constants for Cd2+ (KdCd
)
and Zn2+ (KdZn) are not sufficiently large in many cases. With these
facts for a background, it is still a challenge to develop a fluorescent
sensor for Cd2+ with a high selectivity over Zn2+ as well as
sensitivity.
Herein, we report a novel anthracene-based Cd2+ sensor 1
(Scheme 1), which allows highly selective detection of Cd2+ even
in the presence of Zn2+ in a pH 7.2 buffer. The sensor features a
1,4,7-triazanonyl group, which functions as a Cd2+-selective chela-
tor with three hydroxy groups as ligands, and confers high water-
solubility on 1. In addition, we describe that N-methylated 1, that
is, 2 exhibited very low responsiveness toward Cd2+, which was
informative to elucidate the origin of the performance of 1 as a
Cd2+ sensor.
Sensor 1 was prepared by reductive amination of anthracene-9-
carbaldehyde with 6-(2-aminoethyl)-3-(2-hydroxyethyl)-3,6-dia-
zaoctan-1,8-diol in 75% yield (see Supplementary data). It should
be mentioned here that 1 is water-soluble, and can be handled as
aqueous working solutions without any organic solvents. Com-
group as a chelator for Cd2+ 3e
With this sensor, marked reduction
.
in response toward Zn2+ is realized. And yet the association con-
stants K11 and K21 for the 1:1 and 2:1 complexes with Cd2+ are as
low as 1.3 Â 105 and 7.2 Â 103 M–1, respectively. Thus it could be
accepted that the higher affinity to Cd2+ a chemosensor has, the
less selectivity to Cd2+ over Zn2+ the sensor exhibits. Meanwhile,
it has been described that design to make a difference between
binding modes against Cd2+ and Zn2+ allowed chemosenors to pro-
vide fluorescent responses at different emission wavelengths to-
ward these metal ions.5 They are superior to sensors working at
a single emission wavelength, due to their utility as dual sensors
for Cd2+ and Zn2+. However, in the presence of Zn2+, Cd2+ is likely
to compete with Zn2+ in chelation with those dual sensors. This
R
N
OH
OH
N
N
OH
1: R = H, 2: R = Me
Scheme 1. Chemical structures of 1 and 2.
⇑
Corresponding author. Tel.: +81 78 304 3175; fax: +81 78 304 2875.
E-mail address: kotukamoto@huhs.ac.jp (K. Tsukamoto).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.055

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K. Tsukamoto et al. / Tetrahedron Letters 54 (2013) 5971–5973
Figure 2. Effects of metal ions (5 mM of Ca2+ and Mg2+, and 5
Mn2+, Fe3+, Co2+, Ni2+, Ag+, Pb2+, Cu2+ and Hg2+) on the fluorescence intensity ratio
(F/F0) from the addition of 1 equiv of Cd2+ into 1 (5
M). F0: fluorescence intensity of
1 (5 M) without any metal ions. As metal reagents, CdCl2, Zn(NO3)2, CaCl2, MgCl2,
l ,
M of Zn2+, Cr3+
l
l
CrCl3, MnCl2, FeCl3, CoCl2, NiCl2, AgNO3, Pb(NO3)2, CuCl2, and HgCl2 were used. All
measurements were taken in a pH 7.2 HEPES buffer (50 mM, I = 0.1 M (KNO3)),
kex = 370 nm, and kem = 416 nm. Error bars represent standard deviations (n = 4).
Figure 1. (a) Fluorescence spectra of 1 (5 l
M) upon the addition of Cd2+. (b) A plot
of the difference between the fluorescence intensities (F – F0) at kem = 416 nm
obtained before and after the addition of Cd2+ into a solution of 1 (5
lM) as a
than pH 6, the background response became high, that would be
attributed to protonation of the N atom in 1, to prevent the PET ef-
fect in 1 from working. With these results in hands, it was con-
cluded that a buffer around pH 7.2 is a solvent of choice for high
selective detection of Cd2+ over Zn2+ using 1.
function of equiv of Cd2+. CdCl2 was used as a Cd2+ reagent. All measurements were
taken in a pH 7.2 HEPES buffer (50 mM, ionic strength (I) = 0.1 M (KNO3)) and
kex = 370 nm. Error bars represent standard deviations (n = 4).
To investigate the detailed mechanism of the reaction of 1 with
Cd2+, N-methylated derivative 2 was prepared and subjected to
fluorometry in the absence or presence of Cd2+ (Figs. S8 and S9).
To our surprise, addition of 1 equiv of Cd2+ to a solution of 2 in
any pH conditions gave rise to little or no enhancement in the fluo-
rescence intensity. The apparent KdCd of 2 at pH 7.2 was estimated
to be 2.1 Â 10–4 M, which was larger by three orders of magnitude
than that of 1 (Fig. S3). On 1H NMR spectra in D2O, all signals for 1
or 2 were shifted downfield in the same manner by the addition of
Cd2+ (Fig. 3). The downfield shift in all the region would be caused
by the shielding effect of Cd2+ chelated with the 1,4,7-triazanonyl
group in 1 or 2.9 Moreover, 8-(anthracen-9-yl)-1,4,7-triazaoctane
8, lacking three 2-hydroxyethyl groups on 1, showed a lower fluo-
pound 1 exhibited a suppressed fluorescent spectrum in a pH 7.2
HEPES buffer (50 mM, I = 0.1 M (KNO3)), and its quantum yield
(a) was estimated to be as low as 0.24 at kex = 370 nm (Fig. 1).6 This
would be ascribed to photo-induced electron transfer (PET) from
the N atom adjacent to the anthracene moiety of 1 (Scheme 2).7
Upon the addition of Cd2+, the fluorescent response from 1 was en-
hanced, and a linear relationship was observed between the re-
sponses and the concentration of Cd2+ up to 0.5 equiv (2.5
lM)
(Fig. 1b). By further addition of Cd2+, the fluorescence intensity in-
creased nonlinearly, and reached a plateau. When 1.0 or 2.0 equiv
of Cd2+ was added, the quantum yield of 1 was recovered to 0.43 or
0.47, respectively (Table S1). A Job’s plot of an increase in the fluo-
rescence intensity due to the reaction of 1 with Cd2+ showed a
maximum at a mole fraction ([1]/([1] + [Cd2+])) of 0.5, which
clearly indicated the formation of a 1:1 complex (Fig. S2). The
apparent dissociation constant of 1 for Cd2+ (KdCd) was estimated
to be 1.0 Â 10–7 M, which is so small as to realize highly sensitive
detection for Cd2+ (Fig. S3).8
In contrast with the case of Cd2+, 1 equiv of Zn2+ was added to a
solution of 1, bringing about negligible increment in the fluores-
cence intensity (Fig. 2 and Fig. S5). The apparent dissociation con-
stant of 1 for Zn2+ (KdZn) was estimated by fluorometry to be
5.6 Â 10–5 M (Fig. S3). This value was 560 times larger than the
KdCd, demonstrating that 1 can distinguish Cd2+ from Zn2+ with
high selectivity. The effects by other metal ions (5 mM of Ca2+
and Mg2+, and 5 M of Cr3+, Mn2+, Fe3+, Co2+, Ni2+, Ag+, Pb2+, Cu2+
l
and Hg2+) were also examined. The fluorescence response induced
by the reaction of 1 with Cd2+ was not disturbed by the examined
metal ions, except for Cu2+ and Hg2+ (Fig. 2 and Fig. S5). The pres-
ence of Cu2+ or Hg2+ quenched the fluorescence response of 1 to-
ward Cd2+. Since practical samples might include Cu2+, the effect
by Cu2+ must be solved.
Next, the effect of pH on the fluorescence intensity of 1 itself
was examined (Fig. S7). The intensity was decreased from pH 6.0
to 9.2, probably due to an increase in the PET quenching effect
through the deprotonation of the N atom adjacent to the anthra-
cene in 1. Although the background signal was significantly low
in these basic conditions, the fluorescent response for the reaction
of 1 not only with Cd2+ but also with Zn2+ increased greatly
(Fig. S7), that is, the selectivity of 1 for Cd2+ over Zn2+ became
poorer with an increase in basicity. Under acidic conditions less
Figure 3. 1H NMR spectra (400 MHz) of 1 and 2 (10 mM) in the absence or presence
of 1 equiv of Cd2+ measured in D2O: (a) 1; (b) 1 with CdCl2 (10 mM); (c) 2 with CdCl2
(10 mM); (d) 2.

K. Tsukamoto et al. / Tetrahedron Letters 54 (2013) 5971–5973
5973
Supplementary data
PET
OH
OH
quenching
H
N
HO
N
Cd2+
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
08.055.
N
N
HO
N
H
Cd2+
N
OH
N
O
H
1
References and notes
OH
OH
1. (a) Waisberg, M.; Joseph, P.; Hale, B.; Beyersmann, D. Toxicology 2003, 192, 95;
(b) Bridges, C. C.; Zalups, R. K. Toxicol. Appl. Pharmacol. 2005, 204, 274; (c) Pari, L.;
Murugavel, P.; Sitasawad, S. L.; Kumar, K. S. Life Sci. 2007, 80, 650.
2. Grant, C. A. Pedologist 2011, 143.
N
N
Cd2+
HO
Cd2+
N
N
HO
OH
N
3. (a) Gunnlaugsson, T.; Lee, T. C.; Parkesh, R. Org. Lett. 2003, 5, 4065; (b) Peng, X.;
Du, J.; Fan, J.; Wang, J.; Wu, Y.; Zhao, J.; Sun, S.; Xu, T. J. Am. Chem. Soc. 2007, 129,
1500; (c) Liu, W.; Xu, L.; Sheng, R.; Wang, P.; Li, H.; Wu, S. Org. Lett. 2007, 9,
3829; (d) Taki, M.; Desaki, M.; Ojida, A.; Iyoshi, S.; Harayama, T.; Hamachi, I.;
Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 12564; (e) Cheng, T.; Xu, Y.; Zhang, S.;
Zhu, W.; Qian, X.; Duan, L. J. Am. Chem. Soc. 2008, 130, 16160; (f) Liu, Z.; Zhang,
C.; He, W.; Yang, Z.; Gao, X.; Guo, Z. Chem. Commun. 2010, 6138; (g) Sahana, A.;
Banerjee, A.; Lohar, S.; Guha, S.; Das, S.; Mukhopadhyay, S. K.; Das, D. Analyst
2012, 137, 3910; (h) Li, Y.; Chong, H.; Meng, X.; Wang, S.; Zhu, M.; Guo, Q. Dalton
Trans. 2012, 41, 6189.
O
H
2
Scheme 2. Proposed mechanism for coordination of 1 and 2 to Cd2+
.
rometric response to Cd2+ than 1, which confirmed the necessity of
the three 2-hydroxyethyl groups for high reactivity of 1 to Cd2+
(Fig. S10). Based on these results, 1 would bind Cd2+ tightly to can-
cel the PET quenching, whereas 2 might also coordinate Cd2+, and
yet some steric hindrance around the N atom adjacent to the
anthracene could prevent the N atom from contacting the chelated
Cd2+ (Scheme 2).
4. Even excellent fluorescent sensors for Zn2+ can also respond to Cd2+
; for
examples of Zn2+ sensors, see: (a) Maruyama, S.; Kikuchi, K.; Hirano, T.; Urano,
Y.; Nagano, T. J. Am. Chem. Soc. 2002, 124, 10650; (b) Taki, M.; Wolford, J. L.;
O’Halloran, T. V. J. Am. Chem. Soc. 2004, 126, 712; (c) Aoki, S.; Kagata, D.; Shiro,
M.; Takeda, K.; Kimura, E. J. Am. Chem. Soc. 2004, 126, 1337; (d) Henary, M. M.;
Wu, Y.; Fahrni, C. J. Chem. Eur. J. 2004, 10, 3015; (e) Komatsu, K.; Kikuchi, K.;
Kojima, H.; Urano, Y.; Nagano, T. J. Am. Chem. Soc. 2005, 127, 10197; (f) Nolan, E.
M.; Ryu, J. W.; Jaworski, J.; Feazell, R. P.; Sheng, M.; Lippard, S. J. J. Am. Chem. Soc.
2006, 128, 15517; (g) Hanaoka, K.; Muramatsu, Y.; Urano, Y.; Terai, T.; Nagano, T.
Chem. Eur. J. 2010, 16, 568.
In conclusion, we have demonstrated that 1 functions as a fluo-
rescent sensor for Cd2+ with high selectivity as well as high sensi-
tivity in a pH 7.2 buffer. Especially, 1 can distinguish Cd2+ from
Zn2+ to a remarkably high degree (KdZn/KdCd = 560). The difference
between 1 and 2 in fluorescent responses toward Cd2+ suggests the
important factor of the steric hindrance around the N atom adja-
cent to the anthracene. This finding is believed to provide useful
structural information for designing more practical Cd2+ sensors.
We are currently working on decreasing the blank signal in the ab-
sence of Cd2+, and on increasing the selectivity for Cd2+ over Cu2+
5. (a) Xue, L.; Liu, C.; Jiang, H. Org. Lett. 2009, 11, 1655; (b) Xu, Z.; Baek, K.-H.; Kim,
H. N.; Cui, J.; Qian, X.; Spring, D. R.; Shin, I.; Yoon, J. J. Am. Chem. Soc. 2010, 132,
601; (c) Jia, J.; Xu, Q.-C.; Li, R.; Tang, X.; He, Y.-F.; Zhang, M.-Y.; Zhang, Y.; Xing,
G.-W. Org. Biomol. Chem. 2012, 10, 6279; (d) Wang, J.; Lin, W.; Li, W. Chem. Eur. J.
2012, 18, 13629; (e) Cai, Y.; Meng, X.; Wang, S.; Zhu, M.; Pan, Z.; Guo, Q.
Tetrahedron Lett. 2013, 54, 1125.
6. Absorption spectra and calculation of relative quantum yields (a) of 1 in the
absence or presence of Cd2+ are summarized in Figure S1 and Table S1.
7. 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.
and Hg2+ as well as Zn2+
.
8. Using CdBr2, CdSO4, Cd(OAc)2, Cd(ClO4)2 or Cd(NO3)2 instead of CdCl2 as a Cd2+
reagent, the fluorescent response of 1 toward Cd2+ was not changed, which was
indicative that the counterion of Cd2+ would have no influence on the Cd2+
sensing of 1 (Fig. S4).
Acknowledgments
9. Although the anthracene moiety might form the cation-
would be anticipated that the cation-
interaction of Cd2+ is not likely to be
p
interaction to Cd2+, it
This work was supported by the Grant-in-Aid for Academic Re-
search from the Iijima Memorial Foundation for the Promotion of
Food Science and Technology, and the Grant for Young Scientist
from Hyogo University of Health Sciences.
p
formed in aqueous solution. Li, Z. H.; Liu, J.; Qiao, M.; Fan, K.-N. Mol. Phys. 2009,
107, 1271.