An ESIPT-active orange-emissive 2-(2′-hydroxyphenyl)imidazo[1,2-a]pyridine-derived chemodosimeter for turn-on detection of fluoride ions via desilylation

Abstract

Fluoride is an essential element for oral health with an optimum concentration of 0.7–1.2 ppm in drinking water, but it is detrimental at higher concentrations, causing fluorosis, acute gastric ulcer, urolithiasis, and kidney infection, which adds immense significance to its detection in water sources. In the current study, a new chemodosimeter (HIPS-Br) is designed by protecting a 2-(2′-hydroxyphenyl)imidazo[1,2-a]pyridine derivative (HIP-Br) with a fluoride recognizable tert-butyldiphenylsilane moiety and utilized for the selective detection of F⁻ ions by an excited-state intramolecular proton transfer (ESIPT)-based fluorimetric response. The probe HIPS-Br exhibits blue fluorescence in solution, and upon the incremental addition of F⁻ ions, it exhibits a turn-on response, exhibiting a strong orange emission at 598 nm by spontaneous cleavage of the tert-butyldiphenylsilane group to release fluorescent HIP-Br in the working solution. HIPS-Br displayed no or insignificant response towards numerous common anions, cations and small molecules, affirming its selectivity to F⁻ ions and offered a low limit of detection (LOD) of 1.2 ppb (6.6 × 10⁻⁸ M). The real sample analysis by spiking fluorides in water and toothpaste samples showed excellent percent recoveries. The chemodosimeter was successfully utilized in the solid-phase detection of F⁻ ions on silica-coated TLC plates and analyzed by ImageJ analysis, marking its utility in on-site quantitation purposes.

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1. Introduction

Fluoride (F⁻) ions are essential micronutrients for proper growth and maintenance of hair, nails, bones, and teeth.¹ For its beneficial effects on human body, F⁻ ions are used as an additive in toothpaste and drinking water.^2,3 Groundwater contains sufficient fluoride ions due to the dissolution of fluoride-rich rocks that primarily contribute to the daily intake of fluoride.^4,5 Otherwise, anthropogenic activities and the widespread use of fluoride-containing products cause high F⁻ assimilation in soil and water.⁶ The World Health Organization (WHO) recommends an optimum fluoride concentration of 0.7–1.2 ppm in water supplies through artificial fluoridation.⁷ Besides their vital roles in physiological functions and biomedical applications, such as the treatment of osteoporosis,⁸ high intake of fluoride ions can cause dental and skeletal fluorosis,^9,10 acute gastric and kidney infections,^11,12 urolithiasis,^13,14 and even cancer at excessive concentrations.^15,16 Because of the adverse effects of fluoride in higher concentrations, the United States Environmental Protection Agency (USEPA) has proposed a permissible limit of 4 ppm for fluoride in drinking water.¹⁷ Considering that the detection and accurate estimation of fluoride ions is essential for human and environmental welfare, several fine analytical techniques based on sophisticated instruments, including ion chromatography,^18,19 high-performance liquid chromatography,^20,21 atomic absorption spectrometry (AAS)²² and ¹⁹F NMR,²³ have been developed for the detection of F⁻ ions. Apart from these expensive tools, researchers have paid attention to developing various colorimetric and fluorimetric sensors owing to the high sensitivity, selectivity, and portability of these molecular probes.^24,25 These chemosensors depend on either the strong hydrogen bonding of F⁻ ions or a deprotonation step driven by F⁻ ions to generate the parent chromophore utilizing its strong affinity towards electropositive boron, silicon, antimony, etc.^26–30 However, many of these chemosensors/chemodosimeters involve multiple synthetic steps and solution-phase reactions and are not explored for on-site detection, making the development of cost-effective and sensitive chemodosimeters necessary.

Small molecule fluorophores with a special property of intense emission in the solid state have attracted considerable research attention in sensing and bioimaging with a focus on on-site device applications.³¹ This is in contrast to conventional organic dyes, which suffer from the aggregation-caused-quenching (ACQ) effect in concentrated solutions or in the solid state.³² Many a time, the enhanced emission is caused by the restriction in the intramolecular rotation around the single bond in conjugated aromatic systems (a class of compounds called AIEgens)^33,34 or intramolecular flipping of H-atom between two hetero-atoms (such as N- and O-) at the excited state, a phenomenon known as excited-state intramolecular proton transfer (ESIPT).^35–37 To date, the most commonly studied ESIPT-active compounds are 2-(2′ hydroxyphenyl)benzothiazole (HBT),^38,39 2-(2′-hydroxyphenyl)benzimidazole (HBI),^40,41 2-(2′-hydroxyphenyl)benzoxazole (HBO),^42,43 and their analogues.

Imidazo[1,2-a]pyridine, an important class of heterocycle^44,45 shows immense biological activities and is quite ubiquitous among several pharmaceutical products.^46,47 In addition, it possesses inherent fluorescence properties and, lately, has been employed in chemosensing applications by tuning its photophysical properties by appropriate structural modifications.^48,49 Imidazo[1,2-a]pyridines with a 2′-hydroxyphenyl unit at C-2 is another class of ESIPT-active compound; however, there are only limited studies on their photophysical properties^50,51 and chemosensing applications.^52,53 The vast synthetic modality for this scaffold is advantageous for photophysical tunability, leading to large Stokes shifts needed for chemosensing applications. With our growing interest in the use of ESIPT-active luminogens for chemosensing applications,^36,38,54 we paid our attention to developing 2-(2′-hydroxyphenyl)imidazo[1,2-a] pyridine-derived chemodosimeter for the selective and sensitive detection of fluoride ions exploiting its affinity towards silicon-atom. Keeping the perspective of current environmental concerns, a sustainable and organic solvent-free mechanochemical method^55,56 was adopted for the synthesis of the probe, HIPS-Br.

2. Experimental section

2.1 Chemicals and reagents

5-Bromo-2-hydroxyacetophenone, 2-aminopyridine and tert-butylchlorodiphenyl silane of AR grade were purchased from TCI India Pvt. Ltd. Other common chemicals, salts, and common solvents of LR grade were obtained from various other commercial suppliers and used without further purification. To monitor the progress of the reaction, thin-layer chromatography (TLC) was used on silica gel plates (0.25 mm, 60F-254). The TLC was visualized using UV lamps with wavelengths of 254 nm and 365 nm. For real sample analysis, water samples were collected from different local water bodies and different brands of toothpaste were procured and utilized as such from the local market. Ultrapure deionized water was obtained from a Millipore water system (18 MΩ cm) and was purged with N₂ for 15 minutes before use.

2.2 Instrumentation and measurements

The mechanochemical reactions were conducted with a RETSCH MM400 instrument, utilizing a 5 mL grinding jar and a 10 mm ball of stainless steel (SS). A 500 MHz Bruker Avance NMR spectrometer was used to record the NMR spectra. LCMS and HRMS spectra were acquired from Agilent LC-MS (model 6460 Triple Quadrupole LC/MS) and HRMS (model 6545 QTOF), respectively, using an ESI ion source. JASCO V770 and FP-8500 model UV-vis spectrophotometer and spectrofluorimeter were used with the data pitch and bandwidth fixed at 1 nm and excitation and emission slit widths maintained at 2.5 nm for all the UV-vis and fluorescence experiments, respectively. Ion chromatography was done on Metroohm Eco IC with 944 professional UV/vis detector, Vario. The photographs for solid-phase studies were captured using a 64-megapixel smartphone (Oneplus 11R) and subjected to ImageJ software for analysis.

2.3 Synthesis of the probe, HIPS-Br

The probe, HIPS-Br, was synthesized by adopting a two-step mechanochemical route.

(a) Synthesis of 4-bromo-2-(imidazo[1,2-a]pyridin-2-yl)phenol (HIP–Br):⁵⁷ 5-Bromo-2-hydroxyacetophenone (1) (112 mg, 0.5 mmol), 2-aminopyridine (2) (61 mg, 0.65 mmol) and iodine (38 mg, 0.15 mmol) were taken in a 5 mL stainless steel (SS) milling jar containing a 10 mm SS ball. The mixture was milled using silica gel (500 mg, 60–120 mesh) as the solid matrix in an MM400 instrument at 25 Hz for 2 h. The slurry was subjected to flash chromatography and eluted with EtOAc–petroleum ether (1 : 4) to afford pure HIP-Br as a yellowish-orange solid (123 mg, yield: 82%); ¹H NMR (500 MHz, CDCl₃): δ (ppm) 12.77 (s, 1H), 8.16 (d, J = 6.7 Hz, 1H), 7.85 (s, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.30–7.24 (m, 2H), 6.92–6.87 (m, 2H); ¹³C {¹H} NMR (125 MHz, CDCl₃): δ (ppm) 156.4, 143.9, 143.6, 132.2, 128.1, 125.6, 125.5, 119.5, 118.0, 116.9, 113.4, 110.7, 107.0.

(b) Synthesis of 2-(5-bromo-2-((tert-butyldiphenylsilyl)oxy)phenyl)imidazo[1,2-a]pyridine (HIPS-Br): In a 5 mL SS milling jar, HIP-Br (72 mg, 0.25 mmol), tert-butylchlorodiphenylsilane (3) (75 mg, 0.27 mmol) and imidazole (88 mg, 1.25 mmol) were mixed with silica gel (350 mg, 60–120 mesh) and milled in an MM400 at 25 Hz for 3 h. The slurry of the crude product was subjected to flash chromatography to get the final probe HIPS-Br as a yellow solid (115 mg, yield: 88%); ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.45 (d, J = 2.6 Hz, 1H), 8.33 (s, 1H), 8.02 (d, J = 6.7 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.47–7.36 (m, 11H), 7.18 (t, J = 7.9 Hz, 1H), 6.94 (dd, J₁ = 8.7 Hz, J₂ = 2.6 Hz, 1H), 6.77 (t, J = 7.9 Hz, 1H), 1.14 (s, 9H); ¹³C {¹H} NMR (125 MHz, CDCl₃): δ (ppm) 151.7, 144.5, 140.3, 136.3, 134.8, 132.1, 131.9, 130.6, 130.2, 129.5, 128.0, 127.6, 126.2, 125.4, 124.8, 121.5, 117.4, 114.1, 113.0, 112.4, 26.9, 19.4; HRMS (ESI-TOF): m/z calcd for C₂₉H₂₇N₂OBrSi [M + H]⁺ 527.1149, found 527.1151.

2.4 Analytical procedures

In order to perform spectrofluorimetric analyses, a stock solution of 1 mM HIPS-Br in THF was prepared. A 1 mM stock solution of fluoride (F⁻) was prepared from its tetrabutylammonium salt in deionized water (Milli-Q, 18 MΩ cm). Deionized water was used for dilution purposes as per the requirement of the spectrofluorimetric studies. For the selectivity studies, stock solutions of different anions were prepared from the corresponding sodium or potassium salts, and nitrates or chlorides were used for the solutions of different cations. Organic small molecules were dissolved either in THF or water as per their solubility. Different toothpaste samples were vacuum-dried and the fine powder was dissolved in water (1 g in 20 mL water) by sonicating for 30 min and incubated for 24 h. A part of the supernatant was collected, diluted with water and used for real sample analysis in toothpaste. Any particulate matter in the solutions was discarded by filtering through 0.22 μm syringe filters before each analysis. After excitation at 350 nm, all of the fluorimetric data were acquired between 355 and 750 nm. The spectroscopic analyses were carried out at room temperature (25 °C), and the average data for each analysis is based on three repetitions.

2.5 Calculation of fluorescence quantum yield

Fluorescence quantum yield was calculated using the equation:
where φ = quantum yield, I = emission intensity, n = refractive index, and A = optical density, std = standard quinine sulphate, and x = HIP-Br.

2.6 Calculation of the limit of detection

The limit of detection was calculated from the 3σ/k equation where σ = standard deviation and k = slope of the linear regression equation.

2.7 DFT calculations

The density functional theory (DFT)⁵⁸ was used to carry out theoretical studies, and for the time-dependent density functional theory (TD-DFT)^59–61 level, the Gaussian 09 program was used.⁶² Becke's three-parameter exchange function (B3) with the Lee-Yang-Parr correlation (LYP) function was employed using a 6-31G basis set for the optimization of molecular geometries.

2.8 Solid-phase sensing of F⁻ using HIPS-Br

For solid-phase sensing of F⁻ ions, silica gel-coated TLC plates were taken and cut into small strips and dipped in the probe solution in CH₂Cl₂ (100 μM) for a few seconds and air-dried. Further, F⁻ (1, 2, 5, 10, 15, 20, 25, 30, 40 and 50 ppm) concentrations prepared in water were drop-casted on HIPS-Br-coated TLC strips. TLC strips were allowed to be air dried at room temperature, further incubated for 1 h, then visualized under a 365 nm UV lamp.

3. Results and discussion

3.1 Design and synthesis of the probe, HIPS-Br

From our earlier studies on the mechanochemical synthetic protocols for imidazo[1,2-a]pyridines,^63,64 we observed that 2-(2′-hydroxyphenyl)imidazo[1,2-a]pyridines emit solvent-dependent strong fluorescence by ESIPT, quite similar to 2-hydroxyphenylbenzothiazoles (HBT), with a higher Stokes shift. Considering a heavy atom like –Br would help a bathochromic shift of λ_max, we planned to synthesize the chemodosimiter (HIPS-Br) from the para-bromo derivative of 2-(2′-hydroxyphenyl)imidazo[1,2-a]pyridine (HIP-Br). Considering fluoride can perform spontaneous desilylation, the probe, HIP-Br, was planned to be protected by the tert-butyldiphenylsilane group. In a two-step sustainable approach, HIPS-Br was synthesized by mechanochemical mixer-milling of 2-hydroxy-5-bromoacetophenone and 2-aminopyridine in the presence of iodine as the catalyst and silica as the grinding matrix to afford HIP-Br in 82% isolated yield. Subsequently, the phenolic –OH group of HIP-Br was protected in a mechanochemical manner by mixing tert-butylchlorodiphenylsilane and imidazole with silica as the grinding matrix and milling at 25 Hz for 3 h affording the chemodosimeter, 2-(5-bromo-2-((tert-butyldiphenylsilyl)oxy)phenyl)imidazo[1,2-a]pyridine (HIPS-Br), in an excellent yield (Scheme 1). HIPS-Br was characterized using ¹H NMR, ¹³C NMR, and HRMS analyses. The disappearance of the peak at δ 12.77 corresponding to the phenolic –OH and the presence of a singlet at δ 1.41 corresponding to the tert-butyl unit in ¹H NMR indicated the formation of the probe, HIPS-Br. Similarly, the presence of peaks at δ 26.9 and 19.4 corresponding to the quaternary carbon and the methyl groups of the tert-butyldiphenylsilane moiety in ¹³C NMR confirmed the formation of the chemodosimeter, HIPS-Br.

Scheme 1 Synthesis of the HIPS-Br probe.

3.2 Photophysical properties of HIP-Br

The imidazopyridine scaffold was anticipated to emit strong fluorescence with higher Stokes shifts in the orange-to-red region due to its intramolecular proton transfer properties similar to HBT. Consequently, the solubility and photophysical properties of the probe, HIP-Br, were initially assessed in various organic solvents. As expected, HIP-Br was highly soluble and exhibited solvent-dependent emission in diverse polar protic and polar aprotic solvents, including DCM, ACN, THF, DMF, DMSO, MeOH, and EtOH. The UV-visible absorption spectrum of HIP-Br (30 μM) in THF revealed a strong absorption band at 350 nm with an additional shoulder peak at 362 nm (Fig. S1, ESI†). Subsequently, the emission properties of HIP-Br (10 μM) were examined with an excitation wavelength of 350 nm. It was noticed that HIP-Br displayed two intense emissions at around λ_max 430 nm and 598 nm in DCM and THF. However, when switching to a polar protic solvent such as EtOH, a notable decrease in emission intensity of the peak at 598 nm was observed while the peak at 430 nm retained its intensity (Fig. 1). Therefore, the proton transfer between oxygen and nitrogen atoms via ESIPT is facile in a polar aprotic solvent allowing the orange emission channel on. Whereas, in polar protic solvent, presumably, the solvation of the phenolic-OH functionality causes hindrance in the proton transfer process; thereby, only inherent blue emission of imidazopyridine was observed from HIP-Br (Fig. 1, inset). The probe displayed a quantum yield of 5.74% and 5.72% in THF and DCM at λ_max 598 nm with a relatively high Stokes shift taking quinine sulfate as standard,⁶⁵ whereas, in DMF and EtOH, a higher quantum yield of 9.10 and 9.72 at λ_max 430 nm was observed (Table 1). The possible aggregation-induced emission (AIE) behavior of HIP-Br was evaluated by gradually increasing the water fractions in water–THF mixtures. However, the probe demonstrated a progressive decrease in emission intensity at 598 nm, with negligible fluorescence in 50% water–THF fractions or above, indicating the absence of typical AIE characteristics (Fig. S2, ESI†). The loss of emission at the red-shifted peak is an indication of diminished ESIPT behavior due to the solvation effect by water around the phenolic-OH group. Notably, the fluorescence loss is nominal at 10% H₂O–THF, giving scope for the detection of water-soluble analytes by the probe. Since 2-(2′hydroxyphenyl)benzothiazole (HBT) is an important class of ESIPT active fluorophores, the photophysical properties of HIP-Br were compared with that of HBT-Br. Interestingly, HIP-Br displayed a larger Stokes shift of 250 nm in THF and a higher quantum yield than its congener HBT-Br (190 nm, 1.25%, Table S1, ESI†), generating our interest for further photophysical studies on this scaffold, tuning its electronic properties by the introduction of suitable substituents; however, these studies are not a part of this article. Similar to HIP-Br, HIPS-Br showed a UV-vis band at around 350 nm and fluoresced blue at λ_max 409 nm when excited at 350 nm (Fig. S3, ESI†). However, the orange emission peak was absent for HIPS-Br as there is no scope for ESIPT. The emission characteristics of HIP-Br were analyzed over a broad pH range (pH 3–12). The fluorescence of HIP-Br was unperturbed at the near-neutral pH (pH 6–8), with the most intense emission occurring at physiological pH 7, offering its potential for sensing applications under physiological conditions (Fig. S4, ESI†). Notably, HIPS-Br also withstood a pH change from pH 6–12 but gradually disintegrated in strongly acidic solutions (Fig. S4, ESI†). It gives us the working range for using HIPS-Br as the chemodosimeter. The chemodosimeter HIPS-Br was examined in various THF–water fractions, but it displayed no fluorescence across all water fractions, likely due to the inhibition of the excited state intramolecular proton transfer phenomenon (Fig. S5, ESI†). Although HIP-Br displayed significant emission in both THF and DCM, considering the prevalence of fluoride ions in water, all studies were carried out in THF-water mixtures (9 : 1). Before proceeding further, a time-dependent response study with HIPS-Br (10 μM) and fluoride ions (60 μM) was conducted, which showed that the maximum fluorescence output was achieved within just 2 min (Fig. S6, ESI†).

Fig. 1 Fluorimetric responses of HIP-Br (10 μM) in different organic solvents depicting intense orange emission in THF and DCM and relatively lower emissions in other polar protic and polar aprotic solvents (λ_ex = 350 nm, λ_em = 598 nm) [inset: images of HIP-Br under UV light in different solvents].

Table 1 Photophysical properties of HIP-Br in different solvents

S. no	Solvent	Absorbance (nm)		Emission (nm)				Stokes shift (nm)	Quantum yield (φ) (%)
		λabs1	λabs2	λem1	Int.	λem2	Int.		φ1	φ2
1	DCM	250	351	455	1567	590	2873	239	7.82	5.72
2	THF	246	348	454	3324	598	2435	250	3.11	5.74
3	ACN	251	351	456	1505	601	559	250	2.00	0.71
4	DMF	—	351	411	4432	—	—	60	9.10	—
5	DMSO	—	351	441	2549	—	—	90	5.32	—
6	EtOH	263	349	459	4498	—	—	110	9.72	—
7	MeOH	243	349	428	2906	—	—	79	3.22	—

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3.3 DFT studies

DFT studies were carried out to align the theoretical predictions with the optical properties of the probe HIPS-Br and HIP-Br as per experimental observations. The optimized structure of HIPS-Br in the excited state revealed a significant electron population spread across the entire molecular framework, with greater density on the imidazopyridine ring. HIP-Br also displayed a similar electron population but with greater electron delocalization in the oxygen atom. The molecular structure obtained after intramolecular proton transfer HIP-Br_IPT, in contrast, displayed a higher electron population on the phenolic ring. The calculated band gaps between the LUMO and HOMO of HIPS-Br (−0.15724) and HIP-Br (−0.15715) were reasonably low, allowing decent electronic population at the excited states upon absorbing light, and upon falling back to S₀, it results in the inherent blue fluorescence from the imidazo[1,2-a]pyridine framework. After a proton transfer, the band gap of HIP-Br_IPT was found to be significantly low (−0.06683) by DFT calculations, which is indicative of a facile ESIPT process and responsible for orange emission upon excitation of HIP-Br at 350 nm (Fig. 2). The LUMO–HOMO orbital transition mainly contributes (98%) to the S₁–S₀ emission transition with an oscillator strength of 0.1716. Additionally, the proton transfer could lead to the distribution of the positive charge between the N-atoms, resulting in a structure with greater charge separation.⁵¹

Fig. 2 Optimized structures, visualized electron distribution and energy levels of LUMO and HOMO of HIPS-Br, HIP-Br and HIP-Br_IPT.

3.4 Fluoride ion sensing studies using HIPS-Br

In order to ensure the sensitive detection of fluoride ions, the fluorimetric responses of HIPS-Br (10 μM in 10% water–THF) solution were recorded at 598 nm upon the incremental addition of F⁻ ions. Upon the addition of F⁻ ions to HIPS-Br, a gradual increase in emission intensities at 598 nm was noticed, while the fluorescence band at 410 nm was mostly unaffected (Fig. S7, ESI†). The increase was proportional to F⁻ ion concentrations, and the saturation point was obtained upon the addition of 60 μM of F⁻ with a 12-fold increase in the fluorescence output (Fig. 3a). A high regression coefficient of 0.9966 was obtained upon plotting the graph of the ratios of relative intensities of the probe at 598 nm as a function of F⁻ concentration (Fig. 3b). In a complementary analysis, we focused on the detection of F⁻ ions at lower concentration ranges and observed a strong linear correlation within the 0–10 μM range, with a high regression coefficient (R² = 0.9947). Using this data, the limit of detection (LOD) was calculated as 6.6 × 10⁻⁸ M (1.2 ppb) using the equation 3σ/k, where σ is the standard deviation and k is the slope (Fig. 3c). As HIPS-Br displays a strong absorption band in the UV-vis spectrum, a study monitoring the absorption changes in the presence and absence of F⁻ ions was performed. The study revealed just a slight shift of 10 nm in the spectrum of HIPS-Br upon adding F⁻ ions without any other noticeable changes (Fig. S8, ESI†).

Fig. 3 (a) Fluorescence spectral output of HIPS-Br (10 μM in 10% water–THF) upon gradual addition of F⁻ (0–80 μM) (λ_ex = 350 nm; λ_em = 598 nm). (b) Plot of the ratio of fluorescence intensities against F⁻ concentrations (0–80 μM). (c) Fluorimetric responses of HIPS-Br (10 μM) at lower concentrations of F⁻ (0–10 μM) (λ_ex = 350 nm, λ_em = 598 nm).

3.5 Selectivity of HIPS-Br towards F⁻

After successfully demonstrating the sensitive detection of fluoride ions (F⁻), the subsequent critical step was to evaluate and address potential interferences from other analytes in the sensing process. A thorough investigation was conducted to identify possible competitors to F⁻, encompassing various anions, metal ions, and neutral molecules. To assess their impact, these analytes were introduced in substantial excess (300 μM) to a 10 μM solution of HIPS-Br, and their individual responses were meticulously recorded. Encouragingly, no significant increase in fluorescence intensity at 598 nm was observed upon the addition of anions like Cl⁻, Br⁻, I⁻, etc., metal ions such as Na⁺, Mg²⁺, Al³⁺, etc., and neutral molecules like urea, HMTA, dopamine, etc. (Fig. 4). These consistent outcomes in all the studies confirmed the selectivity of the probe HIPS-Br towards F⁻. The chemodosimetric approach, which leverages the highly specific fluoride-mediated cleavage of the O-silyl bond, facilitates the selective detection of fluoride ions.

Fig. 4 Fluorimetric responses of various metal ions ((1) Na⁺, (2) Mg²⁺, (3) Al³⁺, (4) K⁺, (5) Ca²⁺, (6) Cr³⁺, (7) Mn²⁺, (8) Fe²⁺, (9) Fe³⁺, (10) Co²⁺, (11) Ni²⁺, (12) Cu²⁺, (13) Zn²⁺, (14) Pd²⁺, (15) Ag⁺, (16) Hg²⁺, (17) Pb²⁺), anions (1) F⁻, (2) Cl⁻, (3) Br⁻, (4) I⁻, (5) CN⁻, (6) N₃⁻, (7) HS⁻, (8) HO⁻, (9) NO₃⁻, (10) NO₂⁻, (11) SO₄²⁻, (12) PO₄³⁻, (13) SCN⁻, (14) ClO⁻, (15) S²⁻), neutral molecules ((1) urea, (2) HMTA, (3) dopamine, (4) Et₃N, (5) guanine, (6) benzylamine, (7) Et₂NH, (8) 2-aminopyridine, (9) 3-aminopyridine, (10) dicyclohexylamine, (11) pyridine, (12) melamine, (13) 4-aminopyridine, (14) dodecylamine) (300 μM) towards HIPS-Br (10 μM) under optimized conditions (λ_ex = 350 nm; λ_em = 598 nm).

3.6 Sensing mechanism

The sensing mechanism relies on the strong affinity between silicon and fluoride ions. HIPS-Br was protected by a bulky silyl functionality. Fluoride, because of its ability to form a strong Si–F bond, serves as the most efficient deprotection agent, resulting in a spontaneous and fast cleavage of the Si–O bond at room temperature. The desilylation of HIPS-Br resulted in the formation of HIP-Br in solution, restoring the orange emission by ESIPT (Scheme 2). Presumably, the formation of the charged intermediate at the excited state via proton transfer is responsible for the larger Stokes shift as compared to its HBT derivative (Scheme 2a). To further confirm the sensing mechanism, an LCMS analysis of HIPS-Br was carried out before and after the addition of fluoride. Before F⁻ ion addition, the spectrum displayed two peaks of equal intensity centered at m/z 527, 529 corresponding to HIPS-Br [M + H]⁺. After the addition of fluoride, peaks at m/z 289 and 291, corresponding to HIP-Br [M + H]⁺, were observed with a bromide pattern in MS retained (Scheme 2b). These observations confirmed the proposed chemodosimetric behavior of HIPS-Br. The electron distribution obtained through TD-DFT studies indicates that in HIPS-Br, greater electron density resides on the imidazopyridine ring, giving it blue fluorescence, whereas in the ESIPT-active state (HIP-Br_IPT), greater delocalization is seen on the phenolic ring, giving rise to its orange emission.

Scheme 2 (a) Schematic of the sensing mechanism of fluoride ions with the probe, HIPS-Br. (b) The mass spectra of the probe before and after treatment of fluoride ions.

3.7 Determination of F⁻ in real samples using HIPS-Br

To demonstrate the practical applicability of the imidazopyridine-based sensing system in real-world scenarios, water samples were collected from various sources, including ponds, rivers, seas, taps, lakes, and rain, and were subsequently spiked with predetermined concentrations of fluoride ions (F⁻). These spiked samples were treated with the probe HIPS-Br sensing assay, and their fluorescence output was recorded. All measurements were performed in triplicate, yielding a relative standard deviation (RSD) within 3–4%, which signifies the reproducibility of the data. The percent recovery for all real samples was above 100%, indicating the efficient performance of the sensing assay in detecting fluoride ions in real water samples (Table 2). The higher recovery also suggests the natural presence of fluoride ions in real water samples. To further validate, we tested the probe's performance on several toothpaste brands, all of which had a maximum fluoride content of 1000 ppm. The extraction process involved drying the toothpaste, then sonicating 1 g of the dried mass in 20 mL of water for 30 min and further incubation for 24 h. After centrifugation, the aqueous supernatant was used for real sample analysis of fluoride in toothpaste samples. After initial calibration with known fluoride concentrations, fluoride sample extracts from different concentrations of toothpaste were analysed by fluorimetric analysis, and the corresponding concentrations were obtained from the standard plots and presented in ppm. These results of fluoride contents in the toothpaste samples were compared with ion chromatography (IC) data for further validation (Table 3). The values from the developed probe closely matched those from IC, confirming the high accuracy of the newly developed probe for fluoride estimation in real samples.

Table 2 The %recovery of real sample analysis in different food samples pre-spiked with a known concentration of F⁻ ions

S. no	Sample	F^− added (μM)	F^− found (μM)	Recovery (%)	RSD (n = 3)
1	Tap water	1.5	1.53	102.0	2.8
2	River water	3.5	3.61	103.1	3.2
3	Field water	5.5	5.76	104.7	2.6
4	Pond water	7.5	7.92	105.6	3.1
5	Lake water	9.5	9.90	104.2	3.5

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Table 3 Real sample analysis data for different toothpaste samples. Comparison between IC and HIPS-Br for fluoride detection

Toothpaste	Conc. from IC (ppm)	Conc. from probe HIPS-Br (ppm)
1	0.946	0.95
2	0.764	0.72
3	0.882	0.9
4	0.765	0.74
5	0.685	0.72

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3.8 Solid phase detection of F⁻ ions

Recently, smartphone-based devices have been effectively employed in the detection and quantification of analytes through rapid image analysis, emerging as a user-friendly approach for on-site detection.³⁸ To our advantage, the small molecule probe, HIP-Br, is strongly fluorescent in the solid phase due to the restriction of molecular motion at the ESIPT-active state (HIP-Br_IPT) by the transfer of H-atom from phenolic –OH to ring nitrogen. For the purpose of solid-phase detection, we prepared strips of HIPS-Br using silica-coated TLC plates as the solid platform. The TLC strips were prepared by dipping them into the probe solution (100 μM in DCM) and subsequent air drying. HIPS-Br did not display its inherent fluorescence in the solid phase (on TLC strips), presumably due to aggregation-caused quenching (ACQ). The dried strips were then dipped into an aqueous solution with varying concentrations of fluoride ions. All strips dipped into the fluoride solutions displayed bright orange fluorescence proportional to the concentration of fluoride (Fig. 5). The images of the strips were taken through a mobile camera (One plus 11R, 64 MP) and analyzed through ImageJ software to generate the count of total fluorescence (CTCF) values. For the analysis of each sample, four different regions within the circular area were randomly selected using the background as a control. The CTC values of the images were plotted against the concentrations of fluoride ions. Notably, the solid phase provided a significant fluorescence response in the 0–50 ppm fluoride range, with a regression coefficient of R² = 0.9964 (Fig. 4). The sensor was able to detect 1 ppm of fluoride in the solid state, displaying enhanced fluorescence. Notably, the USEPA set a limit for fluoride in drinking water as 4 ppm, which is well above the lower detection limit of the current protocol in the solid phase. This demonstrates the potential of using image analysis techniques for the quantification of fluoride in real-life applications. A selectivity study with several common anions was also conducted in the solid phase to ensure the specificity of HIPS-Br-coated TLC strips towards fluoride ions. Only fluoride ions displayed a significant response in the strips, displaying the selective nature of the chemodosimeter.

Fig. 5 (a) Fluorescence photographs of silica-coated TLC strips soaked in HIPS-Br solution (100 μM) and drop-casted with different concentrations of F⁻ (0–50 ppm), photographed under 365 nm UV light. (b) The corresponding CTCF plots. (c) Solid-phase fluorimetric responses of HIPS-Br coated TLC strips after the addition of 50 ppm of various competing analytes.

3.9 Comparative study

Finally, a comparative assessment of the imidazopyridine-based sensor (HIPS-Br) with other available methods, focusing on sensitivity, selectivity, and applicability, was conducted using selected ESIPT-based and desilylation strategy-based molecular probes for fluorimetric detection of fluoride ions. As shown in Table S2 of ESI,† the current probe has a lower detection limit, fast signal transduction compared to other molecular probes in consideration, and is synthesized by a green and solvent-free approach, mechanosynthesis, which is a sheer advantage over others. The two-step high-yielding synthesis makes this molecular probe more cost-effective than others. Additionally, the use of HIPS-Br-coated TLC strips demonstrates better ability in solid-phase estimation of fluoride in real samples, enabling the scope of on-site real-world applications.

4. Conclusion

In this study, we developed an efficient ESIPT-active orange-emissive chemodosimeter, HIPS-Br, for the selective and sensitive turn-on detection of fluoride ions (F⁻). The probe was synthesized using a sustainable mechanochemical approach, which is both cost-effective and environmentally friendly. HIPS-Br demonstrated remarkable selectivity towards F⁻ ions over a range of common anions, cations, and small organic molecules. The probe's strong orange emission at 598 nm upon interaction with F⁻ ions provides a significant advantage for fluorimetric detection over other blue-emissive ESIPT probes, ensuring high sensitivity and accuracy. The sensing mechanism relies on the strong affinity of Si and fluoride ions, which leads to the desilylation of HIPS-Br to generate orange emissive HIP-Br with an impressive detection limit of 1.2 ppb, which is significantly lower than the USEPA limit for fluoride in drinking water (4 ppm). Furthermore, the solid-phase detection capability on silica-coated TLC plates marks the probe's utility for on-site and real-time fluoride quantitation, enhancing its practicality for diverse applications. The sensor was able to detect fluoride levels as low as 1 ppm in the solid phase. The successful application of HIPS-Br in real sample analysis, including spiked water, with excellent recovery rates, underscores its potential for practical applications in environmental monitoring and public health. This work not only presents a highly sensitive chemodosimeter for fluoride detection but also opens new avenues for developing sustainable and efficient sensing materials for various analytes. Our findings highlight the importance of integrating green chemistry principles in sensor design, paving the way for future advancements in analytical chemistry and environmental sciences.

Data availability

This is to declare that the data of this work will be available on request from readers for the following manuscript titled “An ESIPT-active orange-emissive 2-(2′-hydroxyphenyl)imidazo[1,2-a]pyridine-derived chemodosimeter for turn-on detection of fluoride ions via desilylation”.

Author contributions

A. A. B.: investigation, analysis, validation. M. B.: conceptualization, supervision, resources, writing – original draft, review & editing. A. T.: validation, visualization, writing – review & editing. P. D. V.: investigation, validation. A. C.: supervision, resources, writing – review & editing.

Conflicts of interest

The authors declare no personal, financial, or organizational conflict of interest.

Acknowledgements

A. A. B. expresses gratitude to BITS Pilani, KK Birla Goa Campus, for the research fellowship. A. T. is thankful to BITS Pilani, KK Birla Goa Campus, for the research fellowship. NMR and LCMS data were obtained from the Central Sophisticated Instrumentation Facility (CSIF), BITS Pilani, KK Birla Goa Campus.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ra05823b

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