Highly Selective Detection of Hypochlorous Acid ... - ACS Publications

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Highly Selective Detection of Hypochlorous Acid by a Bisheteroleptic Ru(II) Complex of Pyridyl-1,2,3-triazole Ligand via C(sp2)−H Hydroxylation Bhaskar Sen,† Sanjoy Kumar Sheet,† Sumit Kumar Patra,† Debaprasad Koner,‡ Nirmalendu Saha,‡ and Snehadrinarayan Khatua*,† Centre for Advanced Studies, Department of Chemistry, ‡Department of Zoology, North Eastern Hill University, Shillong, Meghalaya-793022, India

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S Supporting Information *

ABSTRACT: A Ru(II) complex (Ru-1) of a substituted pyridyl-1,2,3-triazole ligand (BtPT) for highly selective “lightup” detection of hypochlorous acid is presented. An unusual anti-Markovnikov HOCl addition to the CC bond of 1,2,3triazole and a highly specific C(sp2)−H hydroxylation over epoxidation made Ru-1 a highly selective luminescent HOCl probe. The abnormal regio- and stereoselective HOCl addition and subsequent hydroxylation mechanism in detail is supported by the combination of ESI-MS, 1H/13C NMR spectroscopy, and 1H NMR titration. The hydroxylation at the C5 center in 1,2,3-triazole increases the electron density and makes BtPT a better σ-donor as well as π-donor, which in turn increases the 3MC−3MLCT energy gap and inhibits the nonradiative decay from the excited state of Ru-1 and is the key reason for luminescence light-up. Most importantly, the exogenous and endogenous HOCl imaging in the living HEK293T cells is also demonstrated. The probe showed low cytotoxicity and efficiently permeated the cell membrane. The cell-imaging experiments revealed rapid staining of the extranuclear region of HEK293T cells which clearly indicates the presence of cytoplasmic HOCl. The endogenous HOCl generation and imaging, stimulated by lipopolysaccharides (LPS) and paraquat in the HEK293T cells, is also demonstrated.

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INTRODUCTION

bond, leading to the formation of the corresponding aldehyde (Table S1).8 Recently, C−H functionalization has shown great potential to form new chemical bonds.9 Metal-catalyzed C−O bond formation is more challenging compared to C−C and C−X (X = heteroatom) bonds.10 From an economic and environmental viewpoint, C(sp2)−H hydroxylation with an inexpensive oxidant is highly desirable and remains a very challenging task.11 Despite that reports on catalytic C−H functionalization of 1,2,3-triazoles at the 5-position exit,12 to date, there are no reports on luminescent ROS detection via C−H hydroxylation. The photochemistry of d6-metal complexes containing a 1,2,3-triazole ligand has been expansively studied, but the sensing field is quiet unexplored.13 We have developed few Ru(II) and Ir(III) based probes of the 1,2,3-triazole ligand for sensing and bioimaging based on C-H analyte interaction.14 Ru(II) polypyridyl complexes have been extensively used as sensors, PDT agents, and bioimaging due to the excellent photochemical properties, stability in aqueous media, and good cell permeability.15,16 While a few Ru(II) based HOCl selective

Reactive oxygen species (ROS) are produced mainly in mitochondria by ATP assisted oxidative phosphorylation in a series of electron-transport process in living cells and control various biological events in the human body.1,2 Among various ROS, hypochlorous acid/hypochlorite (HOCl/ClO−), generated from H2O2 and Cl− by myeloperoxidase (MPO)catalyzed reaction, constructs an innate host defense system against various types of pathogens in living organisms.3 An appropriate HOCl level helps normal functioning of the cellular system, but abnormal HOCl production has been linked to cardiovascular disease, neurodegeneration, and cancers.4 Thus, a highly selective and sensitive detection and imaging of endogenous HOCl has received a great importance in chemistry and biology.5 The existing HOCl probes are mostly based on rhodamine, fluorescein, BODIPY, pyrene, cyanine, and metal complexes,6,7 where most of them used HOCl/ClO− promoted spirolactam ring opening, oxidation of the B−H bond, pyrrole ring, pmethoxyphenol, chalcogenides, and deoximation reactions for sensing (Table S1).5−7 Apart, few probes have also been established for HOCl via epoxidation of the acyclic CC © XXXX American Chemical Society

Received: April 17, 2019

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DOI: 10.1021/acs.inorgchem.9b01125 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Scheme 1. Schematic Representation of HOCl Detection by Previous8 and Our Approach

Scheme 2. Synthesis of BtPT Ligand and Probe Ru-1a

a

(Inset) Chemical structure of Ru-2, used for control experiment.

probes via oxidation of hydrazide-derived linker and sulfur containing heterocycles have been reported,17 a metal complex based HOCl specific probing by new protocol will need to be developed. Herein, for the first time, we demonstrate HOCl specific luminescent detection via C(sp2)−H hydroxylation in a bisheteroleptic Ru(II) complex (Ru-1) of a benzothiazole substituted pyridyl-1,2,3-triazole ligand (BtPT) (Scheme 1). Extensive NMR study furnishes a detailed picture of the hydroxylation mechanism. The ability of Ru-1 for endogenous HOCl imaging, stimulated by lipopolysaccharides (LPS) and paraquat in the HEK293T cells, is also demonstrated.

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Figure 1. Perspective view of Ru-1·2CHCl3 with 30% thermal ellipsoid probability. Only non-carbon and non-hydrogen atoms are labeled.

RESULTS AND DISCUSSION

Synthesis and Characterization of Probes, Ru-1 and Ru-2. The BtPT ligand was synthesized from azide/tetrazole (A/B) derivatives and 2-ethynylpyridine by a click reaction and characterized spectroscopically (Scheme 2, Figures S1− S5). Probe Ru-1, readily prepared from BtPT and cis[Ru(phen)2]Cl2 (Scheme 2), was characterized by 1D (1H and 13C) and 2D (COSY, HSQC, and HMBC) NMR, ESI-MS (Figures S6−S11), and single-crystal X-ray diffraction (Figure 1 and Tables S2 and S3). Like previously reported Ru(II) based probes,13,14 here, the Ru(II) center adopts a distorted octahedral geometry with the trans angles ranging from 170.69(18)° to 172.54(17)°. Additionally, complex Ru-2 of the methyl substituted pyridyl triazole ligand was synthesized

to support the mechanistic details of the probe analyte reaction (Scheme 2, inset). UV−vis and PL Response of Probe Ru-1 toward HOCl. The UV−vis spectrum of Ru-1 (50 μM) revealed broad MLCT bands with λmax at 400 and ∼433 nm in PBS buffer/ DMSO (v/v, 9.5:0.5, pH 7.4) solution which are assigned by TDDFT studies (Supporting Information). Probe Ru-1 emits weakly at 580 nm (λex = 400 nm; Φ = 0.008) (Figure S12) because of nonradiative decay from the 3MC state.13 Upon screening of several ROS/RNS (ONOO−, H2O2, NO•, O2•−, • OH, 1O2, tBuOOH, and HOCl; aq NaOCl as a source of HOCl) and anions (F−, Cl−, Br−, I−, AcO−, OH−, CN−, HS−, B


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Inorganic Chemistry

Figure 2. (a) PL intensity of Ru-1 (50 μM) with various analytes in PBS buffer (pH 7.4). (A-V: blank, F−, Cl−, Br−, I−, AcO−, OH−, CN−, HS−, HSO4−, S2O32−, H2PO4−, NO2−, NO3−, ONOO−, H2O2, NO•, O2•−, •OH, 1O2, tBuOOH, and HOCl). (Inset) PL selectivity plot and photographs of Ru-1 with/without HOCl under UV irradiation (365 nm). (b) PL titration of Ru-1 (50 μM) with HOCl (0−20 equiv). (Inset) Plot of PL intensity vs HOCl concentration.

Scheme 3. Synthetic Route for Ru-1-OH from Probe Ru-1

Figure 3. (a) Compounds Ru-1 and Ru-1-OH with atom labeling scheme in BtPT ligand. (b) 1H and (c) 13C NMR spectra of Ru-1 and Ru-1-OH in CD3CN.

C


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Inorganic Chemistry

Figure 4. (a) 1H NMR titration of Ru-1 with HOCl (0−10.0 equiv) in DMSO-d6. (b) Plausible mechanism established from the 1H NMR titration, 1H/13C NMR of the Ru-1 and Ru-1-OH.

and Cl− in the neutral pH range, and the maximum decomposition rate is observed at pH ∼ 6.89.18 HOCl also decomposes to Cl2 gas at very low pH (below pH 3). Thus, more HOCl was available in the high pH media to react with CC of 1,2,3-triazole and a more rapid change in emission intensity was achieved. To further support this, we did a PL titration in pure DMSO media, where only 5 equiv of HOCl was required to attain the saturation (Figure S20b). Mechanistic Investigation of HOCl Detection by ESIMS and NMR Spectroscopy and Control Experiments. The ESI-MS of the Ru-1 and NaOCl mixture shows a clear peak at m/z = 770.13, corresponding to [C39H26N9ORuS]+, which indicates oxidation in Ru-1 (Figure S21). While Ru-1 may undergo HOCl/ClO− mediated S-oxidation of benzothiazole to sulfoxide or sulfonate,19 the possibility of oxidation in 1,2,3-triazole is considered since our previous work on Ru(II) based probes attests that the reactive C-H of 1,2,3triazole is responsible for the PL enhancement.14 To establish the oxidation reaction precisely, we synthesized the oxidized product, Ru-1-OH, by reacting Ru-1 with NaOCl in aqueous CH3CN (Scheme 3), and the solution structure was determined by NMR spectroscopy and ESI-MS (Figure 3, Figures S22−S25). 1H NMR spectra of Ru-1-OH revealed the loss of a triazole proton (Hg) signal, observed initially at δ = 9.70 ppm for Ru-1. Also, the pyridine ring protons of BtPT (Ha, Hb, Hc, and Hd) shifted to the upfield region with Δδ = 0.39, 0.48, 0.30, and 0.30 ppm, respectively (Figure 3b). Most importantly, the triazole carbon (Cg) signal has been shifted downfield from 123.6 to 152.1 ppm (Δδ = 28.5 ppm) in Ru-1OH (Figure 3c). Therefore, 1H/13C NMR together with ESIMS designates the hydroxylation at C5 of 1,2,3-triazole in Ru1. Although the UV−vis spectra of probe Ru-2 of a methyl substituted 1,2,3-triazole pyridine ligand shows a negligible change in the presence of NaOCl (20.0 equiv), the PL spectra of Ru-2 with 20.0 equiv of NaOCl shows ∼1.7-fold PL enhancement at 592 nm (λex = 403 nm) and the less PL

HSO4−, S2O32−, H2PO4−, NO2−, and NO3−) in UV−vis (Figures S13−S15) and PL spectroscopy (Figure 2a), probe Ru-1 (50 μM) solely shows absorbance change, enhanced emission (at 587 nm), and red luminescence in the presence of HOCl (1.0 mM). No apparent change in PL has been accounted in the presence of a 10-fold excess of all other analytes (10.0 mM), entailing exceptional selectivity to HOCl (Figure 2a and inset). A titration experiment reveals that the PL of Ru-1 is gradually increased upon addition of 0−20 equiv of HOCl (Figure 2b), and a distinct turn-on emission with ∼9fold PL enhancement at 587 nm (Φ = 0.053) is observed. A plot of PL intensity vs HOCl concentration (0−1.0 mM) shows a steady linear increment (Figure 2b, inset) in the 0−0.4 mM concentration of HOCl, and the detection limit was calculated as 76 nM, lower than the intracellular HOCl concentration and other reported probes (Figures S16 and S17a, Table S1).5−8,17 While a 1:200 mixture of Ru-1 and ROS, RNS and other competitive anions did not show remarkable PL enhancement at 587 nm, an immediate enhancement was observed upon the addition of only 20 equiv of HOCl (Figure S17b). The lifetimes (τavg) measured in PBS buffer were found to be 14.63 and 79.30 ns for Ru-1 and the Ru-1 + HOCl mixture (1:20), respectively (Figure S18). The PL intensity of the free probe Ru-1 was not affected by the pH of the medium, but the PL intensity of the mixture of the probe and HOCl (i.e, Ru-1 + HOCl) is affected by the pH of the medium; the PL intensities of Ru-1 and the NaOCl mixture (1:20) were enhanced above pH 5 and steadily increased to pH 7 and further slowly above pH 8 (Figure S19). Further, a time course study in PL reveals that the faster PL response to HOCl was achieved with increasing DMSO content in a PBS buffer-DMSO mixture (Figure S20a). In the 95% PBS buffer medium (pH 7.4), the available HOCl is comparatively less than that in the 50% PBS buffer-DMSO medium where buffer pH is not maintained (pH = 11.19 after addition of NaOCl solution). It is a well-known fact that the aqueous HOCl normally decomposes to ClO3− D


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Inorganic Chemistry enhancement can readily be explained by high luminescence of the blank sample (Figures S26 and S27). It is noteworthy that the benzothiazole unit was introduced in 1,2,3-triazole pyridine (BtPT) to diminish the PL of the analyte free Ru-1 via PET from the electron rich benzothiazole group. The ESI-MS of the Ru-2 and NaOCl mixture shows a peak at m/z = 637.16 corresponding to [C32H23N8ORu]+, further supporting hydroxylation in triazole (Figure S28). To gain mechanistic insight into the hydroxylation, 1H NMR titration of Ru-1 with HOCl (0−10.0 equiv; aq NaOCl as a source) in DMSO-d6 (Figure 4a) was performed. The titration data undoubtedly authenticate the progress of hydroxylation reaction through the chlorohydrin intermediate, Ru-1-ClOH (Figure 4b). The highly acidic triazole proton (Hg) signal of Ru-1 at 10.42 ppm has been shifted downfield (Δδ = 0.26 ppm), weakened gradually (0−5.0 equiv), and vanished completely after addition of 10.0 equiv of NaOCl. Most importantly, two new doublets at 4.91 and 4.73 ppm (3J = 11.2 Hz) have appeared which may due to the interaction between hydroxyl (HY) and methine proton (HX), respectively. The fading of the Hg signal and the appearance of doublets for vicinal protons (HX and HY) undeniably confirm the formation of the chlorohydrin intermediate, Ru-1-ClOH. In contrast to reported HOCl mediated epoxidation in acyclic CC,8 in Ru1, unusual anti-Markovnikov HOCl addition and subsequent hydroxylation after the β-HXCl elimination (Figure 4b) is presumably assumed. It is also expected that the chlorohydrin in Ru-1 may be in an abnormal syn-orientation, so the alkoxide (O−) cannot attack the backside of the C−Cl bond and thus the epoxide is not formed. Notably, the unusual regio- and stereoselectivity extremely depends on the electronic effect of CC substituents and solvent polarity which was previously reported for a four- to seven-membered ring system.20 Notably, the C−H hydroxylation was also observed in free BtPT but was not useful for probing HOCl as it finally decomposed to picolinic acid (Figures S29 and S30). While 1,2,3-triazole based anion/cation sensors are only known, a probe has not been designed for HOCl detection.21 Similar decomposition was also observed for Ru-1, with excess NaOCl (100 equiv, 24 h), which yielded a nonemissive heteroleptic Ru-3 of picolinic acid and characterized by UV−vis/PL, 1 H/13C NMR, ESI-MS, and X-ray structure (Figures S31−S35, Tables S3 and S4). Electrochemical Study. To gain deeper understanding of the PL enhancement in Ru-1-OH, cyclic voltammetry (Figure 5) studies were performed. Both Ru-1 and Ru-1-OH show a quasi-reversible (ΔEp = 83 mV) Ru2+/Ru3+ redox couple at E1/2ox = +1.427 V and +1.166 V vs Fc/Fc+, respectively. The 113 mV anodic and 148 mV cathodic shifts for Ru-1 and Ru-1OH in comparison to [Ru(phen)3]2+ (E1/2ox = +1.314 V) are readily explained by the weak and strong σ- as well as πdonation of BtPT before and after hydroxylation, respectively. Theoretical Study. Density functional theory (DFT) and time dependent-density functional theory (TD-DFT) calculations (Tables S5−S10) were performed to obtain insight into the electronic transitions responsible for the absorption spectra and luminescence spectra of Ru-1 and Ru-1-OH. It is expected that the Ru-1-OH in 95% aqueous buffer solution exists as enolate, so the deprotonated form, Ru-1-O−, was used for all computation. As shown in the ground-state optimized structure, the Ru−NTriazole bond lengths are shortened in Ru1-O− (2.068 Å) compared to Ru-1 (2.084 Å), which indicates stronger σ- and π-donation of the hydroxylated BtPT ligand

Figure 5. RuII/RuIII based redox wave for Ru-1, Ru-1-OH, and [Ru(phen)3](PF6)2 in CH3CN.

(Figures S36−S38 and Table S5).13b Like the previously reported Ru(II) complex by Schubert et al.,13b here, the trans Ru−Npy bond is elongated from 2.114 to 2.130 Å due to the influence of the trans effect (Figure S36 and Table S5). The HOMO of Ru-1-O− is based on hydroxylated BtPT, while it is based on Ru(dz2) for Ru-1, which once again supports the increased electron density on the hydroxylated BtPT ligand (Figures S39−S42). Similar to previous reports,13 and the calculated energies of principal MOs for the optimized groundstate geometries (Figure 6a), here, we believe that the 3MC (dd*) state in Ru-1 is close to the 3MLCT state and the thermal population of 3MC states is leading to the nonradiative decay and weak luminescence. Further, due to the strong σ-donation of BtPT in Ru-1-O−, the 3MLCT is stabilized and the 3MC state destabilized, which increases the 3MLCT−3MC energy gap and assists to emit from the 3MLCT exited state. The TDDFT calculations at the triplet excited state reveals that the weak emission of Ru-1 at 580 nm is due to the nonradiative decay from the 3MC[Ru(dz2)→Ru(dσ*)] state, assigned as a HOMO-5→ LUMO transition at 559 nm. The experimental very strong emission band of Ru-1-O− at ∼587 nm arises from 3MLCT[Ru(dπ)→phen(Lπ*)] and 3 LLCT[BtPT(Lπ)→phen(Lπ*)] transitions, characterized as HOMO → LUMO+5 and HOMO → LUMO+6 transitions at 654 nm (Figure 6b and Table S10). Exogenous and Endogenous Imaging of HOCl. For biological application of Ru-1, we evaluated its cytotoxicity in HEK293T cells. An MTT assay using of Ru-1 (0−100 μM) suggested low cytotoxicity of Ru-1 (Figure S43). The cell viability gradually decreased with increasing amount of Ru-1 from a concentration range of 10−100 μM. More than 88% of the cells survived at ≤25 μM of Ru-1 after 24 h of treatment. During cell imaging, the confocal laser scanning microscopy (CLSM) images showed no luminescence from the cells, incubated with only Ru-1 (50 μM) (Figure 7a). A bright red luminescence throughout the cell except in the nucleus region was observed when Ru-1 (50 μM) loaded cells were incubated with NaOCl (50 μM), which indicates the ability of Ru-1 to detect HOCl in living cells (Figure 7b). For endogenous HOCl imaging, cells were treated initially with LPS (1 μg/ mL)22 for 2 h and with Ru-1 (25 μM) for a further 15 min. The observed red luminescence from the extranuclear region of the cell designates the endogenous HOCl generation (Figure 8a). Paraquat, a widely used herbicide in agriculture, enhances the oxidative stress in humans and results in E


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Inorganic Chemistry

Figure 6. (a) Energy level diagram for the molecular orbitals of Ru-1 and Ru-1-O− with corresponding graphical plots of HOMOs, LUMO, and dσ* orbitals shown at the ground-state optimized geometry. (b) Representative plots (isovalue = 0.03) of selected MOs for Ru-1 and Ru-1-O− at the triplet excited state optimized geometry.

Figure 7. CLSM images of HEK293T cells, (a) treated with Ru-1 (50 μM, 15 min) and (b) pretreated with HOCl (50 μM, 15 min) and then incubated with Ru-1 (50 μM, 15 min). Nucleus marker DAPI was used in all experiments. Images were taken using 405 nm (for DAPI) and 488 nm (Ru-1) excitation and emission windows of 420−510 nm (blue) and 510−630 nm (red).

neurodegeneration.23 However, paraquat assisted HOCl 24

generation is rarely reported in the literature.

min indicates the aptness of Ru-1 for endogenous HOCl

Similar red

emission from cells treated with 1 mM of paraquat for 1.5 h and successive incubation with Ru-1 (25 μM) for another 15

imaging (Figure 8b). F


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Inorganic Chemistry

Figure 8. Endogenous HOCl imaging: Cells pretreated with (a) LPS (1 μg mL−1) for 2 h and (b) paraquat (1 mM) for 1.5 h and then Ru-1 (25 μM) for 15 min. Nucleus marker DAPI was used in all experiments. Images were taken using 405 nm (for DAPI) and 488 nm (Ru-1) excitation and emission windows of 420−510 nm (blue) and 510−630 nm (red).

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fluorescence images of stained HEK293T cells were acquired with a confocal laser scanning microscope (Leica, TCS SP5, Germany). (Caution! Covalent azides are potentially hazardous and can decompose explosively under various conditions. It should be handled with care). Synthesis. Synthesis of 2-Azido-4-methylbenzo[d]thiazole/ methylbenzo[4,5-d]thiazolo[3,2-d]tetrazole, A/B. 2-Amino-4-methyl benzothiazole (5.0 mmol, 0.819 g) was dissolved in 80% phosphoric acid (32 mL), and the solution was placed in an ice bath to maintain the reaction temperature at 0 °C. After that, a conc. nitric acid (18 mL) was added, followed by the dropwise addition of aqueous sodium nitrite (50 mmol, 3.530 g) over 10 min. After 30 min stirring, an aqueous solution of sodium azide (25 mmol, 1.624 g) was added. After that, the ice bath was removed and stirring was continued for 2 h at room temperature. Afterward, the reaction mixture was poured into 50 mL of ice-cold water; a yellow precipitate was obtained immediately. The precipitate was filtered and washed with distilled water until the pH of the filtrate reached 7. The crude product was purified by 60−120 mesh Silica gel column chromatography using 5% ethyl acetate/hexane (v/v). The desired azide/tetrazole [A/B] yellowish compound was obtained in a good yield (0.781 g, 84%) (Scheme 2). Anal. Calcd for C8H6N4S (Mw = 190.22): C, 50.51; H, 3.18; N, 29.45; S, 16.86. Found: C, 50.48; H, 3.12; N, 29.35; S, 16.76. FTIR in KBr disc (ν/cm−1): 3450, 2128 (NNN stretching), 1650, 1456, 1336, 1215, 1081. Melting point = 98−100 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) = 7.46 (d, J = 7.0 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.30−7.24 (m, 2H), 7.07−6.99 (m, 2H), 2.79 (s, 3H), 2.46 (s, 3H).13C NMR (100 MHz, CDCl3): δ (ppm) = 157.8, 150.1, 133.5, 132.7, 131.7, 129.6, 128.2, 127.9, 127.7, 127.2, 124.6, 122.5, 122.3, 118.9, 18.5, 18.2. Synthesis of 4-Methyl-2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)benzo[d]thiazole, BtPT. The azide/tetrazole [A/B] derivative (2.10 mmol, 0.399 g) was dissolved in THF (15 mL), followed by the addition of CuI (2.10 mmol, 0.399 g), DIPEA (12.6 mmol, 2.195 μL), and 2-ethynylpyridine (2.52 mmol, 255 μL). Then the reaction mixture was stirred for 24 h at room temperature. After evaporating the THF, the crude solid was dissolved in an aqueous ammonia and DCM mixture (50 mL; 1:1, v/v) and stirred at room temperature for 12 h. The organic layer was separated and removed in a rotary evaporator under reduced pressure. The pure yellowish white BtPT ligand was obtained by silica gel column chromatography (20% ethyl acetate/hexane) in a good yield (0.314 g, 51%) (Scheme 2). Anal. Calcd for C15H11N5S (Mw = 293.35): C, 61.42; H, 3.78; N, 23.87; S, 10.93. Found: C, 61.39; H, 3.70; N, 23.81; S, 10.87. FTIR in KBr disc (ν/cm−1): 3450, 1597, 1535, 1450, 1420, 1227, 1021. Melting point = 135−137 °C. ESI-MS: m/z calculated for [C15H11N5S + H]+ 294.07; found: 294.27. ESI-MS: m/z calculated for [C15H12N5S − N2]+ 266.07; found: 266.25. 1H NMR (400 MHz, CDCl3): δ (ppm) =

CONCLUSIONS In summary, an abnormal regio/stereoselective syn-addition of HOCl to triazole CC and subsequent β-elimination make the Ru-1 a HOCl specific probe through unique C−H hydroxylation which has been supported by ESI-MS and 1H NMR titration. The hydroxylation in triazole amplifies the σdonation ability of the BtPT ligand in Ru-1, manipulates the 3 MC vs 3MLCT energy gap, and is crucial for luminescence light-up. The MTT assay on HEK293T cells shows that the probe is less cytotoxic and can efficiently permeate the cell membrane. The bioimaging experiments on HEK293T cells reveals rapid staining of the extranuclear region and indicates the presence of cytoplasmic HOCl. The endogenous HOCl generation and imaging, stimulated by lipopolysaccharides (LPS) and paraquat in the HEK293T cells, is also demonstrated. This unusual, catalyst free C−H hydroxylation in 1,2,3-triazole may provide a practical method to perform C− H to C−O bond functionalization which may be beneficial to design an organic and metal complex based HOCl probe with exceptional selectivity.

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EXPERIMENTAL SECTION

Materials and Physical Measurements. All chemicals used for synthesis and sensing studies were purchased from commercial suppliers (Aldrich, Alfa Aesar, and Spectrochem India) and were used as received without further purification. All 1D and 2D NMR spectra were measured on a Bruker AVANCE II (400 MHz) spectrometer, and chemical shifts were expressed in ppm using the residual protic solvent resonance as the internal standard. ESI mass spectra of all compounds were measured on a Waters ZQ-4000 mass spectrometer. All the NMR and ESI mass spectral data were processed in a MestReNova V12.0.0-20080. Infrared spectra were recorded using a PerkinElmer FT-IR spectrometer with KBr pellets in the range of 4000−400 cm−1. Elemental analysis measurements were done using the PerkinElmer 2500 series II elemental analyzer. UV−vis and PL spectra were recorded on a PerkinElmer Lambda 25 UV−vis spectrophotometer and a Hitachi F-4500 fluorescence spectrophotometer with a quartz cuvette (path length = 1 cm), respectively. The luminescence lifetime measurements were carried out on a timecorrelated single photon counting (TCSPC) spectrometer from Edinburg Instruments Ltd. (Lifespec II, U.K.). Electrochemical experiments were performed using a CHI 600C electrochemical workstation at 25 °C. Excitation and the emission slit for PL data collection were set to 10 mm and the PMT voltage at 700 V. The G


Inorganic Chemistry

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9.21 (s, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.85 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.38−7.30 (m, 3H), 2.73 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) = 154.8, 149.9, 149.5, 149.3, 149.2, 137.1, 133.8, 133.2, 127.7, 126.2, 123.6, 120.9, 119.9, 119.3, 18.1. Synthesis of [Bis(1,10-phenanthroline)(BtPT)] Ruthenium(II) Dihexafluorophosphate], Ru-1. cis-[Ru(phen)2Cl2] was synthesized according to the reported literature procedure23 and used for the synthesis of complex Ru-1 (Scheme 2). A mixture of ligand, BtPT (0.19 mmol, 0. 056 g), and cis-[Ru(phen)2]Cl2 (0.19 mmol, 0.102 g) was refluxed in 20 mL of degassed aqueous ethanol (ethanol/water = 3:1) at 100 °C for 6 h under a N2 atmosphere. Then, ethanol was evaporated and an excess NH4PF6 was added. An orange-red color solid was obtained, which was extracted by DCM, and the solvent was evaporated. A pure deep red colored complex was obtained using silica gel column chromatography (DCM:MeOH = 95:5) in a good (0.160 g, 81%) yield. The diffraction-quality single crystals of complex Ru-1 were obtained from an acetone and chloroform (3:1) mixture after 1 week. Anal. Calcd for C39H27F12N9P2RuS·2CHCl3 (Mw = 1283.51): C, 38.37; H, 2.28; N, 9.82; S, 2.50 Found: C, 38.32; H, 2.30; N, 9.86; S, 2.48. FTIR in KBr disc (ν/cm−1): 3436, 1654, 1510, 1402, 1136, 844 (PF6 stretching), 557. Melting point = >300 °C. ESIMS: m/z calculated for [C39H27F6N9PRuS]+ 900.08; found: 900.08. ESI-MS: m/z calculated for [C39H27N9RuS]2+ 377.56; found: 377.56. 1 H NMR (400 MHz, CD3CN): δ (ppm) = 9.70 (s, 1H, Hg), 8.70 (d, J = 8.2 Hz, 2H, H4,4′), 8.61 (d, J = 8.3 Hz, 1H, H7′), 8.56 (d, semicovered, J = 7.6 Hz, 1H, H7), 8.55 (d, J = 7.6 Hz, 1H, H2′), 8.36− 8.33 (m, 2H, H2,d), 8.27 (d, J = 4.8, 2H, H5′,6′), 8.24 (d, J = 6.2, 2H, H5,6), 8.08−8.03 (m, 2H, H9′,c), 7.97 (d, J = 5.2 Hz, 1H, H9), 7.87− 7.82 (m, 2H, H3,3′), 7.76−7.73 (m, 1H, Hl), 7.65−7.56 (m, 3H, H8,a,8′), 7.42−7.37 (m, 2H, Hk,m), 7.26 (t, J = 7.4 Hz, Hb), 2.7 (s, 3H, Ho). 13C NMR (100 MHz, CD3CN): δ (ppm) = 154.6 (1C, Ch), 154.3 (1C, C9′), 154.1 (2C, C9,2′),154.0 (1C, C2), 153.5 (1C, Ca), 151.2 (1C, Ce), 150.1 (1C, Cf), 149.8 (1C, Ci), 149.3 (1C, C12′), 149.0 (1C, C12), 148.8 (1C, C11′), 148.7 (1C, C11), 139.5 (1C, Cc), 138.2 (1C, C4′), 138.1 (1C, C4), 138.0 (1C, C7′), 137.8 (1C, C7), 134.8 (1C, Cn), 134.0 (1C, Cj), 132.1(2C, C13′,13), 132.0 (1C, C14′), 131.5 (1C, C14), 129.1 (3C, C5′,6′,5), 129.0 (1C, C6), 128.9 (1C, Cm), 128.1 (1C, Ck), 127.6 (1C, Cb), 127.2 (1C, C3′), 127.1 (1C, C3), 127.0 (1C, C8′), 126.3 (1C, C8), 124.3 (1C, Cd), 123.6 (1C, Cg), 120.8 (1C, Cl), 17.9 (1C, Co). Synthesis of [Bis(1,10-phenanthroline) (3-(4-Methylbenzo[d]thiazol-2-yl)-5-(pyridin-2-yl)-3H-1,2,3-triazol-4-ol)] Ruthenium(II) Dihexafluorophosphate], Ru-1-OH. The complex Ru-1 (0.07 mmol, 0.073g) was dissolved in a 1:1 acetonitrile/water mixture (10 mL). To this stirred solution was added an aqueous NaOCl (0.7 mmol, 3 mL) dropwise. After 3 h stirring, the organic solvent was evaporated and treated with an excess NH4PF6. The crude product was then collected as a DCM extract and dried under vacuum. Finally, the crude product was purified by silica gel column chromatography (5% CH3CN/DCM as an eluent) to afford brick red colored Ru-1OH in a moderate yield (0.038g, 51%) (Scheme 3). Anal. Calcd for C39H27F12N9OP2RuS (Mw = 1060.75): C, 44.16; H, 2.57; N, 11.88; S, 3.02. Found: C, 44.19; H, 2.54; N, 11.83; S, 3.05. FTIR in KBr disc (ν/cm−1): 3446, 2923, 2848, 1628, 1532, 1431, 841(PF6 stretching), 559. Melting point = >300 °C. ESI-MS: m/z calculated for [C39H26N9ORuS]+ 770.10; found: 770.09. 1H NMR (400 MHz, CD3CN): 8.74 (d, J = 6.3 Hz, 1H, H4′), 8.64 (d, J = 9.3 Hz, 1H, H4), 8.57 (d, J = 8.3 Hz, 1H, H2′), 8.46 (d, J = 8.3 Hz, 1H, H7′), 8.39−8.34 (m, 2H, H2,7), 8.24−8.17 (m, 2H, H5′,6′), 8.09−7.99 (m, 4H, H5,6,d′,9′), 7.91−7.82 (m, 3H, H9,3′,3), 7.78−7.73 (m, 2H, Hc′,l), 7.54 (dd, J = 5.2, 8.2 Hz, 1H, H8′), 7.34−7.31 (m, 1H, H8), 7.23−7.19 (m, 2H, Ha′,m), 7.11 (d, J = 7.0 Hz, 1H, Hk), 6.78 (t, J = 7.3 Hz, 1H, Hb′), 2.08 (s, 3H, Ho). 13C NMR (100 MHz, CD3CN): δ (ppm) = 156.8, 155.8, 155.1, 153.8, 153.3 (2C), 152.1, 151.2 (2C), 149.1, 148.9, 148.6, 148.4, 148.3, 138.0, 137.4, 137.3, 136.8 (2C), 133.2, 131.8, 131.7, 131.6, 131.2, 131.1, 128.8, 128.7, 128.0, 127.9, 127.8, 126.8, 126.7, 126.4, 126.3, 125.6, 125.4, 121.5, 119.8, 17.7.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.9b01125. Experimental procedures; NMR, ESI-MS, and X-ray data; UV−vis and PL data; theoretical calculation related files; and associated figures and tables (PDF) Accession Codes

CCDC 1497233 and 1831199 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. ORCID

Snehadrinarayan Khatua: 0000-0003-0992-4800 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work has been financially supported by DST, India (No. SB/FT/CS-115/2012). We thank the DST Purse program for the single-crystal X-ray diffraction facility and Sophisticated Analytical and Instrumentation Facility (SAIF), North Eastern Hill University (NEHU), for NMR and ESI-MS data. We thank Dr. B. Banerjee, NEHU, for his help in bioimaging. Dr. P. N. Chatterjee (NIT, Meghalaya), Dr. A. K. Pal (NEHU), Dr. P. Pahari (CSIR-NEIST), and Dr. S. C. Pal (Midnapore College) are acknowledged for useful discussions. B.S, S.K.S., and S.K.P thank CSIR (SRF) and RGNF for their fellowships. Also, we would like to thank the reviewers for their comments and suggestions. The present work is dedicated to Prof. Michael Schmittel (Universität Siegen) on the occasion of his 62th birthday.

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