Substituent-dependent fluorescent sensors for zinc ions based on carboxamidoquinoline

Article abstract of DOI:10.1039/c2dt31139a

A series of carboxamidoquinoline-based fluorescent sensors (the AQZ family) were synthesized and characterized. The AQZ family members were highly soluble in water and showed good selectivity for Zn²⁺via enhanced fluorescence in aqueous buffer solution. Fluorescence signals could be tuned from dual-wavelength ratiometric changes to changes in the intensity of a single wavelength upon binding Zn²⁺ through the introduction of different substituents onto the quinoline ring. Concentrations of free Zn²⁺ of 10^-5-10^-6 M could be detected using the sensors. Changes of substituents and their positions on the quinoline ring influenced the sensitivity for Zn²⁺, but had little effect on Zn²⁺ affinities.

Full text of DOI:10.1039/c2dt31139a

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PAPER
Substituent-dependent fluorescent sensors for zinc ions based on
carboxamidoquinoline†
a
a
a
a
a
a
b
Yu Zhang, Xiangfeng Guo,* Lihua Jia, Shicheng Xu, Zhihui Xu, Libo Zheng and Xuhong Qian*
Received 26th May 2012, Accepted 25th July 2012
DOI: 10.1039/c2dt31139a
A series of carboxamidoquinoline-based fluorescent sensors (the AQZ family) were synthesized and
characterized. The AQZ family members were highly soluble in water and showed good selectivity for
2
+
Zn via enhanced fluorescence in aqueous buffer solution. Fluorescence signals could be tuned from
dual-wavelength ratiometric changes to changes in the intensity of a single wavelength upon binding
2
+
Zn through the introduction of different substituents onto the quinoline ring. Concentrations of free
2
+
−5
−6
Zn of 10 –10 M could be detected using the sensors. Changes of substituents and their positions
2
+
2+
on the quinoline ring influenced the sensitivity for Zn , but had little effect on Zn affinities.
Introduction
Using carboxamidoquinoline instead of the traditional sulfo-
namidoquinoline can result in improved water solubility. Our
previous contribution to this area was the synthesis of a ratio-
The development of fluorescent sensors for the selective detec-
tion of chemically and biologically significant metal ions con-
tinues to attract the worldwide attention. Because Zn , the
second most abundant transition metal in the human body, has a
2+
metric Zn
sensor derived from carboxamidoquinoline
1
2+
17
2+
(
AQZ), which was tested as a cell-permeable Zn -responsive
reagent in yeast. Subsequently, carboxamidoquinoline was
widely applied to the design of sensors. Such research has
focused on three aspects: the introduction of various receptors
2
large spectrum of functions at the cellular level, sensors target-
2+
3
ing Zn have received huge interest. However, because of its
1
0
0
18
closed-shell 3d 4s electronic configuration and the absence of
into carboxamidoquinoline, the use of carboxamidoquinoline
19
redox activity, the exact roles, either structural or functional, of
as a receptor, and the preparation of nanoparticles functiona-
2
+
2a
20
Zn in biological systems are not entirely clear. Therefore, the
lized with carboxamidoquinoline. However, few reports have
investigated the use of carboxamidoquinoline as a fluorophore.
Unmodified carboxamidoquinoline usually exhibits relatively
weak fluorescence emission, which potentially limits intracellu-
lar fluorescence imaging. For example, the fluorescence quantum
2
+
design of robust sensors for Zn that are sensitive, selective,
and show temporal fidelity will remain a research hot spot for a
long time.
2
+
Recently, numerous fluorescent Zn
sensors, based on
4
5
2+
various fluorophores such as quinoline, naphthalimide, bipyri-
yield of AQZ is only 0.064 even after complexation with Zn .
It is well known that incorporating an appropriate substituent
into a fluorophore can improve its luminescent properties. In par-
6
7
8
9
10
dyl, bodipy, fluorescein, rhodamine, pyrene, benzoxa-
11
12
13
zole, coumarin, etc., have been reported. Among these, the
quinoline fluorophore can simultaneously act as metal-binding
2+
ticular, the sensitivity of 8-aminoquinoline derivatives to Zn
may depend on substituents and their positions on the quinoline
14
ligand. This duality helps to reduce the size of the sensors. The
most common fluorescent histological Zn stains originated
from quinoline, 6-methoxy-(8-p-toluenesulfonamido)quinoline
2
+
21
ring. Herein, we reported the carboxamidoquinoline-based
AQZ family (Scheme 1), which was formed by introducing
different substituents onto the quinoline ring. It was expected
15
and its congeners, are sulfonamidoquinoline derivatives that
show substantial fluorescence enhancement upon coordination of
2
+
Zn .
The major limitation of these sensors is their limited solubility
1
6
in neutral aqueous solution.
a
College of Heilongjiang Province Key Laboratory of Fine Chemicals,
Qiqihar University, Qiqihar, 161006, China. E-mail: xfguo@163.com;
Tel: +86-452-2742563
b
Shanghai Key Laboratory of Chemical Biology, East China University
of Science and Technology, Shanghai, 200237, China.
E-mail: xhqian@ecust.edu.cn; Tel: +86-21-64252603
†
Electronic supplementary information (ESI) available: Experimental
details, synthetic details of 6 and 7, additional spectroscopic data, and
copies of NMR and MS spectra. See DOI: 10.1039/c2dt31139a
Scheme 1 The carboxamidoquinoline-based AQZ family.
11776 | Dalton Trans., 2012, 41, 11776–11782
This journal is © The Royal Society of Chemistry 2012

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that the introduction of substituents would improve the sensi-
tivity of carboxamidoquinoline for Zn , while maintaining
selectivity in aqueous buffer solution.
2-(2-(2-Hydroxyethoxy)ethylamino)-N-(4-(piperidin-1-yl)-
2
+
quinolin-8-yl)acetamide (AQZ4PP). 83 mg, 68% yield, brown
1
oil. H-NMR (CDCl
, 400 MHz): δ 11.25 (NH, s, 1H), 8.73 (d,
3
J = 7.6 Hz, 1H), 8.63 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 9.6 Hz,
H), 7.45 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 3.73
OCH CH OH, m, 4H), 3.59 (COCH , NHCH CH , m, 4H),
1
(
Experimental section
2
2
2
2
2
3
.19 (N(CH CH ) CH , t, J = 4.8 Hz, 4H), 2.95 (CH NHCH , t,
2 2 2 2 2 2
Preparation of the target sensors
J = 4.8 Hz, 2H), 1.84 (N(CH CH ) CH , m, 4H), 1.71
(N(CH CH ) CH , m, 2H) ppm. C-NMR (CDCl , 100 MHz):
2 2 2 2 3
δ 170.9, 158.5, 149.1, 140.5, 134.8, 125.7, 123.7, 118.4, 116.5,
109.3, 72.6, 71.0, 62.1, 54.1, 53.8, 49.6, 26.3, 24.7 ppm. HRMS
m/z (TOF MS ES ) calcd for C H N O (M + H ) 373.2234,
found 373.2240. FT-IR (KBr): νmax 3292.74, 2933.14, 2854.79,
1683.16, 1517.95, 1414.25, 1338.51, 1115.46, 1064.84, 815.36,
763.42 cm .
2
2 2
2
13
Compound 7 (100 mg), appropriate amine (10 equiv.), N,N-di-
isopropylethylamine (10 equiv.), and potassium iodide (10 mg)
were added to acetonitrile (30 mL). The stirred mixture was
heated at reflux for 6 h under a nitrogen atmosphere. The
mixture was cooled to rt and evaporated to afford a brown oil,
which was further purified by column chromatography on silica
gel (100–200 mesh) using a mixture of chloroform–methanol as
the eluent. Yields and spectral details of each product are given
below.
+
+
+
20 29 4 3
−1
2-(2-(2-Hydroxyethoxy)ethylamino)-N-(2-morpholinoquinolin-
8
-yl)acetamide (AQZ2MP). 81 mg, 66% yield, brown oil.
2
-(2-(2-Hydroxyethoxy)ethylamino)-N-(4-chloroquinolin-8-yl)-
1
H-NMR (CDCl , 400 MHz): δ 11.22 (NHCO, s, 1H), 8.76 (d,
J = 7.6 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H), 7.69 (d, J = 8.8 Hz,
1
3
1
acetamide (AQZ4Cl). 100 mg, 79% yield, brown oil. H-NMR
CDCl , 400 MHz): δ 11.34 (NHCO, s, 1H), 8.88 (d, J = 7.6 Hz,
H), 8.72 (d, J = 4.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.64 (t,
J = 8.0 Hz, 1H), 7.55 (d, J = 4.4 Hz, 1H), 3.73 (OCH CH OH,
m, 4H), 3.58 (COCH , NHCH CH , m, 4H), 2.97 (CH NHCH ,
t, J = 5.0 Hz, 2H) ppm. C-NMR (CDCl , 100 MHz): δ 171.4,
48.3, 143.5, 140.2, 135.0, 128.9, 126.8, 122.2, 118.4, 117.9,
2.8, 71.2, 62.3, 54.2, 49.9 ppm. HRMS m/z (TOF MS ES )
calcd for C H ClN O (M + H ) 324.1109, found 324.1118.
(
1
3
H), 7.48 (t, J = 8.2 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 3.99
(O(CH CH ) N, t, J = 4.2 Hz, 4H), 3.74 (OCH CH OH, m,
2
2 2
2
2
2
2
4
H), 3.59 (COCH , NHCH CH , m, 4H), 3.24 (O(CH CH ) N,
2 2 2 2 2 2
2
2
2
2
2
t, J = 4.2 Hz, 4H), 2.97 (CH NHCH , t, J = 4.8 Hz, 2H) ppm.
2
2
1
3
13
3
C-NMR (CDCl , 100 MHz): δ 170.5, 156.7, 148.8, 140.1,
3
1
7
1
5
34.6, 125.8, 122.9, 117.4, 116.3, 108.9, 72.1, 70.4, 66.7, 61.6,
+
+
3.5, 52.4, 49.2 ppm. HRMS m/z (TOF MS ES ) calcd for
+
3 3
+
+
+
15
19
C H N O (M + H ) 375.2027, found 375.2041. FT-IR
19 27 4 4
FT-IR (KBr): νmax 3268.97, 2918.69, 2867.99, 1685.41,
521.72, 1480.42, 1353.89, 1111.56, 1055.12, 798.96,
55.40 cm .
(KBr): νmax 3265.75, 2920.55, 2843.84, 1684.92, 1520.86,
1
7
−1
1
414.99, 1305.79, 1114.59, 1066.71, 816.05, 762.30 cm .
−1
2
-(2-(2-Hydroxyethoxy)ethylamino)-N-(5-morpholinoquinolin-
2
-(2-(2-Hydroxyethoxy)ethylamino)-N-(4-methoxyquinolin-8-yl)-
8
-yl)acetamide (AQZ5MP). 86 mg, 70% yield, brown oil.
H-NMR (CDCl , 400 MHz): δ 11.11 (NHCO, s, 1H), 8.86 (d,
J = 4.0 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.8 Hz,
H), 7.46 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 3.96
O(CH CH ) N, t, J = 4.4 Hz, 4H), 3.74 (OCH CH OH, m,
H), 3.59 (COCH , NHCH CH , m, 4H), 3.06 (O(CH CH ) N,
2 2 2 2 2 2
t, J = 4.4 Hz, 4H), 2.97 (CH NHCH , t, J = 5.0 Hz, 2H) ppm.
2 2
C-NMR (CDCl , 100 MHz): δ 170.3, 148.5, 144.2, 140.0,
acetamide (AQZ4MO). 101 mg, 79% yield, brown oil.
H-NMR (CDCl , 400 MHz): δ 11.23 (NHCO, s, 1H), 8.79 (d,
J = 8.8 Hz, 1H), 8.69 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 9.2 Hz,
H), 7.49 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 5.2 Hz, 1H), 4.05
OCH , s, 3H), 3.73 (OCH CH OH, m, 4H), 3.58 (COCH ,
NHCH CH , m, 4H), 2.96 (CH NHCH , t, J = 5.0 Hz, 2H)
ppm. C-NMR (CDCl , 100 MHz): δ 170.7, 162.5, 149.6,
39.8, 133.9, 126.2, 121.1, 117.1, 115.8, 100.6, 72.3, 70.7, 61.8,
1
1
3
3
1
(
4
1
(
2
2 2
2
2
3
2
2
2
2
2
2
2
1
3
3
13
3
1
5
+
132.3, 130.5, 123.9, 120.9, 116.7, 115.9, 72.3, 70.6, 67.4, 61.8,
53.7, 53.6, 49.4 ppm. HRMS m/z (TOF MS ES ) calcd for
5.8, 53.8, 49.4 ppm. HRMS m/z (TOF MS ES ) calcd for
+
+
+
C H N O (M + H ) 320.1605, found 320.1617. FT-IR
1
6 22 3 4
+
+
C H N O (M + H ) 375.2027, found 375.2019. FT-IR
19 27 4 4
(
1
KBr): νmax 3258.85, 2915.07, 2860.08, 1655.01, 1524.33,
412.38, 1314.80, 1117.38, 1062.19, 808.16, 758.78 cm .
−1
(KBr): νmax 3263.73, 2922.08, 2859.30, 1654.86, 1529.38,
405.71, 1338.81, 1113.00, 1065.44, 824.17, 800.79 cm .
−1
1
2
-(2-(2-Hydroxyethoxy)ethylamino)-N-(4-morpholinoquinolin-
8
-yl)acetamide (AQZ4MP). 92 mg, 75% yield, brown oil.
2-Butylamino-N-(quinolin-8-yl)acetamide (AQZ8BA). 99 mg,
1
1
H-NMR (CDCl , 400 MHz): δ 11.28 (NHCO, s, 1H), 8.76 (d,
85% yield, brown oil. H-NMR (CDCl , 400 MHz): δ 11.42
3
3
J = 8.0 Hz, 1H), 8.69 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 8.4 Hz,
(NHCO, s, 1H), 8.87 (d, J = 6.0 Hz, 1H), 8.84 (d, J = 9.2 Hz,
1H), 8.18 (d, J = 10.0 Hz, 1H), 7.55 (m, 2H), 7.46 (m, 1H), 3.58
(COCH , s, 2H), 2.78 (NHCH CH CH CH , t, J = 6.8 Hz, 2H),
1
H), 7.48 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 4.8 Hz, 1H), 3.99
(
O(CH CH ) N, t, J = 4.4 Hz, 4H), 3.73 (OCH CH OH, m,
2
2 2
2
2
2
2
2
2
3
4
H), 3.59 (COCH , NHCH CH , m, 4H), 3.24 (O(CH CH ) N,
1.63 (NHCH CH CH CH , m, 2H), 1.49 (NHCH CH CH CH ,
2 2 2 3 2 2 2 3
2
2
2
2
2 2
t, J = 4.2 Hz, 4H), 2.96 (CH NHCH , t, J = 4.8 Hz, 2H) ppm.
m, 2H), 0.95 (NHCH CH CH CH , t, J = 7.6 Hz, 3H) ppm.
2 2 2 3
C-NMR (CDCl , 100 MHz): δ 170.8, 148.5, 139.0, 136.2,
3
2
2
1
3
13
C-NMR (CDCl , 100 MHz): δ 170.7, 156.9, 149.0, 140.3,
3
1
5
34.8, 126.1, 123.1, 117.6, 116.5, 109.1, 72.3, 70.7, 66.9, 61.8,
134.4, 128.1, 127.4, 121.7, 121.6, 116.5, 53.8, 50.1, 32.4, 20.3,
+
+
3.8, 52.6, 49.4 ppm. HRMS m/z (TOF MS ES ) calcd for
14.1 ppm. HRMS m/z (TOF MS ES ) calcd for C H N O
1
5
20
3
+
+
+
C H N O (M + H ) 375.2027, found 375.2027. FT-IR
(M + H ) 258.1601, found 258.1604. FT-IR (KBr): ν
max
1
9
27
4
4
(
1
KBr): νmax 3283.65, 2920.55, 2854.70, 1670.11, 1517.72,
414.36, 1305.44, 1113.70, 1066.24, 815.82, 764.00 cm .
3280.82, 2921.23, 2868.10, 1687.17, 1527.81, 1421.57,
1319.41, 1131.44, 824.97, 792.28 cm .
−1
−1
This journal is © The Royal Society of Chemistry 2012
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Scheme 2 Synthesis of the carboxamidoquinoline-based AQZ family: (a) SnCl
2
·2H
2
O/HCl, ethanol, 40–50 °C, 2 h; (b) 2-chloroacetyl chloride–
pyridine, chloroform, rt, 2 h; (c) appropriate amine/N,N-diisopropylethylamine/KI, acetonitrile, reflux, 6 h; (d) AQZ8MO: Na, methanol, reflux, 4 h.
2
-Methoxy-N-(quinolin-8-yl)acetamide
104 mg, 4.5 mmol) was dissolved in methanol (30 mL), and
then 2-chloro-N-(quinolin-8-yl)acetamide 7g (100 mg,
.45 mmol) was added. The stirred mixture was heated at reflux
(AQZ8MO). Na
(
0
for 4 h under a nitrogen atmosphere. The mixture was cooled to
rt and evaporated to afford a brown solid, which was further
purified by column chromatography on silica gel
(100–200 mesh) using a mixture of the chloroform–ethyl acetate
as the eluent. AQZ8MO: 53 mg, 54% yield, brown solid, mp:
1
5
1
6.6–57.9 °C. H-NMR (CDCl , 400 MHz): δ 10.74 (NHCO, s,
3
H), 8.87 (d, J = 5.6 Hz, 1H), 8.81 (d, J = 9.2 Hz, 1H), 8.18 (d,
J = 10.0 Hz, 1H), 7.55 (m, 2H), 7.46 (m, 1H), 4.17 (COCH , s,
2
1
3
2
1
H), 3.62 (OCH , s, 3H) ppm. C-NMR (CDCl , 100 MHz): δ
3 3
68.3, 148.6, 138.8, 136.3, 133.9, 128.1, 127.3, 122.1, 121.7,
+
Fig. 1 Normalized fluorescence intensity of carboxamidoquinoline
116.8, 72.8, 59.6 ppm. HRMS m/z (TOF MS ES ) calcd for
2
+
(10 μM) at the emission maxima of Zn complexes in the presence of
+
+
C H N O (M + H ) 217.0972, found 217.0983. FT-IR
1
2 13 2 2
different metal ions (5 equiv.) at pH 7.2 (methanol–water = 1 : 9 (v/v),
I = 0.1 (KCl), 100 mM HEPES).
(KBr): νmax 3332.37, 2923.92, 2852.67, 1684.29, 1537.44,
−1
1
413.87, 1325.70, 1108.46, 825.82, 793.90 cm .
spectra of sensors were obtained by excitation at the absorption
maximum of each ligand.
Results and discussion
As seen in Fig. 1, no appreciable spectral changes were
+
2+
2+
2+
+
+
Synthesis
observed in the presence of Ag , Ca , Mg , Pb , Na , K , or
3+
Fe , but fluorescence intensities were obviously quenched by
Cu , Co , and Ni because of energy transfer from the photo-
excited quinoline ring to their empty d-orbitals.
The synthesis of the carboxamidoquinoline scaffold is outlined
in Scheme 2. Quinoline was easily converted to chloroquinoline
2+
2+
2+
24
2
2
following a literature procedure. Nitroquinoline 5 was prepared
in two steps by nitration of chloroquinoline and subsequent
nucleophilic substitution by methanol or an appropriate
2+
Complexation with Zn
led to remarkable fluorescence
enhancement of the sensors, except for AQZ5MP and
AQZ8MO, mainly resulting from the deprotonation of the car-
21,23
amine.
25
2+
boxamido group. After binding Zn , the intramolecular
hydrogen bond of 8-aminoquinoline is broken, so intramolecular
Carboxamidoquinoline was synthesized in three steps, starting
with reduction of nitroquinoline 5 using stannous chloride
crystal and concentrated HCl in ethanol at 40–50 °C to produce
aminoquinoline 6. Using 2-chloroacetyl chloride as an acetylated
reagent, aminoquinoline 6 was converted to the corresponding 7
in chloroform at rt. Finally, the target sensors were obtained by
heating 7 with the appropriate amine in acetonitrile at reflux.
AQZ8MO was prepared by heating 2-chloro-N-(quinol-8-yl)-
acetamide 7g in methanol at reflux under basic conditions.
3a,26
2+
2+
electron transfer is forbidden.
In contrast, Cd and Hg ,
which are in the same group of the periodic table and have
2+
similar properties to Zn , only caused small fluorescence
2+
enhancement. Thus, these sensors could discriminate Zn from
its IIB homologues, avoiding false positive signals from ions
2+
mimicking Zn . AQZ5MP showed no fluorescence emission in
2+
2+
the presence of Zn , whereas AQZ8MO did not recognize Zn
under the same conditions.
Metal ion selectivity studies
Substituent studies
All photophysical studies of the sensors binding metal ions were
conducted in neutral aqueous buffer solution. Fluorescence
To explore the influence of different substituents at the same
position of the quinoline ring on recognition performance, the
11778 | Dalton Trans., 2012, 41, 11776–11782
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2
+
2+
4
-substituted carboxamidoquinoline were titrated with Zn
while both absorption and emission spectra were recorded
Fig. 2).
As the concentration of Zn was increased, the intensity of
just 2 nm in the presence of Zn , indicating that the piperidinyl
group effectively prevented ICT.
(
2
+
2
+
the absorption bands produced by the Zn -free sensors gradu-
ally decreased, accompanied with new absorption bands pro-
duced by the Zn -bound sensors appearing at longer
wavelength and gradually increasing in intensity. The spectra
obtained during the stepwise addition showed three isosbestic
points. The obvious red shift can be explained as follows: the
binding of sensors to Zn produces a five-membered chelate
ring through two nitrogen atoms of carboxamidoquinoline,
which increases conjugation and reduces the energy gap between
the HOMO–LUMO. Simultaneously, Zn -induced deprotona-
tion strengthens the electron-donating ability of the 8-amino
residue to the quinoline ring. Electron transfer from the hetero-
2+
2
+
27
2+
2
+
cyclic nitrogen atom to Zn further enhances intramolecular
charge transfer (ICT). Moreover, as the electron-donating ability
of the substituent at the 4-position improves, the electron density
of the heterocyclic ring in the quinoline group increases, which
weakens ICT. Thus, the red shift of the absorption maxima
gradually decreased from 51 to 18 nm as the electron-donating
ability of the substituent at the 4-position increased (Table 1).
To our surprise, fluorescence spectral changes were distinct
2
+
from those of the absorption spectra during the Zn titration
process, suggesting that the influence of the substituent at the
4
-position on the excited state of carboxamidoquinoline was far
greater than that on the ground state. For AQZ4Cl, the fluore-
2
+
scence response to Zn was similar to that of AQZ, exhibiting
ratiometric signals with a clear isoemissive point at 436 nm. The
2
+
red shift of the emission maxima induced by Zn was 83 nm
because of the electron-withdrawing Cl substituent. The red shift
decreased remarkably by incorporation of electron-donating sub-
stituents at the 4-position, showing that ICT from the 8-amino
residue to the quinoline ring was disturbed. This interference
effect gradually intensified as the electron-donating ability of the
substituent at the 4-position increased, which mainly appeared as
the transformation of fluorescence signals for Zn from dual-
wavelength ratiometric changes to changes in intensity of a
single wavelength. In particular, AQZ4PP showed a red shift of
Fig. 2 Absorption (left) and fluorescence (right) spectra of carboxami-
doquinoline (10 μM) (a) AQZ4Cl, (b) AQZ, (c) AQZ4MO, (d)
AQZ4MP, and (e) AQZ4PP as a function of added the range of concen-
2
+
2
+
trations of free Zn from 0 to 100 μM at pH 7.2 (methanol–water = 1 : 9
(v/v), I = 0.1 (KCl), 100 mM HEPES, 10 mM N-(2-aminoethyl)ethane-
2
+
1,2-diamine, 0–5.0 mM Zn ).
a
2+
Table 1 Photophysical data for carboxamidoquinoline (10 μM) in the absence and presence of Zn
2
+
Free sensors
Zn complexes
Red shift
b
ε (M−1 cm−1
c
ε (M−1 cm−1
d
× 10−5 (M)
λ
ex/λem (nm)
)
Φ
λ
ex/λem (nm)
)
Φ
K
d
Δλex (nm)
Δλem (nm)
4
4
AQZ4Cl
AQZ
305/430
305/430
301/393
327/475
334/450
326/477
338/—
7.3 × 104
0.006
0.008
0.010
0.001
0.001
0.002
—
356/513
344/505
330/462
348/482
352/452
348/482
372/—
339/505
—
6.4 × 10
5.6 × 10
1.1 × 10
1.4 × 10
1.9 × 10
1.3 × 10
7.2 × 10
5.8 × 10
—
0.048
0.064
0.78
0.22
0.029
0.18
—
1.0 ± 0.02
1.0 ± 0.01
0.68 ± 0.02
0.67 ± 0.01
0.67 ± 0.01
0.69 ± 0.02
1.0 ± 0.02
1.0 ± 0.03
—
51
39
29
21
18
22
34
38
—
83
75
69
7
2
5
—
78
—
4
6.5 × 10
4
5
AQZ4MO
AQZ4MP
AQZ4PP
AQZ2MP
AQZ5MP
AQZ8BA
AQZ8MO
9.6 × 105
5
1.1 × 10
5
5
1.3 × 105
5
1.0 × 10
4
4
7.9 × 104
4
301/427
301/423
9.9 × 10
8.5 × 10
0.003
0.014
0.049
—
4
a
All data were obtained at pH 7.2 (methanol–water = 1 : 9 (v/v), I = 0.1 (KCl), 100 mM HEPES, 10 mM N-(2-aminoethyl)ethane-1,2-diamine,
2
+
b
c
0
–5.0 mM Zn ).
λex and λem are the maximum absorption and emission wavelength, respectively. The fluorescence quantum yield was determined
29 d 15b,30
using that of quinine bisulphate (Φ = 0.55) in 100 mM H
A
2
SO
4
as a standard.
K
d
was calculated using the equation:
d
A = (AminK +
2
+
2+
d
max[Zn ]free)/(K + [Zn ]free).
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 11776–11782 | 11779

View Article Online
In addition, the sensitivity of carboxamidoquinoline for
electron-donating ability of the phenyl ring in the quinoline
group. These results are similar to those for 5-methoxy sulfon-
amidoquinoline described by Ward et al. Thus, like sulfonami-
2+
sensing Zn was significantly improved by the presence of sub-
stituents at the 4-position. Compared with AQZ, the introduction
of Cl led to weaker emission in both the absence and presence of
21
doquinoline, 4-substituted carboxamidoquinoline exhibited the
2
+
2+
2+
Zn , while AQZ4MO and its Zn complexes showed stronger
fluorescence intensity than AQZ because of the electron-donat-
ing methoxy group. In particular, the fluorescence quantum yield
optimal fluorescence signals for detecting Zn in aqueous
buffer solution.
2
+
of AQZ4MO increased to 0.78 after binding Zn , which is
about 12 times higher than that of AQZ. However, incorporating
aliphatic cyclic amino groups, which have a stronger electron-
donating ability than a methoxy group, resulted in unexpected
changes of fluorescence emission. For AQZ4MP and AQZ4PP,
the background fluorescence was too weak to be observed in the
Coordination mode studies
To investigate the coordination mode between carboxamidoqui-
2+
noline and Zn , AQZ8BA and AQZ8MO were prepared by
replacing the 2-(2-hydroxyethoxy)ethylamino group of AQZ
with n-butylamino and methoxy groups, respectively.
2+
absence of Zn (Φ = 0.001), and the fluorescence quantum
17
2+
In previous research, the 2-(2-hydroxyethoxy)ethylamino
yields of their Zn complexes were also far lower than that of
AQZ4MO. The reasons for this phenomenon are not clear.
However, these two sensors could offer a better signal-to-noise
ratio for sensing because of the completely quenched fluor-
group of AQZ was considered to provide two metal-coordination
2+
sites to chelate Zn . However, AQZ8BA showed the similar
2+
spectral changes to those of AQZ upon binding Zn under
the same conditions (Fig. 4), indicating that the O atom of the
2
+
escence before binding Zn . As a rare off–on sensor based on
ICT (most sensors employ the photoinduced electron transfer
2
8
2+
mechanism), AQZ4MP showed very high sensitivity for Zn .
There was an about 220-fold enhancement in the fluorescence
2
+
quantum yield of AQZ4MP upon addition of Zn .
Effect of substituent position
To study the effect of the same substituent at different positions
of the quinoline ring on the recognition performance of the
ligands, two analogues of AQZ4MP possessing a morpholino
group at position 2 or 5 of the quinoline ring were synthesized.
Under the same conditions, the recognition signals of
2+
AQZ2MP for Zn were similar to those of AQZ4MP, except
2
+
that the fluorescence from the Zn complexes was weaker
Fig. 3). In sharp contrast, AQZ5MP showed no emission in
(
2
+
Fig. 4 Absorption (left) and fluorescence (right) spectra of carboxami-
doquinoline (10 μM) (a) AQZ8BA and (b) AQZ8MO as a function of
added the range of concentrations of free Zn from 0 to 100 μM at pH
either the absence or presence of Zn . The red shift of its
2
+
absorption maxima induced by Zn (Δλex = 34 nm) was more
2+
than those of the other complexes because of the stronger
7
1
.2 (methanol–water = 1 : 9 (v/v), I = 0.1 (KCl), 100 mM HEPES,
0 mM N-(2-aminoethyl)ethane-1,2-diamine, 0–5.0 mM Zn ).
2
+
Fig. 3 Absorption (left) and fluorescence (right) spectra of carboxami-
doquinoline (10 μM) (a) AQZ2MP and (b) AQZ5MP as a function of
added the range of concentrations of free Zn from 0 to 100 μM at pH
Fig. 5 Normalized fluorescence intensities of carboxamidoquinoine
2
+
2+
(10 μM) at the emission maxima of Zn complexes in the presence of
2
+
7
1
.2 (methanol–water = 1 : 9 (v/v), I = 0.1 (KCl), 100 mM HEPES,
0 mM N-(2-aminoethyl)ethane-1,2-diamine, 0–5.0 mM Zn ).
Zn (5 equiv.) and different metal ions (5 equiv.) at pH 7.2 (methanol–
water = 1 : 9 (v/v), I = 0.1 (KCl), 100 mM HEPES).
2
+
11780 | Dalton Trans., 2012, 41, 11776–11782
This journal is © The Royal Society of Chemistry 2012

View Article Online
Fig. 6 Phase contrast (top) and fluorescence (bottom) microscopy images of yeast cells incubated for 1 h with AQZ4MP (10 μM) with the different
2
+
exposure times (0–16 h) to Zn (4 equiv.).
2
-(2-hydroxyethoxy)ethylamino group had little effect on the
Cell studies
2+
coordination of Zn . In addition, the fact that AQZ8MO had no
recognition response to Zn further confirmed that the N atom
at position 2 of the acetyl group played a critical role in chelation
to Zn .
Moreover, we tried to use the H-NMR titration to elucidate
the coordination mode. But the peak corresponding to the car-
boxamido proton disappeared in the absence of Zn because of
proton exchange in D O. And no obvious changes of carboxami-
doquinoline in both H-NMR signals and fluorescence spectra
were observed upon the addition of Zn in pure DMSO, which
might be due to the fact that DMSO is an aprotic polar solvent.
Job’s plots, which exhibited a maximum at 0.5 M fraction of
Zn , indicated that only a 1 : 1 complex between carboxamido-
quinoline and Zn was formed in aqueous buffer solution (see
3
4
2
+
Using yeast (Saccharomyces cerevisiae) as a cell model, pre-
liminary fluorescent imaging experiments were carried out by
fluorescence microscopy. AQZ4MP was chosen as the imaging
2+
2
+
1
reagent because of its off–on luminescence sensing of Zn . As
2
+
the exposure time to Zn lengthened (0–10 h), the blue-green
emission in living cells gradually enhanced (Fig. 6), indicating
that AQZ4MP is membrane permeable and can signal the pres-
2
+
2
1
2+
ence of intracellular Zn .
2
+
Conclusions
2
+
2+
In summary, we developed a series of fluorescent Zn sensors
from carboxamidoquinoline that operate in aqueous buffer solu-
tion, and possess K in the range of 10 –10 M. Changes of
substituents and their positions on the quinoline ring influenced
the sensitivity of carboxamidoquinoline for Zn , but had little
effect on Zn affinities. Fluorescence signals could be tuned
from dual-wavelength ratiometric changes to changes in the
intensity at a single wavelength upon binding Zn by introdu-
cing different substituents. Although these sensors possess high
2+
−
5
−6
ESI†). Therefore, the coordination mode of the carboxamido-
d
2+
quinoline–Zn system was revised, that is, two N atoms from
-aminoquinoline, one N atom at position 2 of the acetyl group,
and one solvent molecule or anion participate in the four-coordi-
2
+
8
2+
2
+
nate environment of Zn .
2+
Absorption spectra were also used to determine the apparent
2
+
dissociation constants K of the Zn complexes. The results
showed that carboxamidoquinoline responded to concentrations
of free Zn as low as 10 –10 M, and substituents and their
positions on the quinoline ring had little influence on the
affinities of carboxamidoquinoline for Zn (Table 1). Thus,
these sensors may be expected to detect vesicular Zn in syn-
aptic space, where Zn is estimated to achieve a maximum
concentration of 10–30 μM.
d
2
+
sensitivity and selectivity for detecting Zn , they are limited by
their requirement for high-energy UV excitation. Therefore, the
development of new carboxamidoquinoline-based fluorescent
2+
−5
−6
2
+
2+
Zn sensors that possess an excitation wavelength in the visible
region is in progress.
2
+
2
+
3
1
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21176125), the Natural Science
Foundation of Heilongjiang Province of China (QC2010054,
B201114), the Research Foundation of Education Bureau of
Heilongjiang Province of China (2012TD012, 12511z030), and
the Young Teachers Scientific Research of Qiqihar University of
China (2011k-Z03).
Metal ion competition studies
To explore the practical applicability of carboxamidoquinoline as
2
+
Zn -selective sensors, competition experiments were performed
2+
in the presence of Zn mixed with background metal ions such
2
+
+
2+
2+
2+
+
+
3+
2+
2+
as Cd , Ag , Ca , Mg , Pb , Na , K , Fe , Hg , Ni ,
2
+
2+
Co , and Cu . As shown in Fig. 5, the solutions containing
Zn and various metal ions, except for Co and Cu , showed
2
+
2+
2+
2+
high fluorescence enhancement similar to that of Zn alone.
Notes and references
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There was little enhanced fluorescence in the Co and Cu –
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11782 | Dalton Trans., 2012, 41, 11776–11782
This journal is © The Royal Society of Chemistry 2012