Novel highly selective fluorescent chemosensors for Zn(II)

Article abstract of DOI:10.1016/j.tetlet.2006.01.002

Two novel fluorescent Zn²⁺ chemosensors were synthesized in four steps from inexpensive starting materials. They exhibited very strong fluorescence responses to Zn²⁺ and had remarkably high selectivity to Zn²⁺ than other m

Full text of DOI:10.1016/j.tetlet.2006.01.002

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1559–1562
Novel highly selective fluorescent chemosensors for Zn(II)
Xiang-Ming Meng, Man-Zhou Zhu, Lei Liu* and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Received 1 September 2005; revised 31 December 2005; accepted 4 January 2006
Available online 23 January 2006
Abstract—Two novel fluorescent Zn2+ chemosensors were synthesized in four steps from inexpensive starting materials. They exhibi-
ted very strong fluorescence responses to Zn2+ and had remarkably high selectivity to Zn2+ than other metal ions including Mg2+
Ca2+, Ni2+, Cu2+, and Cd2+. These two new molecules could be used as low-priced yet high-quality Zn2+ chemosensors.
ꢀ 2006 Elsevier Ltd. All rights reserved.
,
Zn2+ is the second most abundant transition metal cat-
ion in biology.1 It is required for normal growth and
development. It is also necessary for many cellular pro-
cesses such as neurotransmission and apoptosis. Cur-
rently there is a great interest in the development of
Zn2+ imaging tools for exploring the role of Zn2+ in
medicine and biology. Toward this end, a number of
Zn2+ sensor molecules such as Znpyrs, ZnAFs, and
rhodafluors have been designed and synthesized.2,3 The
application of these Zn2+ chemosensors has led to many
new exciting findings about the functions of Zn2+ in liv-
ing systems.4 Nonetheless, many of the currently avail-
able Zn2+ chemosensors are fairly complex molecules
and their syntheses are often expensive. Furthermore,
most of the currently available Zn2+ chemosensors still
suffer from disadvantages such as high interference from
other metal ions (in particular, Mg2+, Ca2+, Ni2+, Cu2+
and Cd2+).2
,
In an attempt to develop new types of Zn2+ chemosen-
sors that are easier to synthesize, we paid attention to
a very recent interesting finding by Urano et al. that
the carboxylic group plays almost no role in the fluores-
cence properties of the fluorescein molecule.5 Since fluo-
rescence probes are excellent sensors and the removal of
its carboxylic group will simplify its synthesis, we
hypothesized that by attaching appropriate chelator
groups to the decarboxylated fluorescein we would
obtain some novel Zn2+ chemosensors. Herein we report
the first successful examples of such chemosensors (1
and 2 in Scheme 1) and their syntheses and charac-
terizations.
N
N
N
N
N
N
N
N
NH
O
O
N
HN
HO
N
N
O
O
Cl
COOH
COOH
Cl
Cl
COOH
Rhodafluor-2
HO
O
O
ZnAF-1
Znpyr-4
*
Corresponding authors. Tel.: +86 5513607466; fax: +86 5513606689 (L.L.); e-mail: leiliu@ustc.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.002

1560
X.-M. Meng et al. / Tetrahedron Letters 47 (2006) 1559–1562
EtOOC
COOEt
EtOOC
COOEt
NH2
N
BrCH2COOEt
N
DMF/POCl3
86%
K2HPO4, KI, MeCN
reflux, 90%
CHO
COOH
HOOC
EtOOC
COOEt
N
O
N
O
Resorcinols
KOH/H2O
80%
oC
MeSO3H, 80
17%
X
X
X
X
HO
O
HO
O
1: X = H
2: X = Cl
3: X = H
4: X = Cl
Scheme 1.
The syntheses of sensors 1 and 2 started from aniline
(see Scheme 1). It was N-alkylated with ethyl bromo-
acetate (yield = 90%) and then formylated at the 4-posi-
tion (yield = 86%) using the standard procedures. The
subsequent acid-catalyzed condensation with resorcinol
or 6-chlororesorcinol provided the desired decarboxyl-
ated fluoresceins (yield = 17%), which were hydrolyzed
to give the final products (yield = 80%).6–9 Thus, sensors
1 and 2 were successfully synthesized via four steps from
readily available starting materials with an overall yield
of 11%.
The maximum absorption wavelengths of 1 and 2 were
495 and 504 nm. The maximum emission wavelengths
Figure 1. The fluorescence responses of 1 and 2 upon the additions of Zn2+ (experimental conditions: 50 lM sensor, varying amounts of Zn2+
,
100 mM HEPES buffter, 0.1 M KCl, pH = 7.4).

X.-M. Meng et al. / Tetrahedron Letters 47 (2006) 1559–1562
1561
of 1 and 2 were 520 and 534 nm. The fluorescence quan-
tum yields of free 1 and 2 were 0.012 and 0.011 under
physiological conditions (pH 7.4, 0.1 M KCl). Upon
addition of Zn2+, the fluorescence intensities of 1 and
2 increased by about 30-folds, and the corresponding
quantum yields increased to 0.342 and 0.279, respec-
tively (see Fig. 1). The mechanism for the fluorescence
response was presumably the well-known photoinduced
electron transfer (PET) mechanism.10 It is important to
point out that the 30-fold fluorescence enhancement of 1
and 2 is significantly higher than most of the previously
reported Zn2+ sensors (which usually showed about 5–
10-folds fluorescence enhancement).2,3
these two new sensors. Thus, we have studied the
fluorescence responses of 1 and 2 to other metal cat-
ions including Cd2+, Mg2+, Ca2+, Ba2+, Co2+, Ni2+
,
Cu2+, and Mn2+ (see Fig. 2). It was found that 1 and
2 showed almost no fluorescence enhancement in the
presence of Mg2+, Ca2+, Ba2+, and Mn2+. This is very
nice because under many conditions (e.g., physiological
conditions) Mg2+ and Ca2+ may exist at relatively high
concentrations compared to Zn2+
.
It should be noted that the high selectivity of a Zn2+ sen-
sor to Mg2+ and Ca2+ is actually not surprising, because
the electronic structures of Mg2+ and Ca2+ are quite
different from that of Zn2+. On the other hand, because
the electronic structures of Co2+, Ni2+, Cu2+, and particu-
larly Cd2+ are fairly similar to that of Zn2+, most of the
previous Zn2+ sensors do not exhibit good selectivity to
these metal cations (for instance, the selectivity in many
cases is close to 1:1 for Zn2+:Cd2+).2 This may bring
The dissociation constants, Kd, between the two new
chemosensors were determined to be 7.8 · 10À8 and
4.1 · 10À8 M for 1 and 2, respectively.11 These two dis-
sociation constants were comparable to the Kd values
of some previously reported Zn2+ sensors (for instance,
the Kd of FluoZin-3 was 1.5 · 10À8 M, and the Kd of
RhodZin was 6.5 · 10À8 M).2 The detecting limits of
the two sensors were 2.0 · 10À8 and 5.0 · 10À8 M,
respectively. Furthermore, a Hill plot analysis revealed
that the maximum fluorescence could be obtained at
1:1 ratio, which suggested that 1 and 2 should both form
trouble to certain applications where Co2+, Ni2+, Cu2+
,
or Cd2+ are interfering (e.g., in environmental science).
Herein, 1 and 2 showed less than 4-fold fluorescence
enhancement for Cd2+, and less than 2-fold fluorescence
enhancement for Co2+, Ni2+, and Cu2+ (see Fig. 2).
Compared to the 30-fold fluorescence enhancement ob-
served for Zn2+, it was obvious that 1 and 2 were highly
selective. This magnitude of selectivity was actually one
of the best among all the known Zn2+ chemosensors.
Therefore, 1 and 2 would be complementary to the
a 1:1 complex with Zn2+
.
Having confirmed that 1 and 2 were fluorescent sensors
for Zn2+, we next paid attention to the selectivity of
800
716
700
HOOC
COOH
N
600
500
400
300
HO
O
O
1
200
103
100
25
41
38
35
29
23
24
20
0
+Zn2+ +Cd2+ +Ca2+ +Mg2+ +Co2+ +Ba2+ +Cu2+ +Ni2+ +Mn2+
(a)
1
600
500
400
300
200
100
0
482
HOOC
COOH
N
Cl
Cl
O
HO
O
2
56
28
21
18
16
16
17
15
13
+Zn2+ +Cd2+ +Ca2+ +Mg2+ +Co2+ +Ba2+ +Cu2+ +Ni2+ +Mn2+
(b)
2
Figure 2. The fluorescence responses of 1 and 2 to different metal cations (experimental conditions: 20 lM sensor, 20 lM metal cation, 100 mM
HEPES buffter, 100 mM KCl, pH = 7.4).

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X.-M. Meng et al. / Tetrahedron Letters 47 (2006) 1559–1562
previous sensors in the applications where Co2+, Ni2+
Cu2+, or Cd2+ coexists with Zn2+
,
yama, S.; Kikuchi, K.; Hirano, T.; Urano, Y.; Nagano, T.
J. Am. Chem. Soc. 2002, 124, 10650–10651; (d) Hirano, T.;
Kikuchi, K.; Urano, Y.; Nagano, T. J. Am. Chem. Soc.
2002, 124, 6555–6562; (e) Woodroofe, C. C.; Lippard, S. J.
J. Am. Chem. Soc. 2003, 125, 11458–11459; (f) Chang, C.
J.; Jaworski, J.; Nolan, E. M.; Sheng, M.; Lippard, S. J.
Proc. Natl. Acad. Sci. U.S.A. 2003, 101, 1129–1134; (g)
Sensi, S. L.; Ton-That, D.; Weiss, J. H.; Rothe, A.; Gee,
K. R. Cell Calcium 2003, 34, 281–284.
.
In conclusion, we have designed, synthesized, and char-
acterized two novel fluorescent chemosensors that are
highly sensitive to Zn2+. The synthesis of these two
Zn2+ sensors was accomplished in four steps from inex-
pensive starting materials. The two new sensors showed
much better selectivity to many other metal ions as com-
pared to the previously reported Zn2+ sensors. Thus, the
two new sensors reported here add novel tools to the
arsenal of Zn2+ detection and imaging. Furthermore,
the present study has confirmed Urano’s very recent
finding that the carboxylic group plays almost no role
in the fluorescence properties of the fluorescein
molecule.5
5. Urano, Y.; Kamiya, M.; Kanda, K.; Ueno, T.; Hirose, K.;
Nagano, T. J. Am. Chem. Soc. 2005, 127, 4888–4894.
6. Characterization of 3: 1H NMR (DMSO-d6): d 1.23 (6H, t,
J = 7.2 Hz), 4.17 (4H, q, J = 7.2 Hz), 4.32 (4H, s), 6.58–
6.66 (4H, m), 6.77 (2H, d, J = 8.8 Hz), 7.22 (2H, d,
J = 8.8 Hz), 7.28 (1H, s), 7.31 (1H, s). 13C NMR (DMSO-
d6): d 14.3, 53.5, 61.4, 95.6, 104.8, 108.0, 110.2, 114.2,
117.4, 126.5, 128.5, 129.3, 130.1, 148.7, 149.5, 155.2, 157.3,
158.4, 159.6, 169.6, 185.8. HRMS (ESI): 476.1792 (calcd
for C27H26NO7 MH+: 476.1748).
7. Characterization of 4: 1H NMR (DMSO-d6): d 1.21 (6H, t,
J = 7.2 Hz), 4.15 (4H, q, J = 7.2 Hz), 4.33 (4H, s), 6.74–
6.76 (2H, m), 6.83 (2H, d, J = 8.5 Hz), 7.28 (1H, s), 7.33
(2H, d, J = 8.6 Hz), 7.39 (1H, s). 13C NMR (DMSO-d6): d
14.3, 53.3, 61.4, 96.7, 106.3, 109.5, 117.4, 119.3, 123.7,
127.3, 129.2, 130.0, 133.1, 148.8, 149.6, 155.6, 157.8, 159.1,
160.3, 169.7, 178.8. HRMS (ESI): 544.0935 (calcd for
C27H24Cl2NO7 MH+: 544.0927).
Acknowledgements
This research was supported by the NSFC (Nos.
20332020, 20472079).
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1
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(ESI):
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(calcd
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