Fluorescent schiff base probes for sequential detection of Al3+ and F? and cell imaging applications

Article abstract of DOI:10.1016/j.saa.2019.117678

Two novel Schiff-base fluorescent probers SQ and NQ based on 8-hydroxyquinoline moiety were designed and synthesized. The both probes were capable of binding with Al³⁺ by naked eye detection to produce a significant fluorescence enhancement response with a detection limit of 1.48 × 10^?8 and 4.23 × 10^?8 M, respectively. At the same time, the formed complexes SQ-Al³⁺ and NQ-Al³⁺ could sequentially detect F^?, and the detection limits of F^? were determined to be 1.64 × 10^?7 and 3.58 × 10^?8 M, respectively. The “off-on-off” fluorescence response process demonstrated that the binding were reversible. The probes were further successfully utilized to detect Al³⁺ and F^? in vitro PC12 cells.

Full text of DOI:10.1016/j.saa.2019.117678

Journal Pre-proof
3+
−
Fluorescent schiff base probes for sequential detection of Al and F and cell
imaging applications
Jiaxin Fu, Bai Li, Huihui Mei, Yongxin Chang, Kuoxi Xu
PII:
S1386-1425(19)31068-6
https://doi.org/10.1016/j.saa.2019.117678
SAA 117678
DOI:
Reference:
To appear in: Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy
Received Date: 13 September 2019
Revised Date: 28 September 2019
Accepted Date: 17 October 2019
Please cite this article as: J. Fu, B. Li, H. Mei, Y. Chang, K. Xu, Fluorescent schiff base probes for
3+
−
sequential detection of Al and F and cell imaging applications, Spectrochimica Acta Part A:
Molecular and Biomolecular Spectroscopy (2019), doi: https://doi.org/10.1016/j.saa.2019.117678.
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8-Hydroxyquinoline-based probes SQ and NQ revealed excellent selective
recognition towards Al3+ with obvious vision changes of color in DMSO-H2O (1/2,
v/v) solution. The both complexes SQ-Al3+ and NQ-Al3+ can further detect F− with
the detection limits 1.64×10−7 and 3.58×10−8 M, respectively. The fluorescence
spectra, UV spectra, HRMS and so on were used to obtain a 1:1 complex between the
sensors SQ and NQ and Al3+, and the complexation mode between the complexes was
inferred by nuclear magnetic titration. In addition, filter paper and cell imaging
experiments proved the probes SQ and NQ had the potential application value to
monitor Al3+ and F− in environment and vivo.

Fluorescent schiff base probes for sequential detection of Al3+ and F− and
cell imaging applications
Jiaxin Fu, Bai Li, Huihui Mei, Yongxin Chang, Kuoxi Xu
College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, Henan, China
Abstract: Two novel Schiff-base fluorescent probers SQ and NQ based on
8-hydroxyquinoline moiety were designed and synthesized. The both probes were
capable of binding with Al3+ by naked eye detection to produce a significant
fluorescence enhancement response with a detection limit of 1.48×10−8 and 4.23×10−8
M, respectively. At the same time, the formed complexes SQ-Al3+ and NQ-Al3+ could
sequentially detect F−, and the detection limits of F− were determined to be 1.64×10−7
and 3.58×10−8 M, respectively. The “off-on-off” fluorescence response process
demonstrated that the binding were reversible. The probes were further successfully
utilized to detect Al3+ and F− in vitro PC12 cells.
Keywords: Schiff base; Visible sensing; Al3+ and F−; off-on-off; Cells imaging
1. Introduction
Among variant analytes, the role of metal ions in environment and living
organisms cannot be ignored, particularly Al3+, distributing in all corners of the earth
and frequently utilized in various fields, such as high tension wire, space shuttle,
kitchenware and clinical drugs [1]. Nevertheless, soil acidity increasing Al3+ ion
caused is detrimental to growing crops [2, 3] and marine lives. The toxic impact of
Al3+ ion is not only known to affect the plants and aquatic ecosystem but also
confined to humans. It is threatening even deadly that exposure of mankind to the
inevitable aluminium environment for a long time, which probably poses several
neurodegenerative diseases, including representative Alzheimer's disease [4] and
Parkinson's disease [5], as well as glucose intolerance, memory loss and cardiac arrest
[6, 7]. Though conventional analytical techniques like as atomic absorption
spectrometry (AAS) [8, 9], ion chromatography (IC) [10, 11] and inductively coupled
plasma mass spectrometry (ICP-MS) [12, 13] are employed to detect ions or neutral
molecule at short intervals. However, the vital drawbacks still exist where
cumbersome pretreatment test only in vitro, poor real-time monitoring and high
maintenance costs make them subject to a good deal of restrictions in practical
applications. Fluorescent probe, as the crucial research realm of supramolecular
Corresponding author. E-mail addresses: xukx@henu.edu.cn.
1

chemistry, occupies a valuable position in molecular recognition, which is relevant to
its traits containing facile operational procedures, high selectivity and sensitivity in
fluorescent assays [14-16], alongside the possibility of applications in biologically
and environmentally pertinent species [17-19]. Although many Al3+ fluorescent probes
have been developed, there still exist some shortages, such as suffering from the
interferences of Fe3+, Cu2+ and Zn2+ ions, poor water-solubility. Thus it is
indispensable and pressing to go in quest of highly selective and sensitive Al3+
fluorescent probe. Meanwhile, the function of anions cannot be neglected as well on
the environment and biology, particularly F−, which plays the part of the field of
biology and environment, such as pharmaceutical agent, therapy of osteoporosis and
prevention of dental caries [20, 21]. The disorder of F− is in charge of several diseases
containing stomach ulcer and urolithiasis [22, 23], and hence it is high time to identify
F− to guard against related untoward conditions.
8-Hydroxyquinoline and its derivatives were selected for synthesis not only as
fluorophore and recognition group, but also due to the features of high absorption
coefficient, long-wave absorption and emission wavelength after modification.
Considering that poor coordination ability of Al3+ compared to transition metals and
the lack of spectroscopic chatacteristics [24, 25], the introduction of the C=N double
bond also enhances its ability of selection and recognition for Al3+. So Schiff-base
ligands 8-hydroxy-N'-(2-hydroxybenzylidene)quinoline-2-carbohydrazide SQ and
8-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)quinoline-2-carbohydrazide NQ
based on 8-hydroxyquinoline were applied in this paper to detect Al3+ and F− [26, 27].
The detection of F− through particular interactions between Al3+ and F− utilize the
non-covalent interactions with low energy to form [AlFx]n− complex [28, 29], which
saves the cost, enhances specific recognition and flexibility. Due to excited-state
intramolecular proton transfer (ESIPT) and C=N isomerization, the fluorescence
intensities of SQ and NQ were greatly reduced, but once combining with Al3+ to form
complexes, the rigid chelation structure of the whole systems were turned up and the
fluorescence intensity were greatly improved. While the fluorescence of the resulting
2

complex quenched by interacting with F− and the “off-on-off” fluorescent changes
were reflected by changes in the spectrum (UV-vis and fluorescence). These analytical
phenomena were also supported in PC12 cell imaging experiments and indicated the
potential of applications in vivo.
Compared with some of the fluorescent probes recently released for Al3+ ion
detection [30-36], in general, our probes have some advantages over other probes,
while the other probes rarely do better. First, association constant (Ka) represents for
the tightness between host and guest. The Ka values of SQ and NQ are greater than
that of most. Besides, detection limit means the sensitivity of probes towards analyte.
Our probes illustrate 10-8 M sensitivity to metal ions, while few probes evince values
in this range. Finally, our probes both accomplish the anion recognition, paper test and
cell image. Comprehensive comparison is listed in the Table 1.
Table 1 Performance comparison of recently published probes
Detection
limit (M)
Refere
nce
Entry
1
Probe
Media
EtOH
EtOH
Target
Ka (M-1)
Application
photographs
of coated test
papers
Al3+
1.32×104
1.44×10-7
[30]
2
3
Al3+
Al3+
2.50×103
1.30×104
1×10-7
/
[31]
[32]
photograph of
coated test
paper
EtOH/
H2O
3.48×10-8
MeCN/
H2O
4
5
6
Al3+
Al3+
Al3+
2.10×102
2.61×105
2.0 × 107
1.08×10-6
3.1×10-7
3.9×10−6
Cell imaging
[33]
[34]
[35]
MeOH/
PBS
Cell imaging
MeCN/
H2O
Anion
recognition
3

Tris-
HCl
Anion
7
8
Al3+
/
9.2×10−8
recognition;
Cell imaging
[36]
buffer
H
N
N
N
9.40×104
9.40×104
1.48×10−8
4.23×10−8
Anion
O
OH
HO
DMSO/
H2O
recognition;
paper test;
Cell imaging
This
Al3+
work
2. Materials and methods
2.1. Materials and instrumentation
IR spectra was measured using a Nicolet 670 FT-IR spectrophotometer. 1H NMR
and 13C NMR was recorded on Bruker-AV-400 NMR spectrometer. UV-visible
absorption spectra was acquired on
a
Perkin-Elmer Lamda-25 UV-Vis
spectrophotometer. Electrospray ionization mass spectrometry (ESI-MS) spectra was
measured on a Brukerama Zon SL mass instrument. Fluorescence spectral was carried
out in an F-7000 fluorescence spectrophotometer. The melting point was taken on a
MEL-TEMP II melting point apparatus. The fluorescence quantum yield was
evaluated with JY HORIBA FluoroLog-3 Steady-Transient fluorescence spectrometer.
The reagents and pharmaceuticals referred herein were available from commercial
suppliers and used without further processed. The metal ions used were all nitrate or
chloride salts, and the anions were tetrabutylammonium or sodium. The intermediate
compound 1 was prepared with the reported literatures [37, 38].
2.2. Analysis
The nitrate or chloride salt of various metal ions and the tetrabutylammonium or
sodium salt of anions were separately dissolved in 3 mL deionized water to prepare a
stock solution for concentration of 0.1 M, and the corresponding volume was taken up
using a micro syringe during spectrometry. SQ or NQ were formulated into a DMSO
stock solution of 0.01 M, and diluted to 3.33×10−5 M in a cuvette containing
4

DMSO-H2O (1/2, v/v) solution for analysis. The test solution volume was 3 mL. In
the fluorescence spectroscopy experiment, different concentrations of metal ions were
added separately to a series of SQ or NQ solutions and mixed evenly; next the
fluorescence intensity of every system after addition were recorded to judge the
identified metal ion. The screening process of anion was similar to the method above.
Then the affinity of SQ or NQ was evaluated to recognize Al3+ or F− in the presence
of other interfering ions. During the titration experiment, Al3+ or F− was gradually
added to the single SQ or NQ system until equilibrium, and the UV-vis or
fluorescence spectrum data were collected uniformly. The excitation wavelengths of
SQ and NQ were 405 and 455 nm, respectively. In the 1H NMR titration experiment,
Al3+ with different concentrations were added to several DMSO-d6 solutions
containing SQ or NQ, and the chemical shifts were observed.
2.3. Synthesis:
Compound 1: 1H NMR (CDCl3) δ 10.22 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.16 (s,
1H), 8.06 (d, J = 8.5 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.29
(d, J = 7.7 Hz, 1H).
Compound 2: Compound 1 (0.43 g, 2.50 mmol) was placed in a round bottom
flask, 20 mL of 30 % H2O2 and 2 drops of formic acid were added, and the reaction
was stirred at room temperature for 8 h until a yellow precipitate appeared. The solid
was filtered and dried to give compound 2. Yield: 96 %. 1H NMR (DMSO-d6) δ 10.23
(s, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H),
7.54 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H).
Compound 3: Thionyl chloride (0.5 mL) was added dropwise into a continuously
stirring round bottom flask containing 15 mL of methanol in an ice bath, then
compound 2 (0.47 g, 2.50 mmol) was added to the above system and the reaction was
refluxed for 6 h under N2 protection. After the reaction, the solvent was evaporated
1
under reduced pressure to give compound 3 as orange solid. Yield: 82%. H NMR
(CDCl3) δ 8.24 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H),
5

7.33 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 5.6 Hz, 4H), 5.23 (s, 1H), 4.00 (s, 2H).
Compound 4: Compound 3 (0.50 g, 2.50 mmol) was dissolved in a round bottom
flask with 15 mL of ethanol, then 80 % hydrazine hydrate (0.93 mL, 15.00 mmol) was
added and refluxed for 8 h. After the reaction cooled, the solid was precipitated,
filtered, washed with ethanol and dried to give compound 4 as yellow solid. Yield:
87%. 1H NMR (DMSO-d6) δ 10.78 (s, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5
Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H),
4.66 (s, 2H).
SQ
and
NQ:
Salicylaldehyde
(0.31
mL,
3.00
mmol)
or
2-hydroxy-1-naphthaldehyde (0.50 g, 3.00 mmol) was added to a round bottom flask
containing compound 4 (0.51 g, 2.50 mmol) in methanol (20 mL), and refluxed for 6
h, finally the precipitate was filtered and dried.
1
SQ: yield: 86 %. Mp: 129.6-130.7 . H NMR (DMSO-d6) δ 12.66 (s, 1H),
11.08 (s, 1H), 10.19 (s, 1H), 8.87 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 8.5 Hz,
1H), 7.68 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.35
(t, J = 7.2 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 3.9 Hz, 1H), 6.97 (t, J = 8.1
Hz, 1H); 13C NMR (DMSO-d6) δ 160.30, 157.87, 154.10, 149.02, 146.91, 138.62,
136.85, 132.16, 130.38, 130.25, 129.37, 119.98, 119.62, 119.46, 118.22, 116.93,
112.37; IR (KBr) cm-1: 3452, 3203, 1622, 1500, 1366, 1158, 747; MS: Calcd for:
[M+H]+: 308.1030, Found: 308.1033.
1
NQ: yield: 89 %. Mp: 264.2-264.7 . H NMR (DMSO-d6) δ 12.83 (s, 1H),
12.61 (s, 1H), 10.19 (s, 1H), 9.58 (s, 1H), 8.61 (d, J = 8.5 Hz, 1H), 8.53 (d, J = 8.6 Hz,
1H), 8.27 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.64
(t, J = 7.8 Hz, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.29 (d, J = 5.4
13
Hz, 1H), 7.27 (d, J = 4.0 Hz, 1H); C NMR (DMSO-d6) δ 160.23, 158.65, 154.10,
148.17, 146.83, 138.66, 136.90, 133.52, 132.09, 130.42, 130.29, 129.44, 128.40,
128.32, 124.10, 121.89, 119.65, 119.31, 118.28, 112.42, 109.33; IR (KBr) cm-1: 3373,
3226, 1655, 1502, 1464, 1391, 1324, 1239, 1192, 956; MS: Calcd for: [M+H+]:
358.1186, Found: 358.1190.
6

Scheme 1 Synthetic route of SQ and NQ.
2.4. MTT assay and Cell imaging studies
PC12 cells were cultivated with fetal bovine serum (10 %) in Dulbecco's modified
Eagle's medium (DMEM) at 37 °C and 5% CO2 for 24 h. To begin with, MTT assay
was carried to assess the toxicity of SQ and NQ in PC12 cells at different
concentrations 0, 30, 60, 90, 120 µM and then monitor the livability. Probe with
applicable concentration 10 µL was selected to incubate with PC12 cells at 37 °C for
0.5 h in PBS buffered solution, which were washed with PBS (phosphate-buffered
saline) buffered solution to eradicate the disturbance of residue probe in the
extracellular media. In addition, the cells with probe were incubated with Al3+ another
for 0.5 h. Then F− was added in the same ways. The cells were observed under the
DMI8 inverted fluorescence microscope after every treatment.
3. Results and discussion
3.1. Synthesis and characterization
Taking 8-hydroxyquinaldine as a raw material, the quinoline carboxylic acid
compound 2 was obtained by two oxidations via SeO2 and H2O2, and then compound
4 was obtained by esterification reaction with methanol and subsequent trapping,
which finally condensed with salicylaldehyde or 2-hydroxy-1-naphthaldehyde to give
final compounds SQ and NQ, respectively (Scheme 1). The structures were
7

confirmed by IR, 1H NMR, 13C NMR and HRMS (Fig. s1-s7).
3.2. Spectroscopic studies of probe SQ and NQ on Al3+
Initially, the fluorescence selectivity experiments of SQ and NQ were carried out
on metal ions. Almost no fluorescence emission peaks of SQ (λex: 405 nm, Φ = 0.51)
and NQ (λex: 455 nm, Φ = 2.39) were observed in the DMSO-H2O solution (1/2, v/v).
When Li+, Na+, K+, Ag+, Mg2+, Ca2+, Al3+, Co2+, Ni2+, Cu2+, Fe2+, Mn2+, Pb2+, Zn2+,
Ba2+, Hg2+, Cd2+, Cr3+, Fe3+ ions were added respectively into several solutions
including SQ or NQ, it was found that no obvious fluorescence changes except for
Al3+ (Fig. 1). Once Al3+ existed, SQ and NQ had prominent 270-fold (Φ = 0.86) and
460-fold (Φ = 7.16) fluorescence enhancement at 505 nm and 509 nm, separately,
alongside the colors of both systems changed from colorless to green (under UV-light
365 nm).
(b)
500
400
300
200
100
0
NQ NQ
+Al3+
(a) 300
SQ
SQ
+Al3+
Al3+
250
200
150
100
50
Al3+
SQ, Li+, Na+, K+, Ag+, Mg2+
Ca2+, Co2+, Ni2+, Cu2+, Fe2+
Mn2+, Pb2+, Zn2+, Ba2+, Hg2+
Cd2+, Cr3+ and Fe3+
,
NQ, Li+, Na+, K+, Ag+, Mg2+
,
Ca2+, Co2+, Ni2+, Cu2+, Fe2+
,
,
Mn2+, Pb2+, Zn2+, Ba2+, Hg2+
Cd2+, Cr3+ and Fe3+
,
,
0
500
550
Wavelength (nm)
600
650
450
500
550
600
650
Wavelenth (nm)
Fig. 1. Fluorescence spectrum changes of the SQ (a) or NQ (b) solution (3.33×10−5 M) after
separately different metal ions added in DMSO-H2O (1/2, v/v) solution, inset: color change of SQ
solution before and after adding Al3+ ion. Inset: color change of the NQ or NQ solution before and
after the addition of Al3+.
On top of the phenomenon above, the competition experiment further verified
the specific selectivity of SQ and NQ for Al3+. With different interfering ions (5
equiv.) aforementioned added into the SQ and NQ solution, the fluorescence
intensities had no significant effect. Then Al3+ was added continuously, and the
fluorescence emission data were collected and the intensity values were compared
before and after the addition of Al3+, and drastically enhancement appeared, which
illustrated that SQ and NQ were more intimate to Al3+ in the presence of other
8

interfering ions and had excellent fluorescence selectivity for Al3+ ion (Fig. s8).
In order to investigate the recognition performance of SQ and NQ for Al3+, a
fluorescence titration experiment was performed. During the titration, fluorescence
intensity of SQ or NQ augmented with the incremental concentration for Al3+. When
the Al3+ concentration reached 2.52 and 5.00 equiv., respectively, the fluorescence
intensity of SQ or NQ became steady at 505 nm and 509 nm (Fig. 2). This
phenomenon can be explained by the fact that the imine structure usually makes the
fluorescence of the system weak, partly due to the intramolecular -C=N- double bond
isomerization in the excited state [39, 40], and partly due to the ESIPT [41], in which
protons are transferred from phenol to methylimine N atom. But after forming a stable
complex with Al3+, both processes are inhibited, the molecular rigid structures are
formed, and the chelation between the host and the guest also made fluorescence
enhancement (CHEF), so that the apparent fluorescence-enhanced responses are
captured [42, 43]. According to the fluorescence titration data, a linear fit with the
Benesi-Hildebrand equation [44, 45] to obtain the complex constants (Ka) of SQ and
NQ with Al3+ were both 9.40×104 M−1 (Fig. 3), and the detection limits towards Al3+
were 1.48×10−8 and 4.23×10−8 M (Fig. s9) (3σ/S, where σ is deviation of the blank
signal and S is slope of calibration curve), which met the limit about drinking water
according to the WHO standard (7.41 µM) [46, 47].
600
600
250
500
5.00 equiv.
200
550
500
450
400
350
300
250
200
150
100
50
400
300
200
100
0
250
200
150
100
50
2.52 equiv.
150
100
50
Al3+
Al3+
0
0
0
0.00000
0.00004
0.00008
[Al3+
0.00012
0.00016
0.00000
0.00002
0.00004
[Al3+
0.00006
0.00008
0.00010
]
(M)
]
(M)
0
0
425
450
475
500
525
550
575
600
625
650
475
500
525
550
575
600
625
Wavelength (nm)
Wavelength (nm)
Fig. 2. (a) Fluorescence spectral changes of the SQ (3.33×10−5 M) solution with different ratios of
Al3+ (0-2.52 equiv.) added in the DMSO-H2O (1/2, v/v); (b) Fluorescence spectral changes of the
NQ (3.33×10−5 M) solution with different ratios of Al3+ (0-5.00 equiv.) added in the DMSO-H2O
(1/2, v/v). Insert: error bars were obtained from the standard deviation of three replicate
experiments.
9

(b)
(a)
0.0080
0.0075
0.0070
0.0065
0.0060
0.0055
0.0050
0.0045
0.0040
0.0035
Equation
y = a + b*x
0.99682
Equation
y = a + b*x
0.99338
0.12
0.10
0.08
0.06
0.04
0.02
0.00
Adj. R-Square
Adj. R-Square
Value
-0.01703
1.81089E-7
Standard Error
9.74478E-4
3.40779E-9
Value
0.00351
3.73519E-8
Standard Error
4.77278E-5
B
B
Intercept
Slope
B
B
Intercept
Slope
8.79789E-10
0
20000
40000
60000
80000
100000
0
100000 200000 300000 400000 500000 600000 700000 800000
1/[Al3+
1/[Al3+
]
]
Fig. 3. (a) Linear fitting with the Benesi-Hildebrand equation of SQ and Al3+ for complexing
constant Ka1= 9.40×104 M−1 (R2 = 0.9934); (b) Linear fitting of NQ and Al3+ with
Benesi-Hildebrand equation for the complexation constant Ka2= 9.40×104 M−1 (R2 = 0.9968).
In the UV spectroscopy experiment, as shown in Fig. 4, free SQ had three main
UV absorption peaks, and the UV absorption peaks at 257 nm and 296 nm were
mainly due to intramolecular n-π* electronic transitions and imines -C=N- structure,
while UV absorption at 340 nm was attributed to intramolecular π-π* electronic
transitions and OH-C=C-C=N- chromophore. When the concentration of Al3+ was
gradually increased in the SQ system, the three main absorption peaks of SQ were
gradually decreased, and new two enhanced absorption peaks were generated at 309
and 387 nm, which was attributed to the effective combination of SQ and Al3+, equal
absorption points were formed at 302 nm, 325 nm and 358 nm, which marked the
equilibrium transition between free SQ and SQ-Al3+. Similar to SQ, the free NQ had
three main absorption peaks, the absorption peaks at 256 nm and 331 nm are due to
the intramolecular n-π* electronic transition, and the 373 nm was due to the
intramolecular π-π* electronic transition. After Al3+ gradually added to the NQ system,
the most obvious was the new broadband absorption peak at 404-450 nm, and the
absorption peak intensity at 373 nm gradually decreases, and the equal absorption
points were formed at 349 nm and 395 nm, indicating the balance between NQ and
NQ-Al3+.
10

1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1.2
1.0
0.8
0.6
0.4
0.2
0.0
250
300
350
400
450
500
250
300
350
400
450
Wavelength (nm)
Wavelength (nm)
Fig. 4. (a) UV absorption spectrum changes of SQ (3.33×10−5 M) after adding different ratios of
Al3+ in DMSO-H2O (1/2, v/v) solution, inset: color change of SQ solution before and after adding
Al3+ in day light; (b) The UV absorption spectrum of the solution changes after adding different
ratios of Al3+ to NQ (3.33×10−5 M) DMSO-H2O (1/2, v/v) solution, inset: color change of NQ
solution before and after addition of Al3+ in day light.
3.3. Binding mode studies
In order to explore the complexation mode between SQ and NQ for Al3+, the
Job's curve was first plotted to estimate the stoichiometry of the complexation
between the host and the metal ions, what should do was maintaining the total
concentration of Al3+ and SQ or NQ at 1.00×10−4 M and changing the ratio (1:9-9:1)
between Al3+ and SQ or NQ. The abscissa of largest fluorescence intensity gap was at
0.5, indicating that the ratio of SQ or NQ with Al3+ were both 1: 1 (Fig. s10), which
was also supported by HRMS, Al3+ was added in SQ and NQ system and the peaks
were captured at m/z 395.0579 and m/z 445.0732 respectively assigned to
-
-
[SQ-Al3++NO3 -H+]+ and [NQ-Al3++NO3 -H+]+ (Fig. s11 and Fig. s12).
IR spectra was then made of SQ, SQ-Al3+ and NQ, NQ-Al3+ (Fig. s13), and
3452 and 3373 cm−1 were -OH stretching vibration belonging to the quinoline unit
and salicylaldehyde unit in SQ and NQ, 3203 and 3226 cm−1 were stretching
vibrations of amide NH, 3054 and 3060 cm-1 were due to the presence of quinoline
ring, and 1622 and 1655 cm−1 were peaks of -C=O, and 1500 and 1502 cm−1 were
attributed to the -C=N- extension vibration. When SQ combined with Al3+, the
phenolic hydroxyl stretching vibration at 3452 cm−1 disappeared and the peaks at
1622 and 1500 cm−1 also changed significantly, indicating that the phenolic hydroxyl
atom, oxygen atom of the -C=O group and the nitrogen atom of the -C=N- group
participated in the complexation with Al3+. Similarly, when NQ complexes with Al3+,
11

the phenolic hydroxyl peak at 3373 cm−1 shifted to 3384 cm−1, and the -C=N group at
1502 cm−1 disappeared, the stretching vibration peak at 1655 cm-1 was transferred to
1610 cm−1, indicating that the oxygen atom of phenolic hydroxyl and -C=O group and
the nitrogen atom of the imine group participated in complexation with Al3+.
1
To further explore the complexation pattern of SQ or NQ with Al3+, H NMR
titration experiment was performed in DMSO-d6 solution. As shown in the Fig. 5, a, b,
and c represented separately the NMR spectrum of only SQ, 0.5 equiv. Al3+, 1.0 equiv.
Al3+ to the SQ solution. With the gradual addition of Al3+, the peak of the probe SQ
changed significantly, and the proton signal peak (H1) of the phenolic hydroxyl group
gradually disappeared, indicating that the O atom of phenolic hydroxyl participated in
the coordination with Al3+. The proton signal peak (H3) of the acidamide and the
hydroxyl (H4) signal peak of the quinoline ring did not change significantly (the
integral value did not change). The proton signal peak (H2) of the imine group
(-CH=N-) shifted from 8.86 ppm to a high field to 8.84 ppm, indicating that the
nitrogen atom of the imine group took part in the coordination with Al3+. In addition,
combining with HRMS data, we knew that Al3+ formed an additional coordinate bond
with another oxygen atom through the nitrate anion. The same analyzed way was
carried out for NQ and the results were given in the Fig. s14.
Fig. 5. 1H NMR spectrum of (a) SQ, (b) 0.5 equiv. Al3+ and (c) 1.0 equiv. Al3+ added in DMSO-d6.
In order to further explore the sensing mechanism between the probes SQ or NQ
with Al3+, we performed the B3LYP/6-31G(d) method on the Guassian 09 program
for the optimization structures of the probe SQ, NQ, the complexes SQ-Al3+ and
12

NQ-Al3+ (Fig. 6 and Fig. 7). The quinolyl group and the phenol group of the free
probe SQ were not in the same plane with the dihedral angle 35.46° formed, which
was due to the isomerization of the -C=N- double bond in the SQ molecule. Upon
complexation with Al3+, the quinoline group and the phenol group formed a
coplanarity with Al3+ such that inhibition of -C=N- double bond isomerization and
attenuation of the non-radiative transition of the SQ, resulting in enhanced
fluorescence. According to the results of NMR titration experiments and IR
spectroscopy, it was found that Al3+ formed three coordination bonds with the
carbonyl oxygen atom, nitrogen atom of the imine group and the oxygen atom of the
phenolic hydroxyl group of SQ. The bond lengths of O-Al3+, N-Al3+, and O-Al3+ were
1.8372, 1.9681, and 1.7709 nm, respectively. In addition, Al3+ formed an additional
coordinate bond with another oxygen atom through the nitrate anion. The HOMO and
LUMO orbital energy gaps of SQ before and after complexing Al3+ were calculated
by DFT. The energy gap difference between HOMO and LUMO of composite
SQ-Al3+ (E=1.1070 eV) was much lower than that of SQ (E=3.8708 eV), which
indicated that the free probe and Al3+ tend to complex and the thermodynamics of the
complex SQ-Al3+ was stable. NQ was similar to the coordination of SQ and Al3+.
1
Combining with the above fluorescence and IR spectroscopy, HRMS and H NMR
titration, we proposed the possible complexation mode and sensing mechanism
between the probes SQ or NQ with Al3+ and F− (Scheme 2).
13

Fig. 6. Frontier molecular orbital of SQ and SQ-Al3+ complex.
Fig. 7. Frontier molecular orbital of NQ and NQ-Al3+ complex.
14

Scheme 2. The possible complexation mode and sensing mechanism between the probes SQ or
NQ with Al3+ and F−.
3.4. Determination of Al3+ in filter paper
In order to explore the field-test performance of probes SQ and NQ, a simple
and direct filter paper experiment was conducted. In the first place, 3 µL solution of
SQ (0.1 mM) in ethanol was prepared and dropped on the filter paper to give a dark
yellow dot under the UV lamp. Furthermore, 1 µL metal ions (0.1 µM) to be tested
were covered at the point of SQ. The test method of NQ was the same as SQ. The
final consequence manifested that Al3+ presented a change in fluorescent color
different from other metal ions (Fig. 8 and 9), which laid a foundation in practical
applications.
Fig. 8. Photographic image of metal ions by SQ on filter paper by UV-light (wavelength 365 nm).
15

Fig. 9. Photographic image of metal ions by NQ on filter paper by UV-light (wavelength 365 nm).
3.5. Spectroscopic studies of SQ and NQ on anions
In view of the particular interaction, SQ-Al3+ and NQ-Al3+ were used as anion
probes to perform anion screening, as shown in Fig. 10, different anions F−, Cl−, Br−,
2−
−
−
2−
−
2−
−
−
I−, PO43−, SO3 , NO3 , HSO3 , SCN−, S2−, CO3 , HCO3 , S2O8 , HSO4 , H2PO4 ,
2−
2−
Cr2O7 , SO42−, HPO4 , CH3COO−, PPi and citrate anion (0.1 M) were added
respectively to SQ-Al3+ and NQ-Al3+ in DMSO-H2O (1/2, v/v) solution to determine
its selectivity for anion, and it was found that SQ-Al3+, NQ-Al3+ produced
fluorescence quenching effect only for F− different from other anions, the resulting
fluorescence intensity and color of solution were consistent with the initial free SQ
and NQ.
SQ
+Al3+ +Al3+
SQ
NQ
NQ
SQ
NQ
(a)
300
250
200
150
100
50
(b)
+Al3+ +Al3+
+F-
600
500
400
300
200
100
0
+F-
L5+Al3+, Cl-, Br-, I-, CH3COO-, SO42-
S2O82-, PO43-, NO3-, HSO3-, HSO4- , S2-
SO32-, HCO3- CO32-, H2PO4-, Cr2O72-
SCN-, HPO42-, PPi and citrate anions
,
L6+Al3+, Cl-, Br-, I-, CH3COO-, SO42-
S2O82-, PO43-, NO3-, HSO3-, HSO4- S2-
SO32-, HCO3- CO32-, H2PO4-, Cr2O72-
,
,
,
,
,
,
,
,
HPO42-
,
SCN-, PPi and citrate anions
F-
F-
0
500
550
600
650
450
500
550
600
650
Wavelength (nm)
Wavelength (nm)
Fig. 10. (a) Fluorescence spectral changes of the SQ-Al3+ (3.33×10−5 M) solution after addition of
different anions in DMSO-H2O (1/2, v/v). Inset: color change of SQ-Al3+ before and after F−
added in; (b) Fluorescence spectral changes of the NQ-Al3+ (3.33×10−5 M) solution after addition
of different anions in DMSO-H2O (1/2, v/v). Inset: color change of the NQ-Al3+ solution before
and after F− added in.
A fluorescence competition experiment was then performed to detect the
anti-interference recognition ability of SQ and NQ to identify F− (Fig. s15). The
above anions were added separately in the DMSO-H2O (1/2, v/v) containing SQ-Al3+,
16

NQ-Al3+, then F− was added to these systems and fluorescence data were collected.
The consequence suggested F− still had obvious fluorescence quenching effect on
SQ-Al3+ and NQ-Al3+, which exhibited good anti-interference and selective
recognition ability for F−.
The fluorescence titration experiments were performed on SQ-Al3+ and NQ-Al3+
on F− to explore their sensing properties (Fig. 11). Gradually increasing F− in SQ-Al3+
and NQ-Al3+ (3.33×10-5 M) solutions respectively and collecting fluorescence data. It
was found that the fluorescence emission peaks of SQ-Al3+ at 505 nm and NQ-Al3+ at
509 nm became reduced, until the F− concentration reaching at 1.88 and 1.68 equiv.,
the fluorescence intensity got equilibrium, which was due to the F− gradual pulled
Al3+ out from the SQ-Al3+ and NQ-Al3+ complexes and released free SQ and NQ.
This result was proved in HRMS, after adding F− in the systems of SQ-Al3+ and
NQ-Al3+, respectively, the peaks of SQ and NQ were captured at m/z 308.1033 and
m/z 358.1190, which were assigned as [SQ+H+] and [NQ+H+] (Fig. s16 and Fig. s17).
The detection limits of SQ-Al3+ and NQ-Al3+ for F− were calculated to be 1.64×10−7
and 3.58×10−8 M, respectively (Fig. s18).
350
300
600
250
500
200
400
150
600
500
400
300
200
100
0
300
250
200
150
100
50
300
200
100
0
100
50
0
0.00000 0.00001 0.00002 0.00003 0.00004 0.00005 0.00006 0.00007
[F-] (M)
0.00000 0.00001 0.00002 0.00003 0.00004 0.00005 0.00006
[F-] (M)
0
0
F-
F-
1.88 equiv.
1.68 equiv.
0
450
500
550
600
650
500
550
600
650
Wavelength (nm)
Wavelength (nm)
Fig. 11. (a) Fluorescence titration of SQ-Al3+ (3.33×10−5 M) in the DMSO-H2O (1/2, v/v) solution
with different concentration of F− (0-1.88 equiv.) added; (b) Fluorescence titration of NQ-Al3+
(3.33×10−5 M) in the DMSO-H2O (1/2, v/v) solution with different concentration of F− (0-1.68
equiv.) added. Inset: error bars were obtained from the standard deviation of three replicate
experiments.
In the UV-visible titration experiment of SQ-Al3+ and NQ-Al3+ on F− (Fig. 12), it
was found that the main absorption peaks of SQ-Al3+ at 309 and 387 nm gradually
17

decreased while the F− concentration increasing in the system, and the absorption
peaks at 257 and 340 nm increased. The absorption peak intensity at 405-450 nm of
NQ-Al3+ gradually decreased while the peak at 373 nm gradually increased, and the
peak between 250-349 nm gradually recovered to the same as free NQ, which
indirectly proved that the presence of F− was to pull Al3+ out in the SQ-Al3+ and
NQ-Al3+ systems, releasing free SQ and NQ.
SQ
SQ
SQ
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
(a)
(b)
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
NQ
+Al3+
NQ
NQ
+Al3+ +Al3+
+F-
+Al3+
+F-
250
300
350
400
450
250
300
350
400
450
500
Wavelength (nm)
Wavelength (nm)
Fig. 12. (a) UV absorption spectrum changes of addition different ratios of F− to SQ-Al3+
(3.33×10−5 M) DMSO-H2O (1/2, v/v) solution, inset: color change of SQ-Al3+ solution before and
after F− addition; (b) UV absorption spectrum changes of addition different ratios of F− to SQ-Al3+
(3.33×10−5 M) DMSO-H2O (1/2, v/v) solution, inset: color change of NQ-Al3+ solution before and
after F− addition.
Next, the reversibility of probes SQ and NQ was explored to identify Al3+ and F−
(Fig. s19). Al3+ and F− were alternately added to the SQ and NQ solutions which
caused switchable fluorescence changes and this reversible cycle can be repeated
several times, indicating that SQ and NQ can have an "on" fluorescence response to
Al3+, while the SQ-Al3+ and NQ-Al3+ complexes exhibited a "off" fluorescence
response to F−. After several repetitions, the recognition efficiency of the probes SQ
and NQ for Al3+ and F− was still appreciable.
3.6. pH affection to the recognition of SQ and NQ
pH tests was performed on SQ and NQ in DMSO-H2O (1/2, v/v) systems (Fig.
s20) to explore their effect on recognition for Al3+ and F−. The fluorescence emission
states of SQ and NQ were relatively stable at the physiological pH (6.3~9.3 and
6.3~10.3), but the recognition abilities of SQ and NQ for Al3+ were affected in both
high acid (pH < 5.3) and high alkali (pH > 10.3). The recognition effect of SQ-Al3+
18

and NQ-Al3+ on F− was relatively stable. This phenomenon in vitro at physiological
pH laid a favorable foundation for us to carry out in-vivo object recognition, and it is
expected to be applied in food, environment and organisms.
3.7. MTT assay and Cell imaging
To explore the prospect of application value of probes SQ or NQ in organisms,
MTT assay in PC12 cells was preferentially executed to assess the toxicity of SQ and
NQ to cells at different concentrations 0, 30, 60, 90, 120 µM and the consequence
indicated that SQ was amicable on cells viability even at high concentration, but NQ,
to a certain extent, may exist some threat at high concentration. The fluorescence
imaging experiment was next performed in biological cells. PC12 cells were firstly
incubated with 20 µM SQ and NQ in sterile PBS at 37 °C for 30 min, then were
washed three times with PBS buffer and observed under a fluorescent inverted
microscope. The bright field image indicated good cell configuration (Fig. 13a and
13g), which did not appear fluorescence in dark field (Fig. 13b and 13h). Then, the
cells culture medium with SQ and NQ was incubated with 30 µM Al3+ for 20 min.
After the incubation, the cells were washed three times with PBS buffer, and observed.
The cells showed brightness and green fluorescence under dark field (Fig. 13d and
13j). Finally, when we continued to add 40 µM F− into the cells for another 20 min,
the fluorescence of the cells in the dark field was quenched (Fig. 13f and 13l), which
was consistent with the analysis obtained in our fluorescence spectra.
19

Fig. 13. (a) Bright-field fluorescence microscopic image of live PC12 cells only cultured with SQ;
(b) Dark-field fluorescence microscopic image of a; (c) Bright-field fluorescence microscopic
image treated with Al3+ after a; (d) Dark-field fluorescence microscopic image of c; (e)
Bright-field fluorescence microscopic with F− treated after c; (f) Dark-field fluorescence
microscopic image of e; (g) Bright-field fluorescence microscopic image of live PC12 cells only
cultured with NQ; (h) Dark-field fluorescence microscopic image of g; (i) Bright-field
fluorescence microscopic image with Al3+ treated after g; (j) Dark-field fluorescence microscopic
image of i; (k) Bright-field fluorescence microscopic image with F− treated after i; (l) Dark-field
fluorescence microscopic image of k. Scale bars: 50 µm.
4. Conclusion
In summary, the probes SQ and NQ based on 8-hydroxyquinoline revealed
sequentially recognition towards Al3+ and F- (λex: 405 and 455 nm) with obvious
vision changes of color as well as an ‘OFF-ON-OFF’ fluorescent response in
DMSO-H2O (1/2, v/v) solution. The detection limits of SQ and NQ for Al3+ were
1.48×10−8 and 4.23×10−8 M and for F− 1.64×10−7 and 3.58×10−8 M, respectively. The
complexation mode between the probes SQ or NQ and Al3+ was inferred by
fluorescence spectra, UV spectra, HRMS and NMR titration to obtain a 1:1 complex,
which was through ESIPT and CHEF mechanism. DFT calculation also simulated the
20

distribution of electron clouds and energy changes before and after mating. In
addition, filter paper and cell imaging experiments proved the probes SQ and NQ had
the potential application value to monitor Al3+ and F− in environment and vivo.
Acknowledgements
We thank the Natural Science Foundation of China (No. U1404207) for financial
support.
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25

1. Two fluorescent 8-hydroxyquinoline-based probes SQ and NQ were synthesized.
2. The probes SQ and NQ for the sequentially detected of Al3+ and F− in aqueous
solutions.
3. The binding modes of probes SQ and NQ with Al3+and F− had been well
demonstrated by ESI-MS, 1H NMR and DFT calculation.
4. The filter paper and cell imaging experiments proved probes SQ and NQ had the
potential application value to monitor Al3+ and F− in environment and vivo.

Declaration of interests
The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this
paper.