A Benzothiazole-Based Fluorescent Probe for Ratiometric Detection of

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A benzothiazole-based fluorescent probe for ratiometric detection of Al3+ in aqueous medium and living cells Yahui Chen, Tingwen Wei, Zhijie Zhang, Tiantian Chen, Jia Li, Jian Qiang, Jing Lv, Fang Wang, and Xiaoqiang Chen Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b02979 • Publication Date (Web): 10 Oct 2017 Downloaded from http://pubs.acs.org on October 12, 2017

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Industrial & Engineering Chemistry Research

A benzothiazole-based fluorescent probe for ratiometric detection of Al3+ in aqueous medium and living cells

Yahui Chen, Tingwen Wei, Zhijie Zhang, Tiantian Chen, Jia Li, Jian Qiang, Jing Lv, Fang Wang and Xiaoqiang Chen* State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University, Nanjing 210009, China Abstract Aluminum is the third (after O and Si) most abundant metal in the earth’s crust and associates with neurological diseases when abnormal level of Al3+ occurs in nervous center. Developing highly sensitive and selective methods for Al3+ detection is of significant interest. In this work, we developed an excited state intramolecular proton transfer (ESIPT) and aggregation-induced emission (AIE) active fluorescent probe for ratiometric detection of Al3+ in aqueous medium and living cells. The BTZ-SF can detect Al3+ with high selectivity and a good linear relationship (R2 = 0.9911) between fluorescence intensity ratio (I476

nm/I568 nm)

and Al3+ concentration (0-100 µM). In

addition, the detection limit was calculated as low as 2.2 µM. The single crystal structure of BTZ-SF-Al clearly exhibited the interaction between BTZ-SF and Al3+ with a hexa-coordinated structure. Furthermore, confocal fluorescence images of HeLa cell indicated that BTZ-SF could be used for monitoring Al3+ in living cells. Finally, test strips experiment suggests that the BTZ-SF can recognize the Al3+ selectively accompanied by remarkable color change. Keywords Fluorescent probe, ESIPT, AIE, Ratiometric detection, Aluminum, Single crystal

* Corresponding author Tel. (Fax): +86 025 83587856 E-mail address: [email protected] (X. Chen)

ACS Paragon Plus Environment


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1. INTRODUCTION Aluminum is the third (after O and Si) most abundant metal in the earth’s crust and its application is very extensive in daily life.1-3 It’s known that the free state of aluminum does not exist naturally in nature, while human activities lead to the release of free aluminum ions (Al3+) into the living systems and environment with the extensive use of aluminum.4-6 However, high levels of aluminum ion (Al3+) are regard as neurotoxic, which can cause Alzheimer’s disease,7, 8 Parkinson’s disease 9-11 and dialysis encephalopathy.12 According to the standards developed by World Health Organization (WHO), the daily permissible limitation of Al3+ is about 3-10 mg and the Al3+ concentration in drinking water should not exceed 200 µg/ L, that is, 7.41 µM.13-15 On this account, monitoring the Al3+ level both in living systems and environment is rather essential.16-19 To date, a number of analytical methods, such as electrochemical, photometric determination, 20 electro-thermal atomic absorption spectrophotometry atomic 21 and inductively-coupled plasma mass spectrometry. 22, 23 However, the equipment cost, complexity, sample processing and run times limit the wide application to a certain extent. It’s noteworthy that fluorogenic methods in conjunction with suitable probes are preferable approaches for the measurement of Al3+ with high sensitivity, simplicity and real-time detection. 24 Although plenty of fluorescent sensors based on various fluorophores including julolidine, 25 rhodamines, 4, 31 pyrenes 26 and others 27-30 were developed for detection of Al3+. Most of them for Al3+ are required to be performed in pure organic solvents or organic-water mixed solvents. Owing to the strong hydration of Al3+ in aqueous solution, these probes suffer from the great limitation in imaging applications.32, 33 In addition, many fluorescent sensors underwent small Stokes shifts and thus encountering some interference influence in fluorescence analysis, including self-absorption or inner filter effects. 34, 35 Contrary to the aggregation-caused quenching (ACQ) effect, a number of fluorescent sensors that exhibit AIE (aggregation-induced emission) or AIEE (aggregation-induced enhanced emission) phenomenon possess better attributes and


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have received more and more attention due to the highly emissive in the aggregated state. 36, 37 Generally, these fluorescent sensors display non-emissive or weak emission in dilute solutions due to the strong intermolecular interaction of π-π stacking. However, upon aggregate formation occurring, strong fluorescence emission and high quantum efficiency can be obtained due to the restricted intramolecular motion in the aggregates, especially in solid state. 38-40 Thus the AIE or AIEE active sensors are regard as attractive candidates for sensing various analytes with unique property. 41 Additionally, fluorophores that possess excited state intramolecular proton transfer (ESIPT) attributes have been extensively used due to the large Stokes shifts, which endows them many favorable features including the elimination of inner filter effects or self-absorption process when used in fluorescence analysis 42. Furthermore, it’s known that the emission intensity of fluorescent sensors is influenced by many factors, including the concentration of fluorescent probe, excitation intensity, optical path length and detection efficiency. Ratiometric fluorescent probe can eliminate the effect of above factors by its self-calibration, leading to more precise accurate value through measuring the fluorescence intensity ratio at two different emission wavelengths. 43-46 Based on above rationale, herein we designed and synthesized an ESIPT and AIE-active Schiff base sensor BTZ-SF, which avoided the disadvantages of small Stokes shift and ACQ effect in aqueous media. After binding with Al3+, the BTZ-SF displayed good selectivity towards Al3+ accompanied by remarkable ratiometric fluorescence change (blue-shift). In addition, the single crystal structure of BTZ-SF-Al clearly showed that BTZ-SF chelated Al3+ via the O atoms of phenolic hydroxyl group, the N atoms in -C=N- groups, the carbonyl O and three H2O molecules, composing a hexa-coordinated structure.

2. EXPERIMENTAL SECTION 2.1. Equipments and Instruments Mass spectra were obtained from Q-Tof mass spectrometer (Agilent 6530). 1H NMR and

13

C NMR spectra were obtained using Bruker spectroscopy （Ascend TM

400, 400 MHz. UV-vis absorption spectra were carried out on α-1860A UV/vis



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spectrophotometer. Fluorescence emission spectra were collected using RF-5301/PC fluorophotometer (SHIMADZU). Single crystal structures were obtained using Single-crystal X-ray diffractometer (Bruker SMART APEX II). MTT assay were performed by Multiskan Go (51119200-VAN). The cells were imaged by Confocal Laser Scanning Microscopy (Leica, TCS sp5 II). To gain insight into the morphologies of samples, field-emission scanning electron microscope (SEM) instrument (HITACHI S-4800) was used for the collection of SEM images. The particle size was performed by Dynamic Light Scattering (DLS) instrument (Malvern Zetasizer 3000). 2.2. Materials and Reagents 2-Aminothiophenol, 2-hydroxy-5-methylbenzaldehyde and 2-thiophenecarboxylic acid hydrazide were purchased from J&K SCIENTIFIC LTD. (Beijing, China). All reagents were directly used for the following experiments without further purification. Unless otherwise noted, the aqueous solutions were prepared with deionized water. Chromatography was implemented on silica gel 60 (200-300 mesh ASTM). 2.3. Synthesis 2.3.1. Synthesis of Compound BTZ-PC BTZ-PC was synthesized according to our previous reported literatures

47-50

.

2-hydroxy-5-methylbenzaldehyde (0.55 g, 4.04 mmol) and 2-aminothiophenol (0.46 g, 3.67 mmol) was dissolved in N, N-dimethylformamide (10 mL), and then sodium metabisulfite (Na2S2O5, 0.70 g) was added to 250 mL round-bottom flask for stirring. The mixture was heated to 110 oC for 2 h by oil bath and the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature. There was a lot of precipitation emerged once 50 mL of H2O was added to the reaction mixture, then we washed the precipitation three times with H2O while vacuum filtration processing. Finally, a white solid product (0.79 g, 3.27 mmol) was obtained. Yield: 89%. 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 11.36 (1H, s), 8.13 (1H, d, J = 5.9 Hz), 8.05 (1H, d, J = 6.1 Hz), 7.99 (1H, s), 7.54 (1H, t, J = 5.7 Hz), 7.45 (1H, t, J = 5.7 Hz), 7.22 (1H, d, J=6.2 Hz), 6.98 (1H, d, J=6.2 Hz), 2.33 (3H,


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s); 13C NMR (DMSO-d6, 100 MHz), δ (ppm): 165.94, 154.84, 152.11, 134.90, 133.89, 129.07, 128.93, 127.09, 125.67, 122.70, 122.63, 118.58, 117.53, 20.68. LC-MS (ESI): m/z [M + H] + calcd. for C14H11NOS: 242.0640; found: 242.0572. 2.3.2. Synthesis of Compound BTZ-SA BTZ-PC (0.50 g, 1.86mmol) and hexamethylenetetramine (0.82 g, 5.86 mmol) were mixed in trifluoroacetic acid (10 mL). And then the mixture was heated to 100 o

C, the progress of the reaction was monitored by TLC. After 6 h, the mixture was

cooled to room temperature and 50 mL H2O was added and orange-yellow deposition appeared. The precipitate was filtered off, washed by saturated brine, extracted with dichloromethane for three times, and then the sediment was collected and dried in vacuo. Chromatography of the crude product on silica gel using dichloromethane as eluent afforded compound BTZ-SA (0.43 mg, 1.60 mmol) as a pale-green solid. Yield: 85%. 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 12.76 (1H, s), 10.33 (1H, s), 8.21 (1H d, J=3.2 Hz), 8.11 (2H, d, J=6.1 Hz), 7.73 (1H, s), 7.60 (1H, t, J=5.7 Hz), 7.52 (1H, t, J=5.7 Hz), 2.34 (1H, s);

13

C NMR (DMSO-d6, 100 MHz), δ (ppm): 192.30, 165.67,

157.53, 151.49, 135.76, 134.04, 133.58, 129.78, 127.43, 126.32, 123.73, 122.79, 122.76, 119.60, 20.22. LC-MS (ESI): m/z [M + H] + calcd. for C15H11NO2S: 270.0589; found: 270.0513. 2.3.3. Synthesis of Probe BTZ-SF BTZ-SA (0.27 g, 1.0 mmol) mixed with 2-thiophenecarboxylic acid hydrazide (0.16 g, 1.1 mmol) in methanol (10 mL), accompanied by stirring at room temperature overnight. The resulting precipitate was filtered and washed 3-5 times with 30 mL CH3OH. Finally, a yellow solid was obtained (0.32 g, 0.81 mmol). Yield: 81%. 1H NMR (DMSO-d6, 400 MHz), δ (ppm): 13.16 (1H, s), 12.39 (1H, s), 8.69 (1H s), 8.18 (2H, s), 8.10 (1H, d, J=6.0 Hz), 7.95 (2H, t, J= 4.2), 7.61 (1H, d, J=11.4), 7.56 (1H, d, J=5.8), 7.28 (1H, s), 2.41 (3H, s); 13C NMR (DMSO-d6, 100 MHz),

(ppm): 164.10,

158.11, 154.40, 151.76, 147.74, 137.74, 135.13, 133.34, 132.98, 130.90, 130.03, 129,20, 128.79, 127.02, 125.69, 122.74, 122.57, 120.13, 119.72, 20.41. LC-MS (ESI): m/z [M + H] + calcd. for C20H15N3O2S2, 394.0684; found: 394.0545. 2.3.4. Single-Crystal X-ray Diffraction



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Single crystals of the BTZ-SF suitable for X-ray diffraction analysis were obtained from a liquid (n-hexane)-liquid (DMF) diffusion system at room temperature for three weeks and single crystals of the BTZ-SF-Al suitable for X-ray diffraction analysis were grown from ethanol by volatilization process at room temperature for two weeks. The well-shaped single crystals of BTZ-SF and BTZ-SF-Al were both selected for lattice parameter determination and collection of intensity data at 296 K on a Bruker SMART CCD X-ray diffractometer with a detector distance of 5 cm and frame exposure time of 10 s using a graphitemonochromated Mo-Kα (λ = 0.71073 Å) radiation. The structures were all solved by direct methods and refined on F2 by full-matrix least squares procedures using SHELXTL software 51. All nonhydrogen atoms were anisotropically refined. All H atoms were located from a difference map and refined isotropically. 2.3.5. Fluorescent Assays Stock solution of probe BTZ-SF (1 mM) was prepared in dimethyl sulfoxide (DMSO). Stock solutions (20 mM) of various metal ion analytes, including Al3+, Zn2+, Cu2+, Fe2+, Fe3+, Hg2+, Ag+, Co2+, Ni2+, Cr3+, Ca2+, Cs+, Cd2+, Pb2+, Mn2+, Zr4+, K+, Mg2+, Li+ and Na+, derived from Al(ClO4)3·9H2O, Zn(ClO4)2·6H2O, Cu(ClO4)2·6H2O, Fe(ClO4)2·6H2O, Fe(ClO4)3·xH2O, Hg(ClO4)2·3H2O, ZrCl4, KClO4, AgClO4·xH2O, Co(ClO4)2·6H2O, Ni(ClO4)2·6H2O, Cr(ClO4)3·6H2O, Ca(ClO4)2·xH2O, CsClO4, Cd(ClO4)2·6H2O, Pb(ClO4)2·3H2O, Mn(ClO4)2·xH2O, Mg(ClO4)2, LiClO4, and NaClO4, respectively. All stock solutions of metal ions analytes were prepared by dissolving their perchlorates in deionized water. The fluorescence properties of probe BTZ-SF were performed in HEPES buffer (pH 7.4, 10 mM) at room temperature. 2.4. Determination of Detection Limit On the basis of the fluorescence titration curve of BTZ-SF with the addition of Al3+ (0-100 µM), the detection limit was obtained. The standard deviation of blank control was completed when the fluorescence intensity of BTZ-SF was measured by eleven times. The detection limit was determined by the following equation: Detection limit = 3σi/k Where σi is the standard deviation of the blank experiment, k is the slope between


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the fluorescence ratios (I476 nm/I568 nm) versus Al3+ concentration. 2.5. Determination of Fluorescence Quantum Yield The fluorescence quantum yield of BTZ-SF in aqueous and THF solution were determined by using quinine sulphate in 0.1 M H2SO4 (aq) (ϕS = 0.54) as a standard and calculated with the following equation: 56

=

∙ ∙ ( ≤ 0.05) ∙

where A represents the absorbance, n represents the refractive index of the solution, and D represents the corrected fluorescence emission spectral integral area. The BTZ-SF was dissolved in aqueous and THF solution with the concentration of 1 µM, respectively. quinine sulphate was dissolved in 0.1 M H2SO4 (aq) with the concentration of 1 µM. The excitation wavelength was chosen at 352 nm. 2.6. Cell Culture and Fluorescence Imaging HeLa cells were purchased from Nanjing Bobioer Biosciences Company, incubated in Dulbeccos modified Eagles medium (DMEM) supplement with 10% (V/V) Fetal Fovine Serum (FBS, Gibco), 100 U/mL penicillin, and 100 µg/mL streptomycin at 37 0

C with 5% CO2 in appropriate humidity. Cells were pre-transferred to culture dishes

and then incubated for 20 hours. Two groups were studied as follows: (I) Cells were incubated with the BTZ-SF (30 µM) for 30 min. (II) HeLa cells were pre-treated with BTZ-SF (30 µM) for 30 min and then exposed to Al3+ (0.4 mM) for another 30 min. Cell imaging was carried out after washing the cells by PBS buffer (pH=7.4). All of the cell imagings were collected on a Confocal Scanning Microscopy.

3. RESULTS AND DISCUSSION 3.1 Synthesis of Probe BTZ-SF Compounds of BTZ-PC and BTZ-SA were synthesized according to our previous work. 47-50 As shown in Scheme 1, a Schiff’s base generated by the reaction between compound of BTZ-SA and 2-thiophenecarboxylic acid hydrazide as a yellow solid



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with 81% yield. Compounds of BTZ-PC, BTZ-SA and BTZ-SF were fully characterized by NMR and high-resolution mass spectroscopy. The 1H NMR,

13

C

NMR, and high-resolution mass spectra were provided in the Supporting Information (Figures S9-S17).

Scheme 1. The synthetic routes and the single crystal structure of probe BTZ-SF

3.2. Optical Properties 3.2.1. Aggregation-Induced Emission (AIE) Properties Interestingly, BTZ-SF showed weak fluorescence in pure tetrahydrofuran (THF) solution while the fluorescence became stronger when a suspension was formed in a THF/water mixture solution (Figure 1A). This phenomenon suggests that the probe BTZ-SF is an aggregation-induced emission active (AIE-active) compound. In addition, the fluorescence intensity (Figure 1B) and the fluorescence intensity ratio (I/I0, Figure 1C) increase gradually with the increasing of water fraction (0%-90%). However, an opposite behavior was observed when the water fraction excess 90%, and the formation of its nanoaggregates in aqueous mixtures are amorphous aggregates. 37 It’s noted that when the water fraction increase to 90%, the fluorescence intensity ratio (I/I0) is about 3.0 times greater than that in the pure THF solution and the quantum yield for BTZ-SF in aqueous (ϕaq) and THF solution (ϕTHF) were determined to be 0.055 and 0.019, respectively. Besides, the probe BTZ-SF exhibits 14 nm red shift when it is in solid state (Figure S1). The dynamic light scattering


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(DLS) study and scanning electron microscope（SEM）image for BTZ-SF (10 µM) in THF/water mixture with a water fraction of 90% was obtained to confirm the formation of aggregates (Figure S8).

Figure 1. A) Photograph of AIE visualized under UV-vis light at 365 nm. B) Fluorescence intensity spectral of BTZ-SF (20 µM) in THF/water mixtures. C) The fluorescence intensity ratio (I/I0) versus water fraction in THF/water mixtures at room temperature (λex = 380 nm. Slit: 5 nm/5 nm).

Furthermore, in single-crystal structure studies of the probe BTZ-SF, the distances between phenol hydroxyl center benzene planes and thiophene group plane of two adjacent molecules was 6.032 Å (see Figure 2A) and 4.833 Å (see Figure 2B), respectively. And then, the dihedral angle between the phenol hydroxyl center benzene plane (red plane) and the benzothiazole plane (green plane) is 3.51° (see Figure S4a), displaying a near-planar conformation. However, the dihedral angle between the phenol hydroxyl center benzene plane (red plane) and the thiophene group plane (blue plane) is 46.94° (see Figure 2C), suggesting that the probe BTZ-SF exists as twisted molecular structure, which effectively enlarged the distance between the adjacent phenyl groups and thiophene groups (>4.164 Å). Notably, each BTZ-SF molecular in crystal structure connects its adjacent molecular in a head-to-tail mode



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(Figure 2A), which impeded intermolecular π-π interactions, thus avoid the quenching of fluorescence of the probe BTZ-SF whenever in either the aggregate state or solid state. After calculation, the angle of N1-H-O1 (θ) was 147.35°, the distances between N atom of benzothiazole group and H, O atoms of hydroxy group were 1.869 Å and 2.598 Å, respectively (Figure 2D). The result suggests that the individual molecular of BTZ-SF shows innate intramolecular H-bond interaction between the hydroxy group and the N atom of benzothiazole group. The strong intramolecular H-bond highly enhance the rigidity between the phenol hydroxyl center benzene and benzothiazole group, thus leading to a near-planar conformation,52 corresponding to the little dihedral angle (3.51°) in Figure S4a. Additionally, the crystallographic data and the molecular stacking structure in single crystal of BTZ-SF were shown in Table S1-S2 and Figure S4, respectively.

Figure 2. A, B) The molecular stacking structures of probe BTZ-SF in the crystal structures. C) The dihedral angle between the phenol hydroxyl center benzene plane (red plane) and the thiophene group plane (blue plane). D) The intramolecular H-bond in single crystal structure of probe BTZ-SF.

3.2.2. Fluorescent and Colorimetric Response of BTZ-SF to Al3+ The absorption spectra of BTZ-SF with and without Al3+ were first investigated. When free BTZ-SF dispersed in HEPES buffer (10 mM, pH 7.4), two main absorption peaks at 398 nm and 300 nm were observed. Upon the addition of Al3+, the absorption intensity at the above peaks was decreased and increased at 475 nm accompanied by the color conversion of the solution from colorless to pale-green (Figure S2). Furthermore, the fluorescence titration of BTZ-SF with Al3+ was


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performed. As shown in Figure 3A, the emission peak of BTZ-SF at 568 nm decreased gradually while a new fluorescence band centered at 476 nm emerged with the increasing concentration of Al3+ (0-2 mM), which exhibits a ratiometric fluorescent change of BTZ-SF with Al3+. To investigate the sensitivity of BTZ-SF towards Al3+, titration of Al3+ at low level was performed, too. According to the titration profiles, the fluorescence intensity ratio (I476 nm/I568 nm) increases steadily with the increasing Al3+ concentration and there is a good linear relationship between the fluorescence intensity ratio (I476 nm/I568 nm) and Al3+ concentration in the range from 0 to 100 µM (Figure 3B). In addition, the detection limit (S/N = 3) of BTZ-SF towards Al3+ is determined to be 2.2 µM, which indicates that the BTZ-SF is highly sensitive to detect Al3+ in aqueous solution. To verify whether the BTZ-SF can selectively respond to Al3+, the fluorescence sensing selectivity of BTZ-SF towards various metal ions, including Al3+, Zn2+, Cu2+, Fe2+, Fe3+, Hg2+, Ag+, Co2+, Ni2+, Cr3+, Ca2+, Cs+, Cd2+, Pb2+, Mn2+, Zr4+, K+, Mg2+, Li+ and Na+ at 100 equiv. was performed in HEPES buffer (10 mM, pH 7.4). As shown in Figure 3C, after 100 equiv. of above metal ions were added, the fluorescence intensity at 568 nm decreased at different degrees, however, only Al3+ leads to remarkable fluorescence enhancement near 476 nm.



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Figure 3. A) Fluorescence spectra of BTZ-SF (10 µM) with Al3+ (0-2 mM). B) The plot of fluorescence intensity ratio (I476 nm/I568 nm) versus Al3+ concentration (0-100 µM). C) Fluorescence spectra of BTZ-SF (10 µM) before and after addition of 100 equiv metal ion analytes, including Al3+, Zn2+, Cu2+, Fe2+, Fe3+, Hg2+, Ag+, Co2+, Ni2+, Cr3+, Ca2+, Cs+, Cd2+, Pb2+, Mn2+, Zr4+, K+, Mg2+, Li+ and Na+. D) Effect of pH on fluorescence intensity ratio (I476 nm/I568 nm) of BTZ-SF (10 µM) without and with Al3+ (0.2 mM). The tests (A-D) were performed in HEPES buffer solution (10 mM, pH 7.4) at room temperature (λex = 380 nm. Slit: 10 nm/5 nm).

In order to explore whether the physiological pH has an effect on the detection of Al3+, the influence of pH on the fluorescence process was further investigated. The fluorescence intensity ratio (I476 nm/I568 nm) of BTZ-SF in the absence and presence of Al3+ were collected, respectively (Figure 3D). The fluorescence intensity ratio (I476 nm/I568 nm)

of BTZ-SF itself changes little when pH ranges from 4 to 9. Upon 20 equiv.

of Al3+ was added, the fluorescence intensity ratio (I476 nm/I568 nm) exhibits a significant enhancement and reaches a maximum value at pH 7.5, which indicates that BTZ-SF can be used to detect Al3+ in biological systems. We further studied whether the BTZ-SF can detect Al3+ with high selectivity and


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dramatic fluorescence changes, the BTZ-SF (10 µM) was treated with above twenty metal ions analytes (2 mM) in 4 mL sample bottles. After the reaction completed, the fluorescence changes were observed under UV-vis light at 365 nm. As depicted in Figure 4, only Al3+ leads to a dramatic ratiometric fluorescent change, suggesting the high sensing selectivity of BTZ-SF towards Al3+.

Figure 4. Photograph of BTZ-SF (10 µM) with 200 equiv of various metal ion analytes (Al3+, Cd2+, Zn2+, Ca2+, Zr4+, Hg2+, Ni2+, Co2+, Pb2+, Ag+, Mg2+, Cs+, Mn2+, Cr3+, Cu2+, Fe3+, Fe2+, K+, Li+ and Na+) visualized under handhold UV lamp in HEPES buffer solution (10 mM, pH 7.4) at room temperature (λex = 365 nm).

3.2.3. Binding Reversibility Easily combine with Al3+, ethylene diamine tetraacetic acid (EDTA) is often used to liberate Al3+ from the metal-ligand complex and release organic ligand due to the high stability of Al3+-EDTA complex (log K Al-EDTA=16.3 53). As see from Figure 5A, when 200 equiv. of EDTA was added to the solution containing BTZ-SF-Al3+, the fluorescence intensity at 476 nm displays a dramatic decrease, while a significant enhancement fluorescence signal at 576 nm was obtained (blue line). The regenerated BTZ-SF can still be employed to bind another Al3+, suggesting that BTZ-SF binding of Al3+ is a chemically reversible process.

Figure 5. A) The fluorescence spectra of BTZ-SF (10 µM) in the presence of Al3+ (2 mM, red line)



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and EDTA (2 mM, blue line). B) Job’s plot for determining the stoichiometry of BTZ-SF and Al3+ in the HEPES buffer solution (10 mM, pH 7.4). The total concentration of BTZ-SF and Al3+ is 200 µM, XAl = [Al3+]/ {[Al3+] + [BTZ-SF]}, monitored at room temperature (λex = 380 nm. Slit: 10 nm/5 nm).

3.2.4. The Binding between Sensor BTZ-SF and Al3+ A Job’s plot analysis was carried out for quantifying the stoichiometry of the complex of BTZ-SF and Al3+. As shown in Figure 5B, the mole fraction (XAl = [Al3+]/ {[Al3+] + [BTZ-SF]}) of Al3+ varies from 0 to 1.0 while the total concentration of BTZ-SF and Al3+ is 200 µM. When the mole fraction is 0.5, the fluorescence intensity ratio reaches maximum value, which indicates that BTZ-SF binds Al3+ with a 1:1 stoichiometry. The assumption was further demonstrated by the high-resolution ESI-MS spectrum. It was noted that three distinct signals at m/z = 394.0643 for [BTZ-SF+H]

+

, 517.9781 for [BTZ-SF-H++Al3++ClO4-]

+

and 617.9342 for

[BTZ-SF+Al3++2 ClO4-] + appeared in the mass spectrum when 100 equiv. of Al3+ was added (Figure S3).

Scheme 2. Proposed binding mechanism of BTZ-SF towards Al3+

The fluorescence response mechanism of BTZ-SF in the presence of Al3+ is described in Scheme 2. The BTZ-SF itself exhibited red fluorescence in solid state with an emission wavelength at 582 nm when excited at 446 nm, which is attributed to the AIE property of BTZ-SF. When BTZ-SF (10 µM) was in solution state, an orange fluorescence with an emission wavelength at 568 nm was observed. In previous reports, N-salicylidenehydrazide ligands are non-fluorescent in aqueous solution. In contrast, the strong fluorescence of the probe BTZ-SF should be


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attributed

to

the

combined

action

of

ESIPT

2-(2-Hydroxyphenyl)-benzothiazole moiety and AIE effect.

48-50, 54

effect

from

The DLS data

showed the formation of nano-aggregates in the aqueous solution containing 10 µM of BTZ-SF, which also provided the evidence for the AIE phenomenon. After Al3+ was added, a strong blue fluorescence enhancement at 476 nm was observed while the emission intensity at 568 nm decreased. The fluorescent changes should be attributed to that the binding of Al3+ and N-salicylidenehydrazide moiety inhibited the ESIPT effect from 2-(2-Hydroxyphenyl)-benzothiazole moiety and AIE effect, while the coordination between Al3+ and amine suppressed the PET effect, resulting in chelation enhanced fluorescence 55. In solid status, the crystallographic data and the molecular stacking structure in single crystals of BTZ-SF-Al were shown Table S1, S3 and Figure S5-S6. BTZ-SF chelated Al3+ via the O atoms of phenol hydroxyl group, the N atoms in -C=N- groups, the O atom of carbonyl group and three H2O molecules, composing a hexa-coordinated structure. Seen from Figure S5, two H2O molecules were shared by two BTZ-SF ligands and acted as a “bridge” in the whole single crystal structure. Compared the single crystal structure parameters of BTZ-SF with BTZ-SF-Al, the dihedral angles between the benzothiazole group and the phenol hydroxyl center benzene varied from 3.51° to 2.58°, that is, the benzothiazole group spun nearly 180°, leading to the H-bond interaction between the N atom of benzothiazole group and phenol hydroxyl group vanished, suggested the suppression of ESIPT effect 50. However, the two BTZ-SF molecules involved in coordination were still in a head-to-tail mode, which avoided π-π interactions. And then, the complex of BTZ-SF-Al displayed strong green fluorescence when it was in single-crystal (solid) state, suggesting the AIE effect of BTZ-SF-Al complex. 3.3. Bioimaging Applications of BTZ-SF in Living Cells Additionally, we have employed a standard MTT assay to estimate cytotoxicity of BTZ-SF in HeLa cells with 0, 10, 20, 30, 40 and 50 µM BTZ-SF for 24 h. The optical density (OD) of formazan solutions produced was recorded on a microplate spectrophotometer at 490 nm. The cell viability was presented as the fold over the control group and was calculated according to the following formula: cell viability (%)



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= (ODsample-ODblank)/ (ODcontrol-ODblank) × 100. The result shows that cell viability was little changed when the concentration of BTZ-SF below 50 µM, suggesting low cytotoxicity of BTZ-SF (Figure S7). Then the BTZ-SF (30 µM) was further applied to image Al3+ in living HeLa cells, strong fluorescence in the red channel (Figure 6c) was observed when HeLa cells was incubated with BTZ-SF for 30 min at 37 oC, while negligible fluorescence in the blue channel (Figure 6b) was obtained. When 0.4 mM of Al3+ was added and incubated for another 30 min at 37 oC, remarkable fluorescence in the blue channel (Figure 6f) and weak fluorescence in the red channel (Figure 6g) were observed. This result reveals that BTZ-SF is capable of detecting Al3+ with ratiometric fluorescence changes in the presence of Al3+ in the living HeLa cells.

Figure 6. Confocal fluorescence imaging of without (a, b, c, d) and with (e, f, g, h) Al3+ (0.4 mM) in HeLa cells using BTZ-SF (30 µM) for 30 min at 37 oC. Red channel (c, g), λex = 380 nm, λem = 565-590 nm; blue channel (b, f), λex = 380 nm, λem = 435-495 nm. Scale bar = 50 µm.

3.4. Applications in Test Strips Based on the dramatic ratiometric fluorescence change of BTZ-SF binding with Al3+, probe BTZ-SF was engaged in test strips to enlarge its application. Firstly, the round filter papers we have prepared were immersed in DMF solution of BTZ-SF (1 mM) overnight to ensure that the BTZ-SF distributed evenly in filter papers, then


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dried in air to prepare test strips. Secondly, 10 µL of various metal ion analytes (10 mM) including Al3+, Cd2+, Zn2+, Ca2+, Zr4+, Hg2+, Ni2+, Co2+, Pb2+, Ag+, Mg2+, Cs+, Mn2+, Cr3+, Cu2+, Fe3+, Fe2+, K+, Li+ and Na+ were dropped on the test strips containing the BTZ-SF. As shown in Figure 7, a remarkable fluorescence quenching phenomenon of BTZ-SF occurred after Hg2+, Ni2+, Co2+, Cu2+, Fe3+and Fe2+ were added, respectively. Remarkably, only Al3+ led to dramatic blue fluorescence was observed under handhold UV lamp.

Figure 7. Photograph of various metal ions (0.1 µmol) detection by BTZ-SF on filter paper visualized under handhold UV lamp at room temperature (λex = 365 nm).

4. CONCLUSIONS In conclusion, we have designed and synthesized a novel fluorescent probe BTZ-SF, which exhibits significant ratiometric (I476 nm/I568 nm) fluorescence response for selective detection of Al3+ in 100% aqueous media. The free BTZ-SF displays dramatic enhanced fluorescence intensity and red shift phenomenon in THF/water system when the water fraction increasing from 0 to 90% due to the excellent AIE attribute of BTZ-SF, leading to a red fluorescence emission around 582 nm. Upon addition of Al3+, a remarkable ratiometric fluorescence change was observed at 476 nm. The single crystal structure of BTZ-SF-Al demonstrated that BTZ-SF chelated Al3+ via the O atoms of phenolic hydroxyl group, the N atoms in -C=N- groups, the carbonyl O and three H2O molecules, composing a hexa-coordinated structure. In addition, The BTZ-SF was applied to image Al3+ in living HeLa cells and exhibited obviously fluorescence change in presence of Al3+. Finally, test strips experiment suggests that the BTZ-SF can recognize the Al3+ selectively accompanied by



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remarkable color change. We anticipate that BTZ-SF will act as a potential tool to respond to Al3+ both in biological and environment systems.

ACKNOWLEDGEMENTS This work was supported by the National Natural Science Foundation of China (Nos. 21722605, 21376117 and 21406109), the Jiangsu Natural Science Funds for Distinguished Young Scholars (No. BK20140043), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No. 14KJA150005), the Qing Lan Project and the Project of Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Appendix A. Supplementary data Supplementary data associated with this article can be found in the online version. Crystallographic data for the structures reported in this article have been deposited with the Cambridge Crystallographic Data Center as supplementary publication Nos. CCDC 1563070 (BTZ-SF), 1563071 (BTZ-SF-Al). Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk (or from the Cambridge Crystallographic Centre, 12 Union Road, Cambridge CB21EZ, UK; Fax: +44 1223 336033; e-mail: [email protected])

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A Benzothiazole-Based Fluorescent Probe for Ratiometric Detection of

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