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BODIPY-based sulfoxide: Synthesis, photophysical characterization and response to benzenethiols
Dyes and Pigments 96 (2013) 328e332
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BODIPY-based sulfoxide: Synthesis, photophysical characterization and response to benzenethiols Chunchang Zhao a, *, Xuzhe Wang a, Jian Cao a, Peng Feng a, Jinxin Zhang a, Yanfen Zhang a, Yang Yang a, Zhenjun Yang b, * a b
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science & Technology, Shanghai 200237, PR China National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 June 2012 Received in revised form 27 August 2012 Accepted 29 August 2012 Available online 13 September 2012
Two BODIPY dyes bearing a sulfur containing function at the 3-position are reported. The 3-benzylthio compound shows spectroscopic features of the classical BODIPY platform, showing minor solvent dependent spectral shift, a relative small Stokes shift and a high fluorescence quantum yield. Oxidation of the sulfur atom to the sulfoxide leads to a large hypsochromic shift in absorption and emission. We also demonstrated that the sulfoxide derivative can be used as a ratiometric fluorescent chemodosimeter for highly toxic benzenethiols in aqueous media. In this dosimeter the sulfoxide is chemospecifically reduced by benzenethiols to obtain the original oxidation state of the sulfur atom, accompanied with a drastic ratiometric fluorescence response. Furthermore, the probe features excellent selectivity over other competing analytes, moderate signal response times and a good linearity range for quantification. All these features render the sensor suitable for detection of benzenethiols in environmental settings. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: BODIPY-based sulfoxide Benzenethiols Ratiometric fluorescence response Chemodosimeter Chemospecific reduction Hypsochromic shifts
1. Introduction BODIPYs (boron-dipyrromethene dyes) are of special interest as chromophores due to their valuable photophysical characteristics [1]. Furthermore, the parent structure of BODIPY is easy to modify chemically for the preparation of various derivatives. The most commonly studied synthetic strategies available for the modification of the BODIPY core are: (1) nucleophilic substitutions of halogen atoms at the 3- and 5-positions [2,3], (2) condensation reactions [4], (3) substitution of the fluorine atoms by C or O atoms [5e7], (4) transition-metal-catalyzed reactions through the use of halogenated BODIPYs [8], and (5) electrophilic substitutions at the 2- and 6-positions [9]. In particular, the facile introduction of different groups at the 3- and 5-positions by nucleophilic substitution of chlorine atoms could be used for fast and easy variation of the BODIPY core to optimize the spectroscopic properties. This approach has caught the attention of several research groups [10], and several BODIPYs, containing sulfur atoms at the
* Corresponding authors. E-mail addresses: [email protected] (C. Zhao), [email protected] (Z. Yang). 0143-7208/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dyepig.2012.08.026
3-and 5-positions, have now been constructed to form thioether compounds [2aec]. Although the sulfur substituted BODIPYs are known, the related fascinating compounds, aromatic sulfoxides, have not been investigated well, so far. Therefore, we initiated the investigation of new BODIPY dyes containing sulfoxide and the BODIPY derivative BODIPY-SO (Scheme 1) was selected for initial evaluation on the basis of ease of synthetic access. In organic compounds, sulfur can have a formal oxidation state ranging from 2 to þ6 [11]. Previously studied BODIPYs are thioethers with oxidation state of 2, while the oxidation state of a sulfoxide is 0. The change in oxidation state would have sufficient effect on the photophysical properties. The electronwithdrawing nature of the oxidized thioether, sulfoxide, would lead to hypsochromic shifts in absorption and emission wavelength compared to that of the thioether. On the basis of this finding, we reasoned that the sulfoxide-sulfide interconversion could be used to construct a reaction-based probe and chemodosimeter. Explorations of sulfoxides in synthesis hold great interest from both laboratory and biological perspectives [12]. Of special interest is the thiol-sulfoxide reactions previously investigated in detail [13]. Theoretically, an interaction between the two species should yield a sulfide, disulfide and water. It is also well known that thiol acidity is of major importance as far as the ease of oxidation is concerned.
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solutions were diluted with aqueous solutions to the desired concentration. 2.2. Synthesis
Scheme 1. Synthesis of BODIPY-SO and the conversion to BODIPY-S by benzenethiols.
The observed ease of thiol oxidation is ArSH > ArCH2SH >> RSH, and aromatic thiols are about 103e104 times more reactive than aliphatic thiols [13d]. Based on this background, a ratiometric fluorescent probe for benzenethiols, BODIPY-based sulfoxide BODIPY-SO, could be designed (Scheme 1). BODIPY-S and its analog BODIPY-SO are fluorescent chromorphores with charateristics of BODIPYs. Sulfoxide BODIPY-SO undergoes a change in the electronwithdrawing nature of the S-group and should show a significant change in photophyscial properties, such as a significant shift in emission wavelength. Thus a fluorescent ratiometric chemodosimeter could be obtained. Several fluorescent sensors that selectively respond to the presence of benzenethiols have been reported [14], most of which respond to benzenethiols with only fluorescence signal turned-on. Unfortunately, single-intensitybased sensing is compromised by the local distribution of probes, drift of light sources and detectors. New ratiometric fluorescent probes that can overcome the limitation of intensity-based probes and provide quantitative measurement are therefore in demand. To our best knowledge, few ratiometric fluorescent probes for benzenethiols have been constructed to date. Herein, we report the synthesis and photophysical properties of a new BODIPY dye, BODIPY-SO, and its potential application as a ratiometric fluorescent chemodosimeter for benzenethiols.
Synthesis of 3-Benzylsulfanyl-5,7-dimethyl-6-ethyl-8phenyl-4,4-difluoro- 4-bora- 3a,4a-diaza-s-indacene (BODIPYS). To a solution of 3-chloro-5,7-dimethyl-6-ethyl-8-phenyl-BODIPY (0.716 g, 2 mmol) in CH3CN (30 mL) was added a-toluenethiol (0.298 g, 2.4 mmol) and Et3N (5 mL), and the reaction mixture was stirred for 3 h at room temperature. Excess CH3CN was removed under vacuum, and the residue was dissolved in ethyl acetate, washed with H2O and dried over Na2SO4. The crude product was purified by flash chromatography (silica gel, eluent: CH2Cl2/ EtOAc ¼ 40:1) to afford BODIPY-S (0.713 g, 80%). mp 169e173 C; FTIR (BODIPY-S) 2963, 1542, 1380, 1189, 1141, 964, 728 cm1; 1H NMR (400 MHz, CDCl3) d 7.43e7.50 (m, 5H), 7.27e7.34 (m, 5H), 6.29 (d, J ¼ 4 Hz, 1H), 6.22 (d, J ¼ 4 Hz, 1H), 4.29 (S, 2H), 2.62 (S, 3H), 2.36 (q, J ¼ 7.6 Hz, 2H), 1.43 (S, 3H), 1.03 (t, J ¼ 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 159.5, 150.2, 140.1, 139.0, 136.2, 136.0, 135.1, 134.4, 132.4, 129.5, 129.4, 129.1, 128.9, 128.8, 128.6, 128.3, 127.5, 127.1, 116.2, 38.0, 17.1, 14.3, 13.0, 12.1; HRMS (ESI) calcd for C26H24N2BF2S [M H]: 445.1721. Found: 445.1760. Synthesis of 3-Benzylsulfinyl-5,7-dimethyl-6-ethyl-8phenyl-4,4-difluoro- 4-bora- 3a,4a-diaza-s-indacene (BODIPYSO). To a solution of BODIPY-S (0.446 g, 1 mmol) in dry dichloromethane (20 mL) was added 0.99 equivalents of m-CPBA (0.17 g, 0.99 mmol) at 0 C. The reaction mixture was stirred for 30 min. Excess potassium carbonate was added to neutralize any acids, and washed with water. The organic layers were dried over anhydrous Na2SO4, and evaporated in vacuo. The crude product was further purified by flash chromatography (silica gel, eluent: CH2Cl2/ EtOAc ¼ 50:1) to afford BODIPY-SO (0.32 g, 70%). mp 180e183 C; FTIR (BODIPY-SO) 1578, 1141, 1071, 1056 (S]O), 731 cm1; 1H NMR (400 MHz, CDCl3) d7.51e7.53 (m, 3H), 7.28e7.40 (m, 7H), 6.56 (d, J ¼ 4 Hz, 1H), 6.26 (d, J ¼ 4 Hz, 1H), 4.51 (d, J ¼ 12.8 Hz, 1H), 4.22 (d, J ¼ 12.8 Hz, 1H), 2.70 (S, 3H), 2.40 (q, J ¼ 7.6 Hz, 2H), 1.51 (S, 3H), 1.07 (t, J ¼ 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.2, 150.4, 143.6, 141.6, 137.7, 136.9, 134.7, 133.5, 130.6, 130.5, 129.6, 128.8, 128.7, 128.6, 128.3, 128.1, 124.1, 115.5, 62.4, 17.2, 14.0, 13.6, 12.5; HRMS (ESI) calcd for C26H24N2BF2S [M H]: 461.1670. Found: 461.1616. 3. Results and discussion
2. Experimental section
3.1. Synthesis of BODIPY-S and BODIPY-SO
2.1. General methods and instruments
BODIPY-SO was readily synthesized in two steps beginning with the key intermediate 1. The overall yield is 56% for two steps. Intermediate 1 was obtained in a one-pot, two-step procedure via condensation of 2,4-dimethyl-3-ethylpyrrole with 2-benzoyl-5chloropyrrole followed by treatment with BF3$OEt2 (Scheme 1) [3b]. a-toluenethiol was then introduced into the BODIPY core to get BODIPY-S by a nucleophilic aromatic substitution reaction. The structures of BODIPY-S and BODIPY-SO were fully characterized by 1 H NMR, 13C NMR, and HRMS analysis.
All chemicals were purchased from commercial suppliers and used without further purification unless otherwise specified. Anhydrous CH2Cl2 was dried and distillated immediately prior to use. 3-chloro-5,7-dimethyl-6-ethyl-8-phenyl-BODIPY [3b] was prepared according to literature procedures. 1 H NMR and 13C NMR spectra were recorded on a spectrometer operating at 400 MHz and 100 MHz, respectively. Deuterated chloroform was used as the solvent, TMS as internal standard. Mass spectra were measured on an HP 1100 LCeMS spectrometer. UVe vis spectra were measured using a Shimadzu UV-2550 spectrophotometer. Fluorescence spectroscopic measurements were conducted on a Varian Cary eclipse fluorescence spectrophotometer. TLC analysis was performed on silica gel plates and column chromatography was conducted over silica gel (mesh 200e300), both of which were obtained from the Qingdao Ocean Chemicals. For absorption or fluorescence measurements, compounds were dissolved in EtOH to obtain stock solutions (2e5 mM). These stock
3.2. Photophysical properties of BODIPY-S and BODIPY-SO Spectroscopic evaluation of BODIPY-S and BODIPY-SO was performed in several solvents of varying polarity (Figure S1, Figure S2, Table S1 in supporting information). The optical features are characteristic of the classical BODIPY platform. As is evident from Figure S1, S2 and Table S1, BODIPY-S shows a narrow, strong absorption band around 545 nm and a shoulder at the short wavelength side in pure solvents. The S0eS1 absorption band shows
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minor solvent-dependent variation, with the maximum being slightly shifted hypsochromically (w7 nm) when the solvent is changed from benzene (550 nm) to acetonitrile (543 nm), which is consistent with the general behavior of other BODIPY chromophores [15]. Similar to the absorption spectrum, the emission spectrum also shows minor solvent-dependent shift with a relative small Stokes shift (w15 nm) and a high fluorescence quantum yield (0.2e0.4). Oxidation of BODIPY-S to the sulfoxide (BODIPY-SO) causes a large hypsochromic shift in absorption and emission relative to the parent compound. This blue shift in emission is accompanied by a decrease in FF, which is consistent with the general behavior of other aromatic sulfur-containing compounds [11b] [16]. The emission maximum shifts from 561 nm for the unoxidized version to 537 nm for the sulfoxide (BODIPY-SO) in EtOH. The broad shape of the S0eS1 transition together with the hypsochromic shifts may be attributed to intramolecular charge transfer character resulting from the strong conjugation of the sulfoxide function with the BODIPY core. All these characteristics demonstrate that changing the oxidation state of the sulfur atom leads to productive changes in the photophyscial properties. Ultimately, the fact that the interconversion of BODIPY-S to BODIPY-SO induces a dramatic shift in emission provides an opportunity for construction of ratiometric chemodosimeters. As sulfoxide reduction by aromatic thiols could yield the corresponding sulfide effectively, the thiol-sulfoxide reactions were therefore chosen to prove the above concept and quantify the toxic benzenethiols. 3.3. Thiol-sulfoxide reaction based response of BODIPY-SO to benzenethiols At first, the time course of the reaction between BODIPY-SO and p-thiocresol was studied by monitoring the variations in the ratios of fluorescence intensities of the reaction mixture at 568 and 536 nm (I568/I536) (Fig. 1). Under pseudo-first-order reaction conditions (10 mM BODIPY-SO and 1 mM p-thiocresol), an observed rate constant (kobs) at pH 7.2 and 40 C is found to be 1.7 min1, indicating that BODIPY-SO reacted rapidly with p-thiocresol under the given experimental conditions. Fig. 2 shows the sensory response of BODIPY-SO to various concentrations of p-thiocresol in buffer solutions at 40 C. Upon addition of increasing concentrations of p-thiocresol to a solution
Fig. 1. Time-course kinetic measurement of the fluorescence response of BODIPY-SO (10 mM) to p-thiocresol (1 mM, 25 mM sodium phosphate buffer, 50% EtOH as co-solvent, pH 7.2) at 40 C. The measurements are taken at 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 11, 16, 26, 36 min lex ¼ 484 nm.
Fig. 2. (a) Absorption and (b) Emission spectra for BODIPY-SO (10 mM) in buffer solution (pH 7.2, 25 mM sodium phosphate buffer, 50% EtOH as co-solvent) in the presence of different concentrations of p-thiocresol (0, 10, 20, 30, 40, 50, 100, 200, 300, 400 mM) at 40 C. Data were acquired 30 min after addition of analytes. The excitation wavelength was 484 nm.
of BODIPY-SO, a decrease in the absorption band at 484 nm and a concomitant increase of a new band at 546 nm were observed, with a distinct isosbestic point at 512 nm. In good agreement with the findings in absorption, the sensor exhibited a ratiometric fluorescent response to p-thiocresol. As shown in Fig. 2, addition of p-thiocresol elicited a dramatic change in the emission spectrum. The intensity of the emission at 536 nm decreased gradually with the simultaneous appearance of a new red-shifted emission band at 568 nm. Notably, the ratio of emission intensities at 568 and 536 nm (I568/I536) upon excitation at 484 nm increases from 0.67 in the absence of benzenethiols to 19.03 after complete conversion to BODIPY-S, showing a 28-fold ratiometric enhancement, indicative of an efficient ratiometric response of BODIPY-SO to p-thiocresol. A good linear calibration curve (R ¼ 0.99) of the emission response in the benzenethiols concentration range of 0e300 mM could be obtained (Fig. 3), indicating that BODIPY-SO would potentially be employed to quantitatively detect p-thiocresol concentrations. The detection limit of BODIPY-SO toward p-thiocresol is evaluated to be 2.1 107 M, which is comparable or superior to most of the reported benzenethiol sensors. The sensory response of BODIPY-SO to other benzenethiols such as thiophenol, 4-chlorobenzenethiol and 4-bromobenzenethiol was also studied. Predictably these benzenethiols induced a significant enhancement of the fluorescence ratio as p-thiocresol did,
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observed upon addition of the representative amino acids, sugar, vitamins, aromatic alcohols and amines. Although aliphatic thiols are known to be able to reduce suilfoxide, the aliphatic thiols are about 103e104 times less reactive than aromatic thiols and the reaction process must proceed at elevated temperature. As expected, under the same experimental condition (in pH 7.2 sodium phosphate buffer/EtOH at 40 C), aliphatic thiols did not undergo any appreciable reaction in the assay time period of 30 min. Even extending the reaction time to 10 h, no appreciable reaction occurred. Only addition of benzenethiols induced a significant enhancement of the fluorescence ratio. Moreover, no obvious interference was observed in the fluorescence spectra, while titrating the different mixtures of competing analytes and BODIPYSO with benzenethiols. These results indicate the excellent selectivity of BODIPY-SO toward the benzenethiols over the other competitive species. 4. Conclusions Fig. 3. Calibration curve of the emission response as a function of p-thiocresol concentration. The standard deviation was obtained by fluorescence responses to be s ¼ 2.22 103, therefore the detection limit was calculated by the formula (3s/k) and gave a result as 2.1 107 M.
indicative of an efficient ratiometric response of BODIPY-SO to benzenethiols. Having determined the sensory process of BODIPY-SO to benzenethiols, we felt it desirable to gain insight into the sensing mechanism. Thus the reaction product of BODIPY-SO þ benzenethiols (100 equiv) was isolated by a silica gel column and was then subjected to standard characterization. Comparison of the 1H NMR (Figure S4), Mass (Figure S5), absorption and emission spectra of isolated compound with BODIPY-S indicates that, indeed, BODIPY-SO was converted to BODIPY-S by thiol - sulfoxide conversion consistent with the general mechanism of thiol oxidation by DMSO determined by Wallace and Mahon [13cee]. BODIPY-SO is also highly selective for benzenethiols over other competing analytes in a buffer solution (Fig. 4). No obvious changes of the ratiometric emission ratio of BODIPY-S to BODIPY-SO were
In summary, we have designed and synthesized sulfur substituted BODIPY fluorophores, BODIPY-S, and the derivative BODIPY-SO. BODIPY-S shows the general photophysical behavior of other BODIPY chromophores with a relatively small Stokes shift and a high fluorescence quantum yield. Conversion of BODIPI-S to BODIPY-SO causes a large hypsochromic shift in absorption and emission. This blue shift in emission is accompanied by a decrease in FF. Based on the fact that the interconversion of BODIPY-S to BODIPY-SO induces a dramatic shift in emission, we applied BODIPY-SO as a ratiometric fluorescent chemodosimeter for benzenethiols. As expected, the probe exhibited a large red shift in absorption and a drastic ratiometric fluorescent response to benezenethiols with the emission intensity ratio (I568/I536) increasing from 0.67 to 19.03. In addition, the probe features excellent selectivity over other competing analytes, moderate signal response times and a good linearity range for quantification. We anticipated all these features render the sensor suitable for detection of benzenethiols in environmental settings. Acknowledgments We gratefully acknowledge the financial support by the National Science Foundation of China (grant no.: 20902021, 21172071, 21190033), the Scientific Research Foundation for the Returned Overseas Chinese Scholars (State Education Ministry) and the Fundamental Research Funds for the Central Universities. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.dyepig.2012.08.026. References
Fig. 4. Fluorescence ratiometric response of BODIPY-SO to 50 equiv of various species (left part from 0 to 7 reprents BODIPY-SO only, p-thiocresol, PhNH2, PhCH2SH, vitamin C, PhOH, CH3(CH2)11SH, and glycine, respectively) and response to 50 equiv of p-thiocresol in the presence of 50 equiv of other analytes (right part from 8 to 14 represents p-thiocresol, PhNH2, PhCH2SH, vitamin C, PhOH, CH3(CH2)11SH, and glycine, respectively). Bars represent emission intensity ratios I568/I536 at 30 min after addition of analytes. Data were acquired at 40 C in 25 mM sodium phosphate buffer (50% ethanol as co-solvent), pH 7.2, with lex ¼ 484 nm.
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(b) Li L, Han J, Nguyen B, Burgess K. Syntheses and spectral properties of functionalized, water-soluble BODIPY derivatives. J Org Chem 2008;73: 1963e70; (c) Yogo T, Urano Y, Ishitsuka Y, Maniwa F, Nagano T. Highly efficient and photostable photosensitizer based on BODIPY chromophore. J Am Chem Soc 2005;127:12162e3. (a) Dodani SC, Leary SC, Cobine PA, Winge DR, Chang CJ. A targetable fluorescent sensor reveals that copper-deficient SCO1 and SCO2 patient cells prioritize mitochondrial copper homeostasis. J Am Chem Soc 2011;133: 8606e16; (b) Domaille DW, Zeng L, Chang CJ. Visualizing ascorbate-triggered release of labile copper within living cells using a ratiometric fluorescent sensor. J Am Chem Soc 2010;132:1194e5; (c) Baruah M, Qin W, Vallée RAL, Beljonne D, Rohand T, Dehaen W, et al. A highly potassium-selective ratiometric fluorescent indicator based on BODIPY Azacrown ether excitable with visible light. Org Lett 2005;7:4377e80. (a) Dane EL, King SB, Swager TM. Conjugated polymers that respond to oxidation with increased emission. J Am Chem Soc 2010;132:7758e68; (b) Malashikhin S, Finney NS. Fluorescent signaling based on sulfoxide profluorophores: application to the visual detection of the explosive TATP. J Am Chem Soc 2008;130:12846e7; (c) Wang XJ, Xing LB, Wang F, Wang GX, Chen B, Tung CH, et al. multistimuli responsive micelles formed by a Tetrathiafulvalene-functionalized amphiphile. Langmuir 2011;27:8665e71; (d) Zhao YP, Wu LZ, Si G, Liu Y, Xue H, Zhang LP, et al. Synthesis, spectroscopic, electrochemical and Pb2þ-binding studies of Tetrathiafulvalene acetylene derivatives. J Org Chem 2007;72:3632e9. (a) Tam JP, Wu CR, Liu W, Zhang JW. Disulfide bond formation in peptides by dimethyl sulfoxide. Scope and applications. J Am Chem Soc 1991;113: 6657e62; (b) Fernández I, Khiar N. Recent developments in the synthesis and utilization of chiral sulfoxides. Chem Rev 2003;103:3651e706; (c) Carreno MC. Applications of sulfoxides to asymmetric synthesis of biologically active compounds. Chem Rev 1995;95:1717e60. (a) Epstein WW, Sweat FW. Dimethyl sulfoxide oxidations. Chem Rev 1967; 67:247e60; (b) Hsu FL, Szafraniec LL, Beaudry WT, Yang YC. Oxidation of 2-chloroethyl sulfides to sulfoxides by dimethyl sulfoxide. J Org Chem 1990;55:4153e5; (c) Wallace TJ. Reactions of thiols with sulfoxides. I. Scope of the reaction and synthetic applications. J Am Chem Soc 1964;86:2018e21; (d) Wallace TJ, Mahon JJ. Reactions of thiols with sulfoxides. II. Kinetics and mechanistic implications. J Am Chem Soc 1964;86:4099e103; (e) Wallace TJ, Mahon JJ. Reactions of thiols with sulfoxides. III. Catalysis by acids and bases. J Org Chem 1965;30:1502e6. (a) Jiang W, Fu Q, Fan H, Ho J, Wang W. A highly selective fluorescent probe for thiophenols. Angew Chem Int Ed 2007;46:8445e8; (b) Jiang W, Cao Y, Liu Y, Wang W. Rational design of a highly selective and sensitive fluorescent PET probe for discrimination of thiophenols and aliphatic thiols. Chem Commun 2010;46:1944e6; (c) Lin W, Long L, Tan W. A highly sensitive fluorescent probe for detection of benzenethiols in environmental samples and living cells. Chem Commun 2010;46:1503e5; (d) Zhao C, Zhou Y, Lin Q, Zhu L, Feng P, Zhang Y, et al. Development of an Indole-based boron-dipyrromethene fluorescent probe for benzenethiols. J Phys Chem B 2011;115:642e7. (a) Qin W, Baruah M, Van der Auweraer M, De Schryver FC, Boens N. Photophysical properties of borondipyrromethene analogueues in solution. J Phys Chem A 2005;109:7371e84; (b) Kollmannsberger M, Rurack K, Resch-Genger U, Daub J. Ultrafast charge transfer in amino-substituted boron dipyrromethene dyes and its inhibition by cation complexation: A new design concept for highly sensitive fluorescent probes. J Phys Chem A 1998;102:10211e20; (c) Filarowski A, Kluba M, Cieslik-Boczula K, Koll A, Kochel A, Pandey L, et al. Generalized solvent scales as a tool for investigating solventdependence of spectroscopic and kinetic parameters. Application to fluorescent BODIPY dyes. Photochem Photobiol Sci 2010;9:996e1008. (a) Cubbage Jerry W, Jenks William S. Computational studies of the ground and excited state potentials of DMSO and H2SO: relevance to photostereomutation. J Phys Chem A 2001;105:10588e95; (b) Lee W, Jencks WS. Photophysics and photostereomutation of aryl methyl sulfoxides. J Org Chem 2001;66:474e80; (c) Vos BW, Jencks WS. Evidence for a nonradical pathway in the photoracemization of aryl sulfoxides. J Am Chem Soc 2002;124:2544e7.
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Dyes and Pigments journal homepage: www.elsevier.com/locate/dyepig
BODIPY-based sulfoxide: Synthesis, photophysical characterization and response to benzenethiols Chunchang Zhao a, *, Xuzhe Wang a, Jian Cao a, Peng Feng a, Jinxin Zhang a, Yanfen Zhang a, Yang Yang a, Zhenjun Yang b, * a b
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science & Technology, Shanghai 200237, PR China National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 June 2012 Received in revised form 27 August 2012 Accepted 29 August 2012 Available online 13 September 2012
Two BODIPY dyes bearing a sulfur containing function at the 3-position are reported. The 3-benzylthio compound shows spectroscopic features of the classical BODIPY platform, showing minor solvent dependent spectral shift, a relative small Stokes shift and a high fluorescence quantum yield. Oxidation of the sulfur atom to the sulfoxide leads to a large hypsochromic shift in absorption and emission. We also demonstrated that the sulfoxide derivative can be used as a ratiometric fluorescent chemodosimeter for highly toxic benzenethiols in aqueous media. In this dosimeter the sulfoxide is chemospecifically reduced by benzenethiols to obtain the original oxidation state of the sulfur atom, accompanied with a drastic ratiometric fluorescence response. Furthermore, the probe features excellent selectivity over other competing analytes, moderate signal response times and a good linearity range for quantification. All these features render the sensor suitable for detection of benzenethiols in environmental settings. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: BODIPY-based sulfoxide Benzenethiols Ratiometric fluorescence response Chemodosimeter Chemospecific reduction Hypsochromic shifts
1. Introduction BODIPYs (boron-dipyrromethene dyes) are of special interest as chromophores due to their valuable photophysical characteristics [1]. Furthermore, the parent structure of BODIPY is easy to modify chemically for the preparation of various derivatives. The most commonly studied synthetic strategies available for the modification of the BODIPY core are: (1) nucleophilic substitutions of halogen atoms at the 3- and 5-positions [2,3], (2) condensation reactions [4], (3) substitution of the fluorine atoms by C or O atoms [5e7], (4) transition-metal-catalyzed reactions through the use of halogenated BODIPYs [8], and (5) electrophilic substitutions at the 2- and 6-positions [9]. In particular, the facile introduction of different groups at the 3- and 5-positions by nucleophilic substitution of chlorine atoms could be used for fast and easy variation of the BODIPY core to optimize the spectroscopic properties. This approach has caught the attention of several research groups [10], and several BODIPYs, containing sulfur atoms at the
* Corresponding authors. E-mail addresses: [email protected] (C. Zhao), [email protected] (Z. Yang). 0143-7208/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dyepig.2012.08.026
3-and 5-positions, have now been constructed to form thioether compounds [2aec]. Although the sulfur substituted BODIPYs are known, the related fascinating compounds, aromatic sulfoxides, have not been investigated well, so far. Therefore, we initiated the investigation of new BODIPY dyes containing sulfoxide and the BODIPY derivative BODIPY-SO (Scheme 1) was selected for initial evaluation on the basis of ease of synthetic access. In organic compounds, sulfur can have a formal oxidation state ranging from 2 to þ6 [11]. Previously studied BODIPYs are thioethers with oxidation state of 2, while the oxidation state of a sulfoxide is 0. The change in oxidation state would have sufficient effect on the photophysical properties. The electronwithdrawing nature of the oxidized thioether, sulfoxide, would lead to hypsochromic shifts in absorption and emission wavelength compared to that of the thioether. On the basis of this finding, we reasoned that the sulfoxide-sulfide interconversion could be used to construct a reaction-based probe and chemodosimeter. Explorations of sulfoxides in synthesis hold great interest from both laboratory and biological perspectives [12]. Of special interest is the thiol-sulfoxide reactions previously investigated in detail [13]. Theoretically, an interaction between the two species should yield a sulfide, disulfide and water. It is also well known that thiol acidity is of major importance as far as the ease of oxidation is concerned.
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solutions were diluted with aqueous solutions to the desired concentration. 2.2. Synthesis
Scheme 1. Synthesis of BODIPY-SO and the conversion to BODIPY-S by benzenethiols.
The observed ease of thiol oxidation is ArSH > ArCH2SH >> RSH, and aromatic thiols are about 103e104 times more reactive than aliphatic thiols [13d]. Based on this background, a ratiometric fluorescent probe for benzenethiols, BODIPY-based sulfoxide BODIPY-SO, could be designed (Scheme 1). BODIPY-S and its analog BODIPY-SO are fluorescent chromorphores with charateristics of BODIPYs. Sulfoxide BODIPY-SO undergoes a change in the electronwithdrawing nature of the S-group and should show a significant change in photophyscial properties, such as a significant shift in emission wavelength. Thus a fluorescent ratiometric chemodosimeter could be obtained. Several fluorescent sensors that selectively respond to the presence of benzenethiols have been reported [14], most of which respond to benzenethiols with only fluorescence signal turned-on. Unfortunately, single-intensitybased sensing is compromised by the local distribution of probes, drift of light sources and detectors. New ratiometric fluorescent probes that can overcome the limitation of intensity-based probes and provide quantitative measurement are therefore in demand. To our best knowledge, few ratiometric fluorescent probes for benzenethiols have been constructed to date. Herein, we report the synthesis and photophysical properties of a new BODIPY dye, BODIPY-SO, and its potential application as a ratiometric fluorescent chemodosimeter for benzenethiols.
Synthesis of 3-Benzylsulfanyl-5,7-dimethyl-6-ethyl-8phenyl-4,4-difluoro- 4-bora- 3a,4a-diaza-s-indacene (BODIPYS). To a solution of 3-chloro-5,7-dimethyl-6-ethyl-8-phenyl-BODIPY (0.716 g, 2 mmol) in CH3CN (30 mL) was added a-toluenethiol (0.298 g, 2.4 mmol) and Et3N (5 mL), and the reaction mixture was stirred for 3 h at room temperature. Excess CH3CN was removed under vacuum, and the residue was dissolved in ethyl acetate, washed with H2O and dried over Na2SO4. The crude product was purified by flash chromatography (silica gel, eluent: CH2Cl2/ EtOAc ¼ 40:1) to afford BODIPY-S (0.713 g, 80%). mp 169e173 C; FTIR (BODIPY-S) 2963, 1542, 1380, 1189, 1141, 964, 728 cm1; 1H NMR (400 MHz, CDCl3) d 7.43e7.50 (m, 5H), 7.27e7.34 (m, 5H), 6.29 (d, J ¼ 4 Hz, 1H), 6.22 (d, J ¼ 4 Hz, 1H), 4.29 (S, 2H), 2.62 (S, 3H), 2.36 (q, J ¼ 7.6 Hz, 2H), 1.43 (S, 3H), 1.03 (t, J ¼ 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 159.5, 150.2, 140.1, 139.0, 136.2, 136.0, 135.1, 134.4, 132.4, 129.5, 129.4, 129.1, 128.9, 128.8, 128.6, 128.3, 127.5, 127.1, 116.2, 38.0, 17.1, 14.3, 13.0, 12.1; HRMS (ESI) calcd for C26H24N2BF2S [M H]: 445.1721. Found: 445.1760. Synthesis of 3-Benzylsulfinyl-5,7-dimethyl-6-ethyl-8phenyl-4,4-difluoro- 4-bora- 3a,4a-diaza-s-indacene (BODIPYSO). To a solution of BODIPY-S (0.446 g, 1 mmol) in dry dichloromethane (20 mL) was added 0.99 equivalents of m-CPBA (0.17 g, 0.99 mmol) at 0 C. The reaction mixture was stirred for 30 min. Excess potassium carbonate was added to neutralize any acids, and washed with water. The organic layers were dried over anhydrous Na2SO4, and evaporated in vacuo. The crude product was further purified by flash chromatography (silica gel, eluent: CH2Cl2/ EtOAc ¼ 50:1) to afford BODIPY-SO (0.32 g, 70%). mp 180e183 C; FTIR (BODIPY-SO) 1578, 1141, 1071, 1056 (S]O), 731 cm1; 1H NMR (400 MHz, CDCl3) d7.51e7.53 (m, 3H), 7.28e7.40 (m, 7H), 6.56 (d, J ¼ 4 Hz, 1H), 6.26 (d, J ¼ 4 Hz, 1H), 4.51 (d, J ¼ 12.8 Hz, 1H), 4.22 (d, J ¼ 12.8 Hz, 1H), 2.70 (S, 3H), 2.40 (q, J ¼ 7.6 Hz, 2H), 1.51 (S, 3H), 1.07 (t, J ¼ 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.2, 150.4, 143.6, 141.6, 137.7, 136.9, 134.7, 133.5, 130.6, 130.5, 129.6, 128.8, 128.7, 128.6, 128.3, 128.1, 124.1, 115.5, 62.4, 17.2, 14.0, 13.6, 12.5; HRMS (ESI) calcd for C26H24N2BF2S [M H]: 461.1670. Found: 461.1616. 3. Results and discussion
2. Experimental section
3.1. Synthesis of BODIPY-S and BODIPY-SO
2.1. General methods and instruments
BODIPY-SO was readily synthesized in two steps beginning with the key intermediate 1. The overall yield is 56% for two steps. Intermediate 1 was obtained in a one-pot, two-step procedure via condensation of 2,4-dimethyl-3-ethylpyrrole with 2-benzoyl-5chloropyrrole followed by treatment with BF3$OEt2 (Scheme 1) [3b]. a-toluenethiol was then introduced into the BODIPY core to get BODIPY-S by a nucleophilic aromatic substitution reaction. The structures of BODIPY-S and BODIPY-SO were fully characterized by 1 H NMR, 13C NMR, and HRMS analysis.
All chemicals were purchased from commercial suppliers and used without further purification unless otherwise specified. Anhydrous CH2Cl2 was dried and distillated immediately prior to use. 3-chloro-5,7-dimethyl-6-ethyl-8-phenyl-BODIPY [3b] was prepared according to literature procedures. 1 H NMR and 13C NMR spectra were recorded on a spectrometer operating at 400 MHz and 100 MHz, respectively. Deuterated chloroform was used as the solvent, TMS as internal standard. Mass spectra were measured on an HP 1100 LCeMS spectrometer. UVe vis spectra were measured using a Shimadzu UV-2550 spectrophotometer. Fluorescence spectroscopic measurements were conducted on a Varian Cary eclipse fluorescence spectrophotometer. TLC analysis was performed on silica gel plates and column chromatography was conducted over silica gel (mesh 200e300), both of which were obtained from the Qingdao Ocean Chemicals. For absorption or fluorescence measurements, compounds were dissolved in EtOH to obtain stock solutions (2e5 mM). These stock
3.2. Photophysical properties of BODIPY-S and BODIPY-SO Spectroscopic evaluation of BODIPY-S and BODIPY-SO was performed in several solvents of varying polarity (Figure S1, Figure S2, Table S1 in supporting information). The optical features are characteristic of the classical BODIPY platform. As is evident from Figure S1, S2 and Table S1, BODIPY-S shows a narrow, strong absorption band around 545 nm and a shoulder at the short wavelength side in pure solvents. The S0eS1 absorption band shows
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minor solvent-dependent variation, with the maximum being slightly shifted hypsochromically (w7 nm) when the solvent is changed from benzene (550 nm) to acetonitrile (543 nm), which is consistent with the general behavior of other BODIPY chromophores [15]. Similar to the absorption spectrum, the emission spectrum also shows minor solvent-dependent shift with a relative small Stokes shift (w15 nm) and a high fluorescence quantum yield (0.2e0.4). Oxidation of BODIPY-S to the sulfoxide (BODIPY-SO) causes a large hypsochromic shift in absorption and emission relative to the parent compound. This blue shift in emission is accompanied by a decrease in FF, which is consistent with the general behavior of other aromatic sulfur-containing compounds [11b] [16]. The emission maximum shifts from 561 nm for the unoxidized version to 537 nm for the sulfoxide (BODIPY-SO) in EtOH. The broad shape of the S0eS1 transition together with the hypsochromic shifts may be attributed to intramolecular charge transfer character resulting from the strong conjugation of the sulfoxide function with the BODIPY core. All these characteristics demonstrate that changing the oxidation state of the sulfur atom leads to productive changes in the photophyscial properties. Ultimately, the fact that the interconversion of BODIPY-S to BODIPY-SO induces a dramatic shift in emission provides an opportunity for construction of ratiometric chemodosimeters. As sulfoxide reduction by aromatic thiols could yield the corresponding sulfide effectively, the thiol-sulfoxide reactions were therefore chosen to prove the above concept and quantify the toxic benzenethiols. 3.3. Thiol-sulfoxide reaction based response of BODIPY-SO to benzenethiols At first, the time course of the reaction between BODIPY-SO and p-thiocresol was studied by monitoring the variations in the ratios of fluorescence intensities of the reaction mixture at 568 and 536 nm (I568/I536) (Fig. 1). Under pseudo-first-order reaction conditions (10 mM BODIPY-SO and 1 mM p-thiocresol), an observed rate constant (kobs) at pH 7.2 and 40 C is found to be 1.7 min1, indicating that BODIPY-SO reacted rapidly with p-thiocresol under the given experimental conditions. Fig. 2 shows the sensory response of BODIPY-SO to various concentrations of p-thiocresol in buffer solutions at 40 C. Upon addition of increasing concentrations of p-thiocresol to a solution
Fig. 1. Time-course kinetic measurement of the fluorescence response of BODIPY-SO (10 mM) to p-thiocresol (1 mM, 25 mM sodium phosphate buffer, 50% EtOH as co-solvent, pH 7.2) at 40 C. The measurements are taken at 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 11, 16, 26, 36 min lex ¼ 484 nm.
Fig. 2. (a) Absorption and (b) Emission spectra for BODIPY-SO (10 mM) in buffer solution (pH 7.2, 25 mM sodium phosphate buffer, 50% EtOH as co-solvent) in the presence of different concentrations of p-thiocresol (0, 10, 20, 30, 40, 50, 100, 200, 300, 400 mM) at 40 C. Data were acquired 30 min after addition of analytes. The excitation wavelength was 484 nm.
of BODIPY-SO, a decrease in the absorption band at 484 nm and a concomitant increase of a new band at 546 nm were observed, with a distinct isosbestic point at 512 nm. In good agreement with the findings in absorption, the sensor exhibited a ratiometric fluorescent response to p-thiocresol. As shown in Fig. 2, addition of p-thiocresol elicited a dramatic change in the emission spectrum. The intensity of the emission at 536 nm decreased gradually with the simultaneous appearance of a new red-shifted emission band at 568 nm. Notably, the ratio of emission intensities at 568 and 536 nm (I568/I536) upon excitation at 484 nm increases from 0.67 in the absence of benzenethiols to 19.03 after complete conversion to BODIPY-S, showing a 28-fold ratiometric enhancement, indicative of an efficient ratiometric response of BODIPY-SO to p-thiocresol. A good linear calibration curve (R ¼ 0.99) of the emission response in the benzenethiols concentration range of 0e300 mM could be obtained (Fig. 3), indicating that BODIPY-SO would potentially be employed to quantitatively detect p-thiocresol concentrations. The detection limit of BODIPY-SO toward p-thiocresol is evaluated to be 2.1 107 M, which is comparable or superior to most of the reported benzenethiol sensors. The sensory response of BODIPY-SO to other benzenethiols such as thiophenol, 4-chlorobenzenethiol and 4-bromobenzenethiol was also studied. Predictably these benzenethiols induced a significant enhancement of the fluorescence ratio as p-thiocresol did,
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observed upon addition of the representative amino acids, sugar, vitamins, aromatic alcohols and amines. Although aliphatic thiols are known to be able to reduce suilfoxide, the aliphatic thiols are about 103e104 times less reactive than aromatic thiols and the reaction process must proceed at elevated temperature. As expected, under the same experimental condition (in pH 7.2 sodium phosphate buffer/EtOH at 40 C), aliphatic thiols did not undergo any appreciable reaction in the assay time period of 30 min. Even extending the reaction time to 10 h, no appreciable reaction occurred. Only addition of benzenethiols induced a significant enhancement of the fluorescence ratio. Moreover, no obvious interference was observed in the fluorescence spectra, while titrating the different mixtures of competing analytes and BODIPYSO with benzenethiols. These results indicate the excellent selectivity of BODIPY-SO toward the benzenethiols over the other competitive species. 4. Conclusions Fig. 3. Calibration curve of the emission response as a function of p-thiocresol concentration. The standard deviation was obtained by fluorescence responses to be s ¼ 2.22 103, therefore the detection limit was calculated by the formula (3s/k) and gave a result as 2.1 107 M.
indicative of an efficient ratiometric response of BODIPY-SO to benzenethiols. Having determined the sensory process of BODIPY-SO to benzenethiols, we felt it desirable to gain insight into the sensing mechanism. Thus the reaction product of BODIPY-SO þ benzenethiols (100 equiv) was isolated by a silica gel column and was then subjected to standard characterization. Comparison of the 1H NMR (Figure S4), Mass (Figure S5), absorption and emission spectra of isolated compound with BODIPY-S indicates that, indeed, BODIPY-SO was converted to BODIPY-S by thiol - sulfoxide conversion consistent with the general mechanism of thiol oxidation by DMSO determined by Wallace and Mahon [13cee]. BODIPY-SO is also highly selective for benzenethiols over other competing analytes in a buffer solution (Fig. 4). No obvious changes of the ratiometric emission ratio of BODIPY-S to BODIPY-SO were
In summary, we have designed and synthesized sulfur substituted BODIPY fluorophores, BODIPY-S, and the derivative BODIPY-SO. BODIPY-S shows the general photophysical behavior of other BODIPY chromophores with a relatively small Stokes shift and a high fluorescence quantum yield. Conversion of BODIPI-S to BODIPY-SO causes a large hypsochromic shift in absorption and emission. This blue shift in emission is accompanied by a decrease in FF. Based on the fact that the interconversion of BODIPY-S to BODIPY-SO induces a dramatic shift in emission, we applied BODIPY-SO as a ratiometric fluorescent chemodosimeter for benzenethiols. As expected, the probe exhibited a large red shift in absorption and a drastic ratiometric fluorescent response to benezenethiols with the emission intensity ratio (I568/I536) increasing from 0.67 to 19.03. In addition, the probe features excellent selectivity over other competing analytes, moderate signal response times and a good linearity range for quantification. We anticipated all these features render the sensor suitable for detection of benzenethiols in environmental settings. Acknowledgments We gratefully acknowledge the financial support by the National Science Foundation of China (grant no.: 20902021, 21172071, 21190033), the Scientific Research Foundation for the Returned Overseas Chinese Scholars (State Education Ministry) and the Fundamental Research Funds for the Central Universities. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.dyepig.2012.08.026. References
Fig. 4. Fluorescence ratiometric response of BODIPY-SO to 50 equiv of various species (left part from 0 to 7 reprents BODIPY-SO only, p-thiocresol, PhNH2, PhCH2SH, vitamin C, PhOH, CH3(CH2)11SH, and glycine, respectively) and response to 50 equiv of p-thiocresol in the presence of 50 equiv of other analytes (right part from 8 to 14 represents p-thiocresol, PhNH2, PhCH2SH, vitamin C, PhOH, CH3(CH2)11SH, and glycine, respectively). Bars represent emission intensity ratios I568/I536 at 30 min after addition of analytes. Data were acquired at 40 C in 25 mM sodium phosphate buffer (50% ethanol as co-solvent), pH 7.2, with lex ¼ 484 nm.
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