Introduction

Considerable attention has been focused on the design of chemosensors for the detection of biologically relevant anions [1–4]. In particular, selective sensing of fluoride ion has gained attention due to its significance in clinical treatment for osteoporosis and dental care [5, 6]. Recently a large number of methods for the sensing of fluoride ion have been reported [7, 8]. In biological systems fluorescence intensity is dependent on the local concentration of the sensors. However, emission intensity is also dependent on other factors, such as bleaching, optical path length, and illumination intensity. It is therefore desirable to eliminate the effects of these factors by using a ratiometric sensor that exhibits a spectral shift upon reaction or binding to the analyte of interest, so that the ratio between the two emission intensities can be used to evaluate the analyte concentration. In this respect, dual fluorescence probes exhibiting two well separated emission bands are of particular interest, since they provide a reliable ratiometric signal independent of the probe concentration [9]. Excited state intramolecular proton transfer (ESIPT) is very effective in the design of probes with dual fluorescence. ESIPT results in the formation of two tautomeric forms when the probe is in the excited state: N*-normal and T*-tautomer forms [10, 11]. ESIPT is one of the most well known photophysical processes occurring in o-hydroxy-benzoxazole, benzimidazole and benzothiazole [12–14]. It is expected that replacement of the oxygen atom in the oxazole ring, with a sulfur atom to form a thiazole cycle, raises molecular polarizabilities and introduces interesting novel spectral-luminescent properties. Formation of an intramolecular hydrogen bond in these compounds promotes luminescence intensity and results in abnormally large Stokes shifts that are essential for practical applications of the luminophores [6].

With reference to binding groups, only a limited number of reports are available which use –OH as a binding site [15–19]. Understanding the nature of intramolecular hydrogen bonding of phenol and fluoride ion is necessary to develop a fluoride ion selective sensor [20]. Electron-donating (CH3) and electron-withdrawing (Br) substituents were incorporated on the para position of the phenol, and fluoride ion selectivity was investigated. We herein report F− selective chemosensors possessing thiazole and a phenolic OH group which are able to bind fluoride ions via H-bond interactions.

Experimental

Apparatus

Melting points were determined using a Thomas-Hoover capillary melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Bruker AM-400 spectrometer using Me4Si as the internal standard. UV–vis absorption spectra were determined using a Shimadzu UV-1650PC spectrophotometer. Fluorescence spectra were measured using a Shimadzu RF-5301 fluorescence spectrometer equipped with a xenon discharge lamp, 1 cm quartz cells. All of the measurements were carried out at 298 K.

X-ray structure determination

All X-ray data were collected with the use of a Siemens P4 diffractometer equipped with a Mo X-ray tube. The orientation matrix and unit-cell parameters were determined by least-squares analyses of the setting angles of 33 reflections in the range 10.0° < 2θ < 25.0°. Intensity data were empirically corrected for absorption with ψ-scan data. All calculations were carried out with the use of SHELXTL programs [21].

Chemicals

Analytical grade acetonitrile was purchased from Merck and dried with CaH2 before use. All other materials used for synthesis were purchased from Aldrich Chemical Co and used without further purification. 2-Hydroxythiobenzamide, 5-methyl-2-hydroxythiobenzamide, and 5-bromo-2-hydroxythiobenzamide were prepared by thionation of the corresponding salicylamide with Lawesson’s reagent. In the titration experiments, all the anions were added in the form of tetrabutylammonium (TBA) salts, which were purchased from Aldrich Chemical Co., stored in a vacuum desiccator and dried fully before diluting to prepare working solutions.

Syntheses of compounds 1, 2 and 3

A solution of 2-hydroxythiobenzamide (1 mmol) and 2-bromoacetophenone (1 mmol) in dry EtOH (20 mL) was stirred at room temperature for 5 h. After the solvent was removed by evaporator, the mixture was extracted with CH2Cl2, dried over anhydrous Na2SO4 and evaporated. The residue was purified using SiO2 column chromatography (elution with EtOAc in hexane) to give compound 1.

Compound 1

Yield 84%; mp 103 °C (CH2Cl2-hexane); 1H NMR (CDCl3) δ 6.92 (dt, J = 7.6, 1.2 Hz, 1H), 7.12 (dd, J = 8.3, 1.0 Hz, 1H), 7.34 (dd, J = 8.3, 1.5 Hz, 1H), 7.38 (s, 1H), 7.40 (dt, J = 8.3, 1.2 Hz, 1H), 7.46 (dt, J = 8.1, 1.5 Hz, 2H), 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.87 (dd, J = 8.5, 1.5 Hz, 2H), 12.45 (bs, OH); 13C NMR (CDCl3) δ 111.3, 117.1, 118.6, 119.6, 126.8, 127.6, 128.8, 129.1, 132.4, 133.2, 154.3, 157.2, 169.4; Anal. Calcd for C15H11NOS: C, 71.12; H, 4.38; N, 5.53; S, 12.66, Found: C, 70.84; H, 4.32; N, 5.46; S, 12.20.

Compound 2

Yield 95%; mp 112–114 °C (CH2Cl2-hexane); 1H NMR (CDCl3) δ 2.2 (s, 3H), 6.87 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.4, 2.4 Hz, 1H), 7.23 (s, 1H), 7.25-7.28 (m, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 11.9 (bs, OH); 13C NMR (CDCl3) δ 20.8, 110.8, 116.7, 117.8, 119.6, 126.4, 127.3, 128.8, 129.0, 133.0, 133.4, 154.4, 154.9, 169.4; Anal. Calcd for C16H13NOS: C, 71.88; H, 4.90; N, 5.24; S, 11.99, Found C, 69.86; H, 4.87; N, 5.08; S, 11.36.

Compound 3

Yield 80%; mp 136–138 °C (CH2Cl2-hexane); 1H NMR (CDCl3) δ 6.83 (d, J = 9.0 Hz, 1H), 7.24–7.27 (m, 2H), 7.25 (s, 1H), 7.31 (t, J = 7.2 Hz, 2H), 7.55 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 12.12 (bs, OH); 13C NMR (CDCl3) δ 111.2, 111.6, 118.5, 119.9, 126.4, 129.0, 129.1, 129.4, 132.9, 134.6, 154.5, 156.4, 167.5; Anal. Calcd for C15H10BrNOS: C, 54.23; H, 3.03; N, 4.22; S, 9.65, Found: C, 53.88; H, 2.90; N, 4.17; S, 9.36.

Results and discussion

Synthesis

The chemosensors 1, 2, and 3 were synthesized in good yields by Hantzsch thiazole synthesis from the reaction of the corresponding 2-hydroxythiobenzamide and 2-bromoacetophenone as shown in Scheme 1. Initial attempts using the Hantzsch method by Bach failed to provide 1 but we succeeded in preparing the desired compounds via a simple condensation reaction [22]. The structures of chemosensors 1–3 were confirmed by 1H, 13C NMR, and elemental analyses data.

Scheme 1
scheme 1

Synthesis of chemosensors 1, 2 and 3

Full size image

Crystal structure of 1

Crystal of 1, suitable for single crystal X-ray diffraction analysis, was obtained from dichloromethane-hexane. The molecular structure of 1 with the atom-numbering scheme is shown in Fig. 1. The overall structure is essentially planar, with dihedral angles between the central thiazole ring and the planar adjacent aryl rings, in the range of 2.3(1)–6.4(1)°. There is an intramolecular O–H···N hydrogen bonding (O1–HO1: 0.89 Å; HO1···N1: 1.83 Å; O1···N1: 2.65 Å; O1–HO1···N1 153°), whose bonding parameters indicate relatively strong hydrogen bonding.

Fig. 1
figure 1

ORTEP drawing of 1 with 50% probability thermal ellipsoids

Full size image

UV–vis responses toward anions

Initial studies of the UV–vis absorption showed that 1 exhibited selectivity toward fluoride ion in CH3CN. Figure 2a, shows the absorption spectra of 1 in CH3CN (30 μM) upon addition of 10 equiv of tetrabutylammonium salts of these anions: F−, CH3CO2 −, H2PO4 −, Cl−, Br−, I−, ClO4 −, NO3 −, and HSO4 −. Only F− and CH3CO2 − showed significant changes over other anions. Upon addition of fluoride ion into the 1 solution a significant red-shift (Δλ = 68 nm) occurred with enhancement of absorbance in the UV–vis absorption spectrum. Sensor 1 exhibited an absorption band at 332 nm (Fig. 2a), sensors 2 (Fig. 2b) and 3 (Fig. 2c) showed absorption bands at 338 and 340 nm, respectively. This may be attributed to a π–π* charge-transfer state; which is favored by the planar orientation enforced by intramolecular hydrogen bonding [23].

Fig. 2
figure 2

UV–vis spectra of (a) 1 (b) 2 (c) 3 in CH3CN (30 μM) in the presence of 10 equiv of various anions. (d) Changes in UV–vis spectra of 1 upon addition of [(Bu)4N]F in CH3CN. Inset: mol ratio plots of absorbance at 332 and 400 nm

Full size image

Titration of 1, as a function of F−, revealed that the intensity of the absorption band at 332 nm decreased and a new absorption band at 400 nm appeared gradually, with an isobestic point at 353 nm (Fig. 2d). The intensity of this peak reached its maximum after the addition of 6 equiv of F− (Fig. 2d, inset). When an excess of tetrabutylammonium salts of anions were added to sensor 1, only F− led to a change in λmax and absorption intensity, although the addition of CH3COO− and H2PO4 − produced changes in λmax, their absorption intensities were very low, whereas the addition of other anions such as Cl−, Br−, I−, ClO4 −, NO3 −, and HSO4 − resulted in insignificant changes in the absorption spectra. In the case of sensor 2, when excess of various anions were added to the solution (Fig. 2b), only F− causes a red shift to 410 nm and the color of the solution changed from colorless to yellow (Fig. 3). Whereas the addition of other anions including CH3COO−, H2PO4 −, Cl−, Br−, I−, ClO4 −, NO3 −, and HSO4 − resulted in negligible changes in the absorption spectra. The color change of 2 in the CH3CN solution can be used for naked-eye detection of F− in the presence of other anions. In sensor 3, when excess of anions were added (Fig. 2c), F−, CH3COO− and H2PO4 − caused a significant red shift to 410 nm whereas the addition of other anions such as Cl−, Br−, I−, ClO4 −, NO3 − and HSO4 − did not produce any change. These photophysical data from the chemosensors are summarized in Table 1.

Fig. 3
figure 3

Color changes of 2 in CH3CN (50 μM) after addition of 10 equiv of representative anions

Full size image
Table 1 The photophysical data of 1, 2 and 3 in CH3CN
Full size table

The resonance structures of the deprotonated form of 1 show that the electron density of phenyl at the para position is increased upon deprotonation as shown in Scheme 2. This indicates that the acidity in this kind of sensor can be tuned by changing the electronic property of the substituent on the para position. The introduction of an electron donating methyl group at the para position decreases the acidity of the proton, and thus the hydrogen bonding ability is reduced. Sensor 2 can only interact with fluoride ions due to their higher electronegativity and their smaller size compared to the other halides. The presence of an electron withdrawing bromide group increases the acidity of the proton and increases the hydrogen bonding ability. Thus sensor 3 loses its selectivity toward anions.

Scheme 2
scheme 2

Resonance structures of 1

Full size image

Fluorescent responses toward anions

The fluorescence studies of 1, 2 and 3 were performed in CH3CN (Fig. 4). Intensities of the normal and the tautomer emissions of 1, 2 and 3 change with the substituents at the para of the phenyl ring. Sensor 1, with excitation at λmax 332 nm, exhibits two emission bands at λmax 369 and 506 nm. The longer wavelength emission is a typical ESIPT emission band [17]. On addition of F− to the solution, a ratiometric change (spectral shift) occurs with the formation of a new emission band at 453 nm with the disappearance of the two emission bands of the sensor, but addition of Cl−, Br−, I−, ClO4 −, NO3 − and HSO4 − results in insignificant changes in the fluorescent spectra. In the case of CH3CO2 − and H2PO4 − anions, two new emission bands appear at 444 and 446 nm, respectively, but the intensity of the CH3CO2 −-induced band is 4 times smaller than that of F− and the H2PO4 −-induced band is 15 times smaller.

Fig. 4
figure 4

Fluorescence spectra of (a) 1, (b) 2, (c) 3 in CH3CN (30 μM) in the presence of 10 equiv of various anions with an excitation wavelength of 332, 338 and 340 nm, respectively. (d) Changes in fluorescent spectra of 1 in CH3CN (30 μM) upon addition of [(Bu)4N]F excited at 332 nm

Full size image

The titration of sensor 1 with F− revealed that the fluorescence intensity reached its maximum after addition of 6 equiv of F− (Fig. 4a, d). In sensor 2 (Fig. 4b), the normal emission band appears at 373 nm and upon addition of F− the emission band shifted to 469 nm and the intensity of the emission band decreased as compared to 1. Selectivity of 2 toward F− is the same as that of 1. The emission band in 3 (Fig. 4c) shifted to 457 nm from the tautomer emission band (513 nm) with a sharp isoemission point at 501 nm. However its selectivity decreased as compared to 1 and 2.

The deprotonation of the phenolic proton induced a great fluorescence enhancement due to the inhibition of ESIPT in the case of chemosensors 1, 2, and 3. The emission of the deprotonated form lies just between the normal and tautomer emissions. In the case of 2, due to the presence of the electron donating group, the normal form is more stable than the tautomer, while in sensor 3 the electron withdrawing group makes the tautomer form more stable than the normal form, but its selectivity toward anions is lost.

1H NMR titration

To examine the ground state behavior of sensor 1 with fluoride ion, 1H NMR experiments involving 1 with TBA+F− were performed in CD3CN. Partial 1H NMR spectra of 1, with different amounts of F−, is shown in Fig. 5. Notably, when 1 equiv of F− was added, disappearance of phenolic proton and upfield shifts of phenyl and thiazole protons were observed. The signal of Hd shows a small upfield shift (Δδ = 0.01 ppm) while the signals of Ha, Hb, Hc and He were shifted upfield significantly (Δδ = 0.08–0.19 ppm) due to the shielding effect. Due to the deprotonation of phenolic proton, the OH proton disappeared and the para proton (Hc, Δδ = 0.19 ppm) shifts upfield substantially, compared to the other phenyl protons (Ha, Hb, Hd). Theses results clearly imply that for 1, phenolic proton strongly binds with F− via H-bond interactions.

Fig. 5
figure 5

Partial 1H NMR (400 MHz) spectra of 1 with [(Bu)4N]F in CD3CN

Full size image

Binding constants

The UV and fluorescence titration studies involving the sensors indicate that the addition of 6 equiv of F− result in the intensities of the absorption and emission bands reaching their maxima. This could be assigned as evidence for the occurrence of hydrogen bond interactions between OH and F− as shown in Scheme 3. Fluorescence based Job’s plot for the complexation of 1-F− shows a 1:2 stoichiometry (Fig. 6).

Scheme 3
scheme 3

The mechanism of the interaction of fluoride ions with 1

Full size image
Fig. 6
figure 6

Job’s plot of sensor 1 with F− in CH3CN using their fluorescence changes measured at 453 nm

Full size image

The binding constants for the sensor-F− complex were obtained from the variation in fluorescent intensity at an appropriate wavelength. The binding constants (Ka) for 1, 2, and 3 with F− were calculated to be 5.8 × 103, 2.1 × 103, and 8.2 × 103 M−1 L, respectively (Error estimated to be ≤10%). Sensor 3 shows the highest binding constant among the tested sensors. This may be due to the presence of the electron-withdrawing group, which results in strong hydrogen bond interactions with F− as compared to 1 and 2. Moreover the hydrogen bonding of F−, reinforces the electron-withdrawing character of the bromo group, thus increasing the extinction coefficient. Sensor 3 also showed binding affinity toward OAc− and H2PO4 − with binding constants 2.0 × 103 and 1.2 × 103 M−1 L, respectively (Error estimated to be ≤10%).

Conclusion

In summary, new ratiometric ESIPT-chemosensors based on 2-hydroxyphenyl-thiazole have been developed for fluoride ion. The acidity of the phenolic proton has been altered by the introduction of electron donating and withdrawing substituents at the para position of the phenyl ring. Sensor 2 showed a color change upon addition of fluoride ion and sensor 3 has a higher binding affinity than 1 and 2.