A new highly selective "turn on" fluorescent sensor for zinc ion based on a pyrazoline derivative

Article abstract of DOI:10.1016/j.jphotochem.2010.11.014

A novel pyrazoline derivative, 2-(4-chloro-2-(1-(6-chloropyridazin-3-yl)-5- phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)acetic acid, was synthesized starting from a chalcone and 3-chloro-6-hydrazinylpyridazine and proposed for the determination of Zn²

Full text of DOI:10.1016/j.jphotochem.2010.11.014

Journal of Photochemistry and Photobiology A: Chemistry 218 (2011) 6–10
Contents lists available at ScienceDirect
Journal of Photochemistry and Photobiology A:
Chemistry
journal homepage: www.elsevier.com/locate/jphotochem
A new highly selective “turn on” fluorescent sensor for zinc ion based on a
pyrazoline derivative
Zhong-Liang Gong, Bao-Xiang Zhao∗, Wei-Yong Liu, Hong-Shui Lv
Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, 27 Shanda Nanlu, Jinan 250100, Shandong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 August 2010
Received in revised form 27 October 2010
Accepted 22 November 2010
Available online 26 November 2010
A
novel pyrazoline derivative, 2-(4-chloro-2-(1-(6-chloropyridazin-3-yl)-5-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)phenoxy)acetic acid, was synthesized starting from
a chalcone and 3-chloro-6-
hydrazinylpyridazine and proposed for the determination of Zn2+ ion with high selectivity and a
low detection limit in CH3CN:EtOH (90/10, v/v). This sensor formed a 1:1 complex with Zn2+ and showed
a fluorescent enhancement with good tolerance of other metal ions.
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Pyrazoline
Fluorescent sensor
Zinc ion
Ratiometric
1. Introduction
papers dealing with solvatochromic effect and the influence of
phenyl ring rotation on the UV–vis absorption spectra of pyra-
Fluorescence measurement of specific biological molecules by
artificial chemosensors is a versatile technique with high sen-
sitivity, rapid response, and easy performance, offering utility
not only for in vitro assays but also for in vivo imaging studies
using fluorescence microscopy [1]. During the past few decades,
much effort has been devoted to the development of fluorescent
chemosensors for various biological substances such as cations,
anions, sugars, and proteins [2]. Therein, the monitoring of zinc
ion with a selective chemical probe is actively investigated, as zinc
is the second most abundant transition metal ion in the human
body after iron and an essential cofactor in many biological pro-
cesses such as brain function and pathology, gene expression,
immune function, mammalian reproduction, apoptosis, enzyme
regulation, neurotransmission [3–10]. And it is believed that dis-
order of zinc homeostasis is implicated in a number of pathological
processes, such as Alzheimer’s disease, epilepsy, infantile diarrhea,
and ischemic stroke [11–13]. Therefore, accurate measurement of
Zn2+ is very important to decrease the probability of such diseases.
Pyrazoline derivatives are attracting attention in conjugated
fluorescent dyes emitting blue fluorescence with high fluo-
rescence quantum yield [14,15] and electroluminescence fields
[16,17]. Attempts have been made to synthesize and elucidate the
effects of substituent on the absorption and fluorescence prop-
erties of this class of compounds [18–22]. Recently interesting
zoline containing compounds have been published [23,24]. In
our previous reports, we described the UV–vis absorption and
fluorescence of a series of novel pyrazoline derivatives [25,26].
Encouraged by these results, we were interested in exploring
fluorescent sensor for zinc ion based pyrazoline structure with
chelating groups. Herein, we would like to report fortunate
results that 2-(4-chloro-2-(1-(6-chloropyridazin-3-yl)-5-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)phenoxy)acetic acid can be used as highly
selective “turn on” fluorescent sensor for zinc ion.
2. Experimental
2.1. Apparatus
Thin-layer chromatography (TLC) was conducted on silica gel
60 F254 plates (Merck KGaA). 1H NMR spectra were recorded on a
Bruker Avance 400 (400 MHz) spectrometer, using CDCl3 as solvent
and tetramethylsilane (TMS) as internal standard. Melting points
were determined on an XD-4 digital micro melting point apparatus.
IR spectra were recorded with an IR spectrophotometer VERTEX
70 FT-IR (Bruker Optics). HRMS spectra were determined on a Q-
TOF6510 spectrograph (Agilent). UV–vis spectra were examined on
a U-4100 (Hitachi). Fluorescent measurements were recorded on a
Perkin-Elmer LS-55 luminescence spectrophotometer.
2.2. Materials
∗
Organic solvents (ethanol, acetonitrile and acetone) used in this
study were of analytical grade. All the reagents were purchased
Corresponding author. Tel.: +86 531 88366425; fax: +86 531 88564464.
E-mail address: bxzhao@sdu.edu.cn (B.-X. Zhao).
1010-6030/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jphotochem.2010.11.014

Z.-L. Gong et al. / Journal of Photochemistry and Photobiology A: Chemistry 218 (2011) 6–10
7
Fig. 1. Synthesis of compound 4.
from commercial suppliers and used without further purification.
2.3.2. Ethyl 2-(4-chloro-2-(1-(6-chloropyridazin-3-yl)-5-phenyl-
The salts used in stock solutions of metal ions were CoCl2·6H2O,
ZnCl2, CaCl2, NaCl, CuCl2·2H2O, NiCl2·6H2O, KCl, CdCl2·2½H2O,
HgCl2, FeCl3·6H2O, AgNO3, PbSO4, SnCl2·2H2O.
4,5-dihydro-1H-pyrazol-3-yl)phenoxy) acetate
(3)
To a stirred solution of 2 (0.238 g, 0.6 mmol) and K2CO3 (0.166 g,
1.2 mmol) in acetone (20 mL) was added ethyl chloroacetate
(0.089 g, 0.72 mmol), then the reaction mixture was refluxed for 3 h.
After cooling, the mixture was filtered and the filtrate was evapo-
rated to afford residue. The residue was crystallized from ethanol
to afford 3 (0.236 g), yield 83%; mp 165–166 ◦C; 1H NMR (400 MHz,
CDCl3): ı 1.23 (t, 3H, J = 7.1 Hz, CH3), 3.54 (dd, 1H, J = 5.5, 18.7 Hz,
4-Htrans), 4.15 (dd, 1H, J = 12.2, 18.7 Hz, 4-Hcis), 4.22 (q, 2H, J = 7.1 Hz,
CO2CH2), 4.62 (s, 2H, OCH2CO), 5.83 (dd, 1H, J = 5.5, 12.2 Hz, 5-H of
pyrazoline), 6.75 (d, 1H, J = 8.9 Hz, Ar-H), 7.18–7.22 (m, 1H, Ar-H),
7.26 (d, 1H, J = 9.4 Hz, pyridazine-H), 7.27–7.32 (m, 5H, Ar-H), 7.75
(d, 1H, J = 9.4 Hz, pyridazine-H), 7.99 (d, 1H, J = 2.7 Hz, Ar-H). HRMS:
calcd for [M+H]+ C23H21Cl2N4O3: 471.0991; found: 471.0986.
2.3. Synthesis
The synthetic routes are shown in Fig. 1.
2.3.1. 4-Chloro-2-(1-(6-chloropyridazin-3-yl)-5-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)phenol
(2)
Starting material chalcone (1) was prepared according to
the literature [27,28]. To
a stirred solution of chalcone (1)
(1.032 g, 4.0 mmol) in ethanol (40 mL) was added 3-chloro-
6-hydrazinylpyridazine (0.868 g, 5.0 mmol) and NaOH (0.48 g,
12.0 mmol) and the reaction mixture was refluxed for 4.5 h. The
progress of the reaction was monitored by TLC. After completion,
the reaction mixture was cooled to room temperature and diluted
with chilled water, and then aqueous hydrochloric acid was added
to neutralize it. The crude product was obtained as yellow pre-
cipitates. The precipitates were filtered, washed with water and
ethanol. After chromatography on silica gel (petroleum ether/ethyl
acetate/dichloromethane = 3/1/1), compound 2 was obtained. Yel-
low solid, yield 40%; mp 208–209 ◦C; IR (KBr, cm−1): 3236.7,
3064.0, 3032.8, 1575.0, 1488.4, 1452.4, 1256.6, 1138.1, 1081.8,
823.0; 1H NMR (400 MHz, CDCl3): ı 3.42 (dd, 1H, J = 5.4, 17.6 Hz,
4-Htrans), 3.98 (dd, 1H, J = 12.0, 17.6 Hz, 4-Hcis), 5.89 (dd, 1H, J = 5.4,
12.0 Hz, 5-H of pyrazoline), 7.01 (d, 1H, J = 8.8 Hz, Ar-H), 7.18 (d,
1H, J = 2.4 Hz, Ar-H), 7.23–7.30 (m, 6H, Ar-H), 7.32 (d, 1H, J = 9.3 Hz,
pyridazine-H), 7.43 (d, 1H, J = 9.3 Hz, pyridazine-H), 10.13 (s, 1H,
OH). HRMS: calcd for [M+H]+ C19H15Cl2N4O: 385.0623; found:
385.0616.
2.3.3. 2-(4-Chloro-2-(1-(6-chloropyridazin-3-yl)-5-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)phenoxy)acetic acid
(4)
To a solution of 3 (0.141 g, 0.3 mmol) in ethanol (6 mL) was
added 0.3 N aqueous potassium hydroxide solution (2 mL). The
solution was stirred at room temperature for 1.5 h. The progress
of the reaction was monitored by TLC. After completion, the sol-
vent was evaporated. Then chilled water (10 mL) was added and
aqueous hydrochloric acid was added to neutralize it to obtain
yellow precipitates. The precipitates were filtered, washed with
water and ethanol to afford 4 (0.123 g). White solid, yield 93%; mp
192–194 ◦C; 1H NMR (400 MHz, DMSO-d6): ı 3.43 (dd, 1H, J = 5.2,
18.8 Hz, 4-Htrans), 4.13 (dd, 1H, J = 12.2, 18.8 Hz, 4-Hcis), 4.77 (s, 2H,
OCH2CO), 5.80 (dd, 1H, J = 5.2, 12.2 Hz, 5-H of pyrazoline), 7.09 (d,
1H, J = 8.9 Hz, Ar-H), 7.21–7.33 (m, 5H, Ar-H), 7.43 (dd, 1H, J = 2.6,
8.9 Hz, Ar-H), 7.60 (d, 1H, J = 9.4 Hz, pyridazine-H), 7.90 (d, 1H,

8
Z.-L. Gong et al. / Journal of Photochemistry and Photobiology A: Chemistry 218 (2011) 6–10
Fig. 3. UV–vis spectra of compound 4 (5 × 10−5 M) and compound 4 (5 × 10−5 M)
upon addition of 1.0 equiv. of Zn2+ in CH3CN:EtOH solution (90/10, v/v). Inset: Job’s
plots according to the method for continuous variations in CH3CN, indicating the
1:1 stoichiometry for 4-Zn2+ (the total concentration of 4 and Zn2+ is 1.0 × 10−4 M).
Fig. 2. UV–vis spectral changes of compound 4 (5 × 10−5 M) in CH3CN:EtOH solution
(90/10, v/v) upon addition of 1.0 equiv. of various metal ions.
J = 9.4 Hz, pyridazine-H), 7.99 (d, 1H, J = 2.6 Hz, Ar-H), 13.10 (s, 1H,
CO2H). HRMS: calcd for [M+H]+ C21H17Cl2N4O3: 443.0678; found:
443.0671.
The spectra of compound 4 were recorded in CH3CN:EtOH solu-
tion (90/10, v/v). It can be found from Fig. 3 that the maximal
absorbance of compound 4 is at 347 nm (ε = 1.43 × 104 M−1 cm−1).
Upon addition of Zn2+ (1.0 equiv.), the absorption intensity at
347 nm decreases, accompanied by the obvious hypsochromic shift
of the absorption peak (from 347 to 316 nm). Simultaneously, a new
shoulder-like peak appears around 375 nm with several isosbestic
points at 256, 282, 318 and 370 nm, indicating the formation of a
new complex between compound 4 and Zn2+. The Job’s plot in Fig. 3
(inset) gives a 1:1 stoichiometric ratio between compound 4 and
Zn2+ ion.
2.4. Analytical procedure
A 1.0 × 10−3 M of stock solution of compound 4 in CH3CN was
prepared. The cationic stocks were all in C2H5OH with a concentra-
tion of 1.0 × 10−3 M for fluorescence and UV–vis spectra analysis.
The UV–vis absorption spectra were recorded in acetonitrile and
the mixture of acetonitrile and ethanol (analytical grade) solutions
(5 × 10−5 M) in a standard 1 cm path length quartz cell in range
220–600 nm with spectral resolution 1 nm. For all measurements
of fluorescence spectra, excitation was at 347 nm with excitation
and emission slit widths at 10.0 nm and scan speed was set at
800 nm min−1 using 1 × 10−5 M of compound 4 in CH3CN:EtOH
solution (90/10, v/v). Moreover, for fluorescence titration experi-
ments, each time a 3 mL solution of compound 4 was filled in a
quartz cell of 1 cm optical path length, and the stock solution of Zn2+
was added into the quartz cell gradually by using a micro-syringe.
After each addition of Zn2+, the solution was stirred for 3 min. The
volume of cationic stock solution added was less than 100 ␮L with
the purpose of keeping the total volume of testing solution without
obvious change. In order to determine stoichiometry of the com-
plex formed from compound 4 and Zn2+, solutions of compound 4
and Zn2+ salt were prepared as 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2
and 9:1 in CH3CN keeping the total concentration is 1.0 × 10−4 M.
These solutions were kept at room temperature for 3 h, and the
absorbance at 347 nm was used for calculations.
3.2. Selective detection of zinc ion
As depicted in Fig. 4 compound 4 showed a very weak fluo-
rescence centered around 480 nm in CH3CN:EtOH solution (90/10,
v/v). Upon interaction with varying metal ions (Ag+, Cd2+, Co2+
,
Cu2+, Fe3+, Hg2+, Ni2+, Pb2+, Sn2+, Zn2+), only Zn2+ ion induced a siz-
3. Results and discussion
3.1. UV–vis studies
Fig. 2 records the UV–vis spectral changes of compound 4
(50 ␮M) in CH3CN:EtOH solution (90/10, v/v) upon addition of
1.0 equiv. of various metal ions. As can be seen from Fig. 2,
when Ag+, Fe3+, Pb2+, Hg2+ and Sn2+ were added, no absorption
curve changes were observed, whereas the absorption intensity at
Fig. 4. Fluorescence spectra of free compound 4 (1 × 10−5 M) in CH3CN:EtOH solu-
tion (90/10, v/v) upon addition of 1.0 equiv. of various metal ions with an excitation
wavelength of 347 nm. (I and I0 denote fluorescence intensity of compound 4 at
480 nm in the presence and absence of Zn2+, respectively).
347 nm can be decreased to some extent when Cd2+, Co2+, Cu2+
,
Ni2+, Zn2+ were added, accompanied by an obviously new absorp-
tion peaks appeared.

Z.-L. Gong et al. / Journal of Photochemistry and Photobiology A: Chemistry 218 (2011) 6–10
9
Fig. 7. Fluorescent response of sensor compound 4 (1 × 10−5 M) containing 10 ␮M
Zn2+ to the selected metal ions (Ag+, Co2+, Cd2+, Cu2+, Fe3+, Hg2+, Ni2+, Pb2+ and
Sn2+ (1 × 10−5 M, respectively) and K+, Na+, Ca2+ (1 × 10−4 M, respectively)) in
CH3CN:EtOH solution (9/1, v/v). Excitation wavelength was 347 nm, and emission
wavelength was 480 nm.
Fig. 5. Fluorescence emission spectra of compound 4 (1 × 10−5 M) was titrated with
Zn2+ (0–5 equiv.) in CH3CN:EtOH solution (90/10, v/v). Excitation wavelength was
347 nm. Inset: Variations of fluorescence intensity of compound 4 (1 × 10−5 M) at
480 nm vs. equiv. of [Zn2+]/[4]. (I and I0 denote fluorescence intensity of compound
4 in the presence and absence of Zn2+, respectively).
more ZnCl2 ethanol solution was titrated, the fluorescence intensity
showed negligible changes and the curve (inset) remained rela-
tively constant, which also gives a 1:1 stoichiometric ratio between
compound 4 and Zn2+ similar to Job’s plot in Fig. 3. The binding
constant of the complex of 4 with Zn2+ was determined by the
nonlinear curve fit according to the fluorescent titration data in
Fig. 5 (coefficient of determination: R2 = 0.997) with a 1:1 asso-
ciation equation in CH3CN:EtOH solution (90/10, v/v) and it was
calculated to be 2.5 × 106 M−1 according to the literature [35]. In
addition, the detection limit of compound 4 for the analysis of Zn2+
ion was estimated to be 4 × 10−7 M. Moreover, the MS analysis
has been used to determine the stoichiometry of complex [36–38].
Thus, in present study, the [(4-H)/Zn]+ complex was calculated at
m/z 504.9813 and measured at m/z 504.9885. These results sup-
port the idea that compound 4 forms a 1:1 complex with Zn2+ as
proposed in Fig. 6
able enhancement in fluorescence intensity. With only 1.0 equiv.
of Zn2+ ion, the fluorescence intensity at 480 nm increased 6-fold;
other representative metal ions, except for the slightly respond-
ing Cd2+ ion increasing about 1-fold, revealed almost insignificant
responses to the fluorescence intensity of compound 4. The sys-
tem shows selective chelation enhanced fluorescence (CHEF) in the
presence of Zn2+ ion and the phenomenon is consistent with the lit-
erature concerning zinc ion sensors [29–32]. The enhancement of
fluorescence is attributed to the strong binding of Zn2+ evident from
a large binding constant value (2.5 × 106 M−1) that would impose
rigidity and hence decrease the nonradiative decay of the excited
state. It is know that transition and post-transition ions with open
shell d-orbitals often quench the fluorescence of fluorophores due
to the electron or energy transfer between the metal ions and flu-
orophores, providing a fast and efficient nonradiative decay of the
excited states [33]. In contrast, the transition ions with close shell d-
orbitals, such as Zn2+, do not introduce low-energy metal-centered
or charge-separated excited states into the molecule, so energy and
electron-transfer processes cannot take place [34]. Thus, when Zn2+
was added, the fluorescence intensity of compound 4 was increased
obviously.
3.4. Interference from other ions
To further detect the selectivity for zinc ion over other metal
ions, we also examined metal ions/zinc coexisted systems. By
3.3. Fluorescence titration studies
The titration of Zn2+ was carried out by adding small aliquots
of ZnCl2 ethanol stock solution (1.0 × 10−3 M) into the solution
of compound 4 (1 × 10−5 M) in CH3CN:EtOH solution (90/10, v/v).
We observed an almost 6-fold enhancement of fluorescence inten-
sity upon titration of 10 ␮M ZnCl2 ethanol solution (Fig. 5). When
Fig. 8. Fluorescence emission spectra of free compound
CH3CN:EtOH solution (90/10, v/v) upon addition of 1.0 equiv. of different zinc salts.
4
(1 × 10−5 M) in
Fig. 6. Proposed complex structure of 4 with Zn2+
.

10
Z.-L. Gong et al. / Journal of Photochemistry and Photobiology A: Chemistry 218 (2011) 6–10
monitoring fluorescence intensity at 480 nm, zinc ions could be
distinguished apparently from other transition metal ions. Further-
more, only Ni2+, Fe3+ and Co2+ have a little impact on the 480 nm
value of the zinc complex as shown in Fig. 7. The results imply the
sensor bears high selectivity for zinc ions in the presence of other
competitive metal ions.
Interestingly, similar fluorescence enhancement was observed
for compound 4 after the addition of Zn2+ salts with different coun-
teranions (NO3−, Cl−, and CH3COO−) as shown in Fig. 8. So the
zinc salts with different anions all can enhance the fluorescence
intensity of compound 4.
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4. Conclusions
In summary, a novel fluorescent sensor based on pyrazoline
with 2-(4-chlorophenoxy)acetic acid and 3-chloropyridazine sub-
stituent was synthesized and proposed for the determination
of Zn2+ ion with high selectivity and a low detection limit in
CH3CN:EtOH (90/10, v/v). This sensor formed a 1:1 complex with
Zn2+ and showed a fluorescent enhancement with good tolerance
of other metal ions. Further fluorescent probe exploration for zinc
ion in live cell will be reported in due course.
[25] Z.L. Gong, L.W. Zheng, B.X. Zhao, D.Z. Yang, H.S. Lv, W.Y. Liu, S. Lian, The syn-
thesis, X-ray crystal structure and optical properties of novel 1,3,5–triaryl
pyrazoline derivatives, J. Photochem. Photobiol. A: Chem. 209 (2010)
49–55.
[26] W.Y. Liu, Y.S. Xie, B.X. Zhao, B.S. Wang, H.S. Lv, Z.L. Gong, S. Lian, L.W. Zheng,
The synthesis, X-ray crystal structure and optical properties of novel 5-aryl-1-
arylthiazolyl-3-ferrocenyl-pyrazoline derivatives, J. Photochem. Photobiol. A:
Chem. 214 (2010) 135–144.
Acknowledgments
This study was supported by 973 Program (2010CB933504) and
the National Natural Science Foundation of China (20972088).
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