A highly selective and sensitive fluorescent chemosensor for Fe 3+ in physiological aqueous solution

Article abstract of DOI:10.1246/cl.2005.98

A novel fluorescent chemosensor in which two aza-18-crown-6 moieties are linked to a coumarin fluorophore has been synthesized for sensing Fe ³⁺. The selective fluorescence enhancement was observed upon binding Fe³⁺ at physiological

Full text of DOI:10.1246/cl.2005.98

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8
Chemistry Letters Vol.34, No.1 (2005)
A Highly Selective and Sensitive Fluorescent Chemosensor for Fe3
in Physiological Aqueous Solution
þ
ꢀ
Jun Hua and Yan-Guang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
(Received September 28, 2004; CL-041145)
A novel fluorescent chemosensor in which two aza-18-
crown-6 moieties are linked to a coumarin fluorophore has been
O
Cl
O
Cl
Cl
synthesized for sensing Fe3 . The selective fluorescence en-
þ
Et3N/Et2O, 0 oC, 4 h
H2N
OH
HN
OH
3þ
3
hancement was observed upon binding Fe at physiological
conditions (pH ¼ 7:4, ½NaClꢁ ¼ 0:135 M, ½KClꢁ ¼ 0:01 M),
2
þ
2þ
þ
þ
2þ
2þ
2þ
whereas other metal ions, such as Li , Na , K , Mg , Ca ,
2þ
2þ
2þ
2þ
2þ
O
O
Cu , Zn , Co , Ni , Mn , Hg and Pb produced no
effect.
7
0% H2SO4
Cl
O
OEt
O
O
O
O
O
O
O
O
O
NH
Cl
Considerable research interest has been focused on the de-
velopment of chemosensors for the selective and efficient detec-
tion of chemically and biologically important ionic species in bi-
O
N
O
O
O
O
O
O
Et3N/MeCN
reflux, 40 h
Cl
N
N
O
O
1
N
H
H
ological and environmental science. The design and synthesis
of a sensitive and selective fluorescent chemosensors is a basic
O
O
1
4
2
aim for organic and analytical chemists. An important area
within this field is the development of new fluorescent chemo-
sensors for many heavy and transition metal ions, particularly
Scheme 1. Synthesis of the chemosensor 1.
which might be able to bind selectively with a metal ion. The pri-
mary test showed that 1 possesses a highly selective and sensi-
tive response of fluorescence enhancement (FE) toward Fe
in neutral buffer aqueous solution.
The synthesis of chemosensor 1 is shown in Scheme 1. At-
kins’ method was used for the preparation of 4-chloromethyl-7-
chloroacetamidocoumarin (4) from 3-aminophenol (2).9
acetylation of the amino group of 2 afforded chloroacetamido-
phenol (3) in 90% yield. A Pechmann condensation of 3 with
ethyl 4-chloroacetoacetate gave 4 in 60% yield. Alkylation of
1-aza-18-crown-6 with 4 afforded compound 1 in 42% yield.11
The photochromic and fluorescence properties of chemosen-
sor 1 were investigated by absorption and fluorescence measure-
ments. After a preliminary survey with various solvent systems,
we have focused our attention on aqueous solution for possible
applications of the present system in the metal ion analysis of
biological samples.
3
in critical analysis of biological (blood and serum) samples
4
3þ
and real-time detection of live cells. The metal–ligand coordi-
native interaction displays its superiorities to hydrogen bonding
and electrostatic interaction in a polar environment. Therefore,
5
the metal–ligand complexes have been reported for effective and
selective recognition of metal ions. Crown ether derivatives are
known to form complexes with various cations and anions selec-
tively. There are numerous examples in the literature of crown
ethers used as sensors for a broad range of metal ions.1
a,10
The
,6
Iron is an essential element for human and plays an impor-
tant role in biochemical and nutritional processes. Many proteins
and enzymes contain ferric ions either for structural purposes or
7
as part of a catalytic site. Therefore, the development of selec-
tive as well as sensitive fluorescent sensors for ferric ions pres-
ents a challenge. However, only a few example of fluorescent
3
þ
8
chemosensor for Fe has been described.
Coumarins generally show good spectral features such as
large Stokes shifts and high quantum yields and have been suc-
ꢃ6
Fluorescence emission titrations of 1 ꢂ 10 M of 1 with
þ
þ
þ
100 equiv. of group I (Li , Na , K ), 1 equiv. of group II
2þ 2þ
9
cessfully employed as PET chemosensor devices. Coumaryl
crown ether based chemosensors were reported to be able to de-
tect selectively saxitoxin in the presence of sodium and potassi-
um ions.9 Mizukami et al. designed and synthesized a fluores-
cent sensor for anions, which contains 7-amino-4-trifluorome-
thylcoumarin as a fluorescent reporter and Cd(II)-cyclen
(Mg , Ca ), and heavy and transition metal ions group III
2
þ 2þ 2þ 2þ 2þ 3þ 2þ 2þ
(Cu , Zn , Co , Ni , Mn , Fe , Hg , Pb ) (as their
ꢃ
ꢃ
ꢃ
Cl , NO3 , or ClO4 salts) are performed in buffered HEPES
solution (0.1 M, pH 7.4) (Figure 1). The results showed that
the alkali and alkaline earth metal ions did not cause significant
changes in fluorescence emission spectra of 1. However, chemo-
sensor 1 has different degree of fluorescence enhancement with
heavy and transition metal ions. In fluorescence titration studies,
chemosensor 1 displayed 15-, 2.5-, and 1.9-fold fluorescence en-
a
9c
4
d
(
ported Mg -selective fluoroionophores based on a coumarin
1,4,7,10-tetraazacyclododecane) as an anion host. Suzuki re-
2þ
derivative and used for Mg2 measurement in a living cell. Here,
þ
3
þ
2þ
2þ
we would like to report a novel and selective fluorescent chemo-
hancements for Fe , Cu , and Hg among 13 metals investi-
gated, respectively. Furthermore, red shift absorption was
3
þ
.
sensor for Fe
3
þ
We designed a sensor molecule 1, in which two aza-18-
crown-6 moieties are linked to a coumarin fluorophore, and hope
this molecule to adopt a semirigid V-shaped conformation,
observed on the addition of Fe . It is worth noting that the
complex 1ꢄFe exhibits 8-nm-red shift. The red shift may be
3þ
due to the intramoleucular excimer formation that is caused by
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.1 (2005)
99
3+
Fe
This work was supported by 973 Program of the Ministry of
Science and Technology (No. 2002CB713808) as well as the
Teaching and Research Award Program for Outstanding Young
Teachers in Higher Education Institutions of MOE, P. R. C.
200
150
100
References and Notes
1
G. W. Gokel, W. M. Leevy, and M. E. Weber, Chem. Rev.,
04, 2723 (2004).
1
2
+
2+
2+
2+
2+
2+
2
a) X. F. Guo, X. H. Qian, and L. H. Jia, J. Am. Chem. Soc.,
126, 2272 (2004). b) Y. J. Zheng, X. H. Cao, J. Orbulescu,
V. Konka, F. M. Andreopoulos, S. M. Pham, and M.
Leblanc, Anal. Chem., 75, 1706 (2003). c) T. Gunnlaugsson,
T. C. Lee, and R. Parkesh, Org. Lett., 5, 4065 (2003). d) S. Y.
Moon, N. R. Cha, Y. H. Kim, and S. K. Chang, J. Org.
Chem., 69, 181 (2004).
(
Co , Ni , Mn , Zn , Pb , Hg
)
5
0
2+
2+
(
Mg , Ca
)
2
+
Cu
+
+
+
(
Li , Na , K )
1
0
4
00
500
Wavelength (nm)
ꢃ5
Figure 1. Fluorescence spectra of free 1 (1 ꢂ 10 M) and 1 in
3
4
H. He, M. A. Mortellaro, M. J. P. Leiner, R. J. Fraatz, and
J. K. Tusa, J. Am. Chem. Soc., 125, 1468 (2003).
buffered HEPES solution (0.1 M, pH 7.4) in the presence of dif-
ferent metal ions (1 ꢂ 10 M) (ꢁex ¼ 336 nm).
ꢃ5
a) G. K. Walkup and S. C. Burdette, J. Am. Chem. Soc., 122,
5644 (2000). b) S. C. Burdette, G. K.Walkup, B. Spingler,
R. Y. Tsien, and S. J. Lippard, J. Am. Chem. Soc., 123,
7831 (2001). c) S. Maruyama, K. Kikuchi, T. Hirano, Y.
Urano, and T. Nagano, J. Am. Chem. Soc., 124, 10650
(2002). d) Y. Suzuki, H. Komatsu, T. Ikeda, N. Saito, S.
Araki, D. Citterio, H. Hisamoto, Y. Kitamura, T. Kubota,
J. Nakagawa, K. Oka, and K. Suzuki, Anal. Chem., 74,
1423 (2002).
a) L. Fabbrizzi, N. Marcotte, F. Stomeo, and A. Taglietti,
Angew. Chem., Int. Ed., 41, 3811 (2002). b) M. S. Han and
D. H. Kim, Angew. Chem., Int. Ed., 41, 3809 (2002).
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Poggi, and A. Taglietti, Coord. Chem. Rev., 219, 821 (2001).
b) C. T. Chen and W. P. Huang, J. Am. Chem. Soc., 124,
6246 (2002).
the decrease in the distance between two crown ethers when fer-
ric ion is bound. These results demonstrated that the selectivity
of chemosensor 1 for Fe 3 is very high.
We also tried to find the possibility of practical applicability
of this chemosensor in the analysis of biological samples by
studying the Fe -selective response of the fluorescence spectra
in the presence of background metal ions of physiologically im-
þ
3
þ
þ
þ
2þ
2þ
portant Na (0.135 M), K (0.01 M), Mg (0.001 M) and Ca
ions (0.001 M). The chemosensor 1 showed a selective response
5
6
3þ
toward Fe ions and was found to have an almost identical re-
sponse and detection limit comparable with the results obtained
in the absence of other background metal ions.
3
þ
The stoichiometry of the 1ꢄFe complex system was deter-
mined by the changes in fluorescence emission spectra of 1 in the
presence of varying concentrations of ferric ions at 412 nm. The
3
þ
results indicated that the complex has 1:1 (host 1: guest Fe
ion) stoichiometry.
The association constant Ka for the interaction of 1 with
Fe3 ions was estimated by the nonlinear curve fitting procedure
7
8
9
B. L. Vallee and D. S. Auld, ‘‘In Methods in Protein
Sequence Analysis,’’ ed. by H. Jornvall, J. O. Hoog, and
A. M. Gustavsson, Birkhauser, Basel (1991).
þ
a) J.-M. Liu, Q.-Y. Zheng, J.-L. Yang, C.-F. Chen, and Z.-T.
Huang, Tetrahedron Lett., 43, 9209 (2002). b) C. Yang and
T. S. Lee, Mol. Cryst. Liq. Cryst., 349, 283 (2000).
a) P. Kele, J. Orbulescu, T. L. Calhoun, R. E. Gawley, and
R. M. Leblanc, Tetrahedron Lett., 43, 4413 (2002). b) H.
Takakusa, K. Kikuchi, Y. Urano, S. Sakamoto, K.
Yamaguchi, and T. Nagano, J. Am. Chem. Soc., 124, 1653
(2002). c) S. Mizukami, T. Nagano, Y. Urano, A. Odani,
and K. Kikuchi, J. Am. Chem. Soc., 124, 3920 (2002).
of the fluorescence titration data. The Ka values of the 1:1 com-
2þ
3
þ
plex formation for 1ꢄFe and 1ꢄCu system were found to be
5
3
ꢃ1
1
:5 ꢂ 10 and 2:4 ꢂ 10 M , respectively.
To explore further the utility of 1 as an selective fluores-
cence chemosensor for Fe , the competition experiments were
3þ
3
þ
ꢃ5
conducted in the presence of Fe at 1 ꢂ 10 M mixed with
2þ
2þ
2þ
2þ
2þ
2þ
ꢃ5
Cu , Zn , Co , Ni , Hg , and Pb at 5 ꢂ 10 M as well
as the mixture of the metal ions in buffered HEPES solution
(
0.1 M, pH 7.4), respectively; no significant variation in its fluo-
10 R. L. Atkins and D. E. Bliss, J. Org. Chem., 43, 1975 (1978).
ꢅ
1
rescence intensity was found by comparison with that without
the other metal ions besides Fe3 . Moreover, no obvious inter-
ference was observed in its fluorescence while performing the ti-
11 Compound 1: mp>300 C; H NMR (DMSO-d6, 500 MHz):
ꢀ 2.78 (t, J ¼ 5:28 Hz ,8H), 3.51–3.57 (m, 40H), 3.61 (s,
2H), 3.89 (s, 2H), 6.50 (s, 1H), 7.58 (dd , J ¼ 2:18 Hz,
1H), 7.88 (s, J ¼ 2:18 Hz, 1H), 7.89 (s, J ¼ 2:18 Hz, 1H),
þ
3
þ
trations with Fe in the physiological important metal ions. The
3
þ
13
above results implied that its selectivity for Fe was remarkable
in physiological conditions.
In conclusion, we have designed and synthesized a new flu-
10.16 (s, 1H); C NMR (DMSO-d6): ꢀ 54.7, 56.2, 59.8,
66.7, 69.7, 70.1, 70.6, 70.9, 106.3 112.4, 114.7, 116.2
126.6, 142.2, 154.2, 155.1, 161.2, 171.7; HRMS-ESI
orescent chemosensor 1, which can detect Fe3 with an excellent
þ
(m=z): Calcd for C36H57N3O13Na ([M + Na] ) 762.3789,
Found 762.3777.
þ
selectivity and molecular sensitivity at physiological conditions.
Published on the web (Advance View) December 18, 2004; DOI 10.1246/cl.2005.98