- Email: [email protected]
aza-BODIPYs
Accepted Manuscript Synthesis and application of methylthio-substituted BODIPYs/aza-BODIPYs Xin-Dong Jiang, Xin Liu, Tao Fang, Changliang Sun PII:
S0143-7208(17)31105-1
DOI:
10.1016/j.dyepig.2017.07.038
Reference:
DYPI 6127
To appear in:
Dyes and Pigments
Received Date: 15 May 2017 Revised Date:
30 June 2017
Accepted Date: 16 July 2017
Please cite this article as: Jiang X-D, Liu X, Fang T, Sun C, Synthesis and application of methylthiosubstituted BODIPYs/aza-BODIPYs, Dyes and Pigments (2017), doi: 10.1016/j.dyepig.2017.07.038. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Synthesis and application of methylthio-substituted BODIPYs/aza-BODIPYs Xin-Dong Jiang, a,b* Xin Liu,a Tao Fanga and Changliang Sunc a
M AN U
SC
RI PT
College of Applied Chemistry, Shenyang University of Chemical Technology, Shenyang, 110142, China. E-mail: [email protected]; Tel: +86 024 89387219. b State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China. c Center of Physical and Chemistry Test, Shenyang University of Chemical Technology, Shenyang 110142, China Corresponding author: Tel: +86 024 89387219. Fax: +86 024 89388211 E-mail: [email protected]
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Abstract: A series of new BODIPYs/aza-BODIPYs with a methylthio group were Herein prepared. Introduction of the electron-donating methylthio substituent into such dyes could reduce the fluoresecence quantum yield, red-shift its emission spectra,
EP
provide higher extinction coefficients and larger Stokes’ shift. Oxidation of the thioether of BODIPY 4 into the corresponding electron-withdrawing sulfoxide by
AC C
HClO can restore the quantum yield and blue-shift its emission spectra, and dye 4 was highly sensitive and selective to HClO. Keywords: Aza-BODIPY • NIR • Fluorescent dye • Methylthio • Oxidation
1. Introduction
Borondipyrromethenes
(BODIPYs)
and
aza-borondipyrromethenes
(aza-BODIPYs) in the family of dyes, are well-known to be highly fluorescent, stable, and have tunable emission wavelengths, and therefore such dyes have been attracting increasing interest [1]. Such dyes and their derivatives
ACCEPTED MANUSCRIPT widespreadly acted as good candidates for biological labeling applications and fluorescent materials and so forth [2]. To enrich the functionalization of BODIPY/aza-BODIPY dyes, the structure innovation and modification are the key content. So, many groups devote their attention to design and synthesize
To
date,
some
reviews
almost
showed
all
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the new structures of BODIPYs/aza-BODIPYs [3]. the
structures
of
BODIPYs/aza-BODIPYs [2,4]. However, methylthio-substituted BODIPYs were found to be so rare (Figure 1) [5], and no aza-BODIPY with a methylthio group
SC
was recorded. Inspired by the aforementioned reports, it urges us to explore to design the platform of BODIPYs/aza-BODIPYs bearing a –SMe group. In
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comparision with the introduction of a –SMe group into BODIPY [5], the creation of a methylthio-substituted pyrrole as a modular unit is of great importance. Our group has been working on pyrroles [6]. Therefore, the new pyrrole bearing a –SMe group was herein prepared and applied to synthesize a series of new BODIPYs/aza-BODIPYs 2-6. Moreover, a near-infrared (NIR)
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BODIPY 4 as a probe was highly sensitive and selective to HClO.
AC C
General:
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2. Experimental methods
1-(4-(Methylthio)phenyl)ethanone (98%) were purchased from Energy Chemical & Technology (Shanghai) Co. Ltd. All other chemicals and solvents used in this work were of analytical grade, purchased from Energy Chemical & Technology (Shanghai) Co. Ltd and used without further purification. 1H NMR spectra were recorded on a VARIAN Mercury 500 MHz spectrometer. 1H NMR chemical shifts (δ) are given in ppm downfield from Me4Si, determined by residual chloroform (δ = 7.26 ppm).
13
C NMR spectra were recorded on a VARIAN Mercury 125 MHz
spectrometer in CDCl3, all signals are reported in ppm with the internal chloroform
ACCEPTED MANUSCRIPT signal at δ 77.0 ppm as standard. Fluorescence spectra were recorded on an F-4600 spectrophotometer and are reported as cm−1. UV/Vis spectra were recorded on a UV-2550 spectrophotometer at room temperature. All pH measurements were performed with a PHS-3E pH meter. The refractive index of
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the medium was measured by 2 W Abbe’s refractometer at 20 °C.
The fluorescence quantum yields (Φf) of the BODIPY/aza-BODIPY systems were calculated using the following relationship (equation 1): Φf = Φref Fsampl Aref n2sampl/Fref Asampl n2ref
SC
(1)
Here, F denotes the integral of the corrected fluorescence spectrum, A is the
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absorbance at the excitation wavelength, and n is the refractive index of the medium, ref and sampl denote parameters from the reference and unknown experimental samples, respectively.
The reference systems used were Nile blue as standard [Φf = 0.27, λex = 625 nm, 0.5% (v/v) 0.1 M HCl in ethanol] [7] for 4-6, and aza-BODIPY 8 as
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standard (Φf = 0.36 in chloroform, λabs = 688 nm) [8] for 2 and 3. The MO calculations were performed at the DFT level, and the frontier molecular
orbitals
of
aza-PODIPY
2
and
aza-BODIPY
8
at
the
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B3LYP/6-31G(d) level with Gaussian 09 [9].
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Preparation of ROS and RNS Various ROS and RNS were prepared according to published methods [10]. Various ROS and RNS including ClO−, · OH, H2O2, 1O2, NO2−, NO, ONOO−, O2−, and tBuOOH were prepared according to the following methods. NaClO obtained commercially from Energy Chemical & Technology (Shanghai) Co. Ltd.
The hydroxyl radical (· OH) was generated by Fenton reaction on mixing Fe(NH4)2(SO4)2·6H2O with 10 equivalents of H2O2; the concentration of · OH was
estimated from the concentration of Fe2+. The concentration of the commercially available stock H2O2 solution was estimated by optical absorbance
ACCEPTED MANUSCRIPT at 240 nm. Singlet oxygen (1O2) was generated by the addition of NaOCl and H2O2 according to the literature [11]. The sources of NO2− were NaNO2. Nitric oxide (NO) was generated from sodium nitroferricyanide(III) dihydrate. Peroxynitrite (ONOO−) was prepared according to the reported method [12]; the concentration of
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peroxynitrite was estimated by using an extinction coefficient of 1670 M−1 cm−1 (302 nm). Superoxide (O2−) was prepared from KO2. tBuOOH was obtained commercially from Energy Chemical & Technology (Shanghai) Co. Ltd.
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Preparation of metal ion titration solutions
Stock solutions (4 × 10−4 M) of the salts of NaCl, HgCl2, MgCl2, AgNO3, CrCl3,
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FeCl3, NiCl2 and CdCl2 in MeCN/PBS (1 : 9, v/v; pH = 7.4) were prepared. BODIPY 4 (1 × 10−4 M) was also prepared in MeCN/PBS (1 : 9, v/v; pH = 7.4). Test solutions were prepared by placing 40 µL of the sensor stock solution into a test tube, then adding an appropriate aliquot of each metal stock (0−1.0 mL),
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and diluting the solution to 4 mL with MeCN/PBS (1 : 9, v/v; pH = 7.4). Synthesis of pyrrole 1
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Under N2, 1-(4-(methylthio)phenyl)ethanone (200.0 mg, 1.2 mmol) was added to NaH (115.4 mg, 4.79 mmol) in DMSO (20 ml) at 20 °C and stirred for 10 min.
AC C
Then, 3-phenyl-2H-azirine (131.3 mg, 1.1 mmol) in THF (5 ml) was added and the resulting mixture was stirred for 2 h at the same temperature. It was quenched with water, neutralized with dilute HCl to a pH about 7. The mixture was extracted with CH2Cl2 (2 × 50 ml), and the organic layer was washed with brine (2 × 50 ml) and dried over anhydrous MgSO4. After removal of the solvents by evaporation, the resulting crude mixture was separated by column chromatography (n-hexane : CH2Cl2 = 1 : 3) to afford 1 as green solids (149.5 mg, 47%). M.p.: 176.5–177.3 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 8.41 (br s, 1H), 7.55 (d, 3J = 8.0 Hz, 2H), 7.43 (d, 3J = 8.0 Hz, 2H), 7.35
ACCEPTED MANUSCRIPT (t, 3J = 8.0 Hz, 2H), 7.29 (d, 3J = 8.0 Hz, 2H), 7.19 (t, 3J = 8.0 Hz, 1H), 7.13 (m, 1H), 6.78 (m, 1H), 2.51 (s, 3H). HRMS-MALDI (m/z): [M + H]+ calcd for C17H16NS: 266.09980; found: 266.09988.
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Synthesis of pyrrole-2-carbaldehyde 7 (Scheme S3) Under N2, POCl3 (0.18 ml, 1.9 mmol) was added dropwise to DMF (0.14 ml, 1.8 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 15 min. The ice bath was replaced to cool the mixture back to 0 °C, then 10
SC
ml of ClCH2CH2Cl was added to the mixture. A solution of pyrrole 1 (200 mg, 0.75 mmol) in 5 ml of ClCH2CH2Cl was added dropwise over 1 min at 0 °C.
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The reaction mixture was refluxed for 30 min and then cooled to room temperature. A solution of K2CO3 (0.5 g, 3.6 mmol) in 10 ml of water was added. The reaction mixture was again refluxed for 20 min. The organic layer was washed with brine (2 × 50 ml) and dried over anhydrous MgSO4. After removal of the solvents by evaporation, the resulting crude mixture was
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separated by column chromatography (n-hexane : CH2Cl2 = 1 : 2) to afford 7 as light green solids (138.4 mg, 63%). M.p.: 162.1–162.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 9.62 (s, 1H), 9.54 (br s, 1H), 7.56 (d, 3J = 8.0 Hz, 2H), 7.54 (d, 3J = 8.0 Hz, 2H), 7.46 (t, 3J = 8.0 Hz, 2H), 7.41 (d, 3J = 8.0 Hz,
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1H), 7.31 (d, 3J = 8.0 Hz, 2H), 6.70 (s, 1H), 2.53 (s, 3H). HRMS-MALDI (m/z):
AC C
[M + H]+ calcd for C18H16NSO: 294.09471; found: 294.09457. Synthesis of aza-BODIPY 2 Sodium nitrite (13 mg, 0.18 mmol) was added to a suspension of pyrrole 1 (100 mg, 0.37 mmol) in a mixture of acetic acid/anhydride (1 ml/0.4 ml) at 0 °C, and was stirred for 15 min. The color changed from colorless to brown, then green, and finally dark green was observed. After 0.5 h stirring at room temperature, the mixture was heated at 70 °C for 0.5 h. Crushed ice was added to the mixture, the resulted dark green dye was filtered, washed with
ACCEPTED MANUSCRIPT water. The dark green dye was dissolved in CH2Cl2, filtered through a pad of alumina (activity III). Solvent was removed under reduced pressure, and the residue was dissolved in dry 1,2-dichloroethane. Triethylamine (0.12 ml, 0.86 mmol) was added, followed by dropwise addition of BF3·Et2O (0.13 ml, 1.05
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mmol) with stirring at room temperature. The mixture was stirred for 0.5 h, then heated in 80 °C for 0.5 h. The reaction was quenched with crushed ice, extracted with CH2Cl2. The resulting crude mixture was separated by column chromatography on silica gel (n-hexane : CH2Cl2 = 1 : 2), and followed by
SC
recrystallization from CH2Cl2/n-hexane to afford 2 (48.7 mg, 46%) as coppery solids. M.p.: 275.6–276.5 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm)
M AN U
8.07 (d, 3J = 8.0 Hz, 4H), 8.01 (d, 3J = 8.0 Hz, 4H), 7.46 (t, 3J = 8.0 Hz, 4H), 7.42 (t, 3J = 8.0 Hz, 2H), 7.32 (d, 3J = 8.0 Hz, 4H), 7.06 (s, 2H), 2.54 (s, 6H). 13
C NMR (125 MHz, CDCl3): δ (ppm) 158.1, 145.6, 143.5, 143.4, 132.3, 129.8,
129.3, 129.2, 128.5, 127.6, 125.4, 118.8, 46.8. HRMS-MALDI (m/z): [M + H]+ calcd for C34H27BF2N3S2: 590.17020; found: 590.17041.
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Synthesis of aza-BODIPY 3 (Scheme S1) Sodium nitrite (31.4 mg, 0.45 mmol) was added to a suspension of
EP
2,4-diphenyl-1H-pyrrole (100 mg, 0.45 mmol) in acetic acid (1 ml) at 0 °C, and was stirred for 10 min. The color changed from colorless to brown, then green,
AC C
and finally brown was observed. The second pyrrole 1 (120.9 mg, 0.45 mmol) was added, followed by addition of acetic anhydride (0.4 ml). The mixture turned blue immediately. After 0.5 h stirring, the mixture was heated at 80 °C for 0.5 h. Crushed ice was added to the mixture, the resulted blue dye was filtered, washed with water. The blue dye was dissolved in CH2Cl2, filtered through a pad of alumina (activity III). Solvent was removed under reduced pressure, and the residue was dissolved in dry 1,2-dichloroethane. Triethylamine (0.28 ml, 2.0 mmol) was added, followed by dropwise addition of BF3·Et2O (0.50 ml, 4.0 mmol) with stirring at room temperature. The mixture was stirred for 0.5 h, then heated in 80 °C for 0.5 h. The reaction was
ACCEPTED MANUSCRIPT quenched with crushed ice, extracted with CH2Cl2, and purified by chromatography
on
silica
gel
followed
by
recrystallization
from
CH2Cl2/n-hexane to afford 3 (151.5 mg, 62%) as coppery solids. M.p.: 198.0–198.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 8.07 (d, 3J =
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8.0 Hz, 4H), 8.02 (d, 3J = 8.0 Hz, 4H), 7.42-750 (m, 9H), 7.32 (d, 3J = 8.0 Hz, 2H), 7.08 (s, 1H), 7.02 (s, 1H), 2.54 (s, 3H). HRMS-MALDI (m/z): [M+H]+ calcd for C33H25BF2N3S: 544.18248; found: 544.18213.
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Synthesis of BODIPY 4 (Scheme S2)
Under N2, pyrrole 1 (100 mg, 0.37 mmol) and 4-nitrobenzaldehyde (22.8 mg,
M AN U
0.15 mmol) was dissolved in CH2Cl2 (10 ml) and 2 drops of trifluoroacetic acid (TFA) were added. The reaction was allowed to proceed for 1 h at room temperature
and
directly
oxidized
with
a
solution
of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 85.6 mg, 0.37 mmol) in CH2Cl2 (20 ml) at room temperature. The reaction was allowed to proceed for
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4 h at room temperature. Et3N (0.14 ml, 1.0 mmol) was added to the solution, which was stirred for 30 min. BF3·Et2O (0.2 ml, 1.6 mmol) was added, and stirring was maintained for 1 h. The reaction mixture was washed with H2O (2
EP
× 50 ml), and the aqueous solution was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude
AC C
product was purified by silica gel column chromatography (CH2Cl2/n-hexane = 1:1) to afford 4 (32.9 mg, 31%) as coppery solids. M.p.: 296.0–296.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.87 (d, 3J = 8.0 Hz, 4H), 7.31 (d, 3J = 8.0 Hz, 4H), 7.28 (d, 3J = 8.0 Hz, 2H), 6.96 (d, 3J = 8.0 Hz, 2H), 6.92 (t, 3
J = 8.0 Hz, 2H), 6.84 (t, 3J = 8.0 Hz, 4H), 6.71 (d, 3J = 8.0 Hz, 4H), 6.56 (s, 2H),
2.53 (s, 6H). HRMS-MALDI (m/z): [M]+ calcd for C41H31BF2N3O2S2: 709.18351; found: 709.18359. Synthesis of BODIPY 5 (Scheme S4)
ACCEPTED MANUSCRIPT 2,4-Diphenyl-1H-pyrrole (82 mg, 0.37 mmol) and pyrrole-2-carbaldehyde 7 (108 mg, 0.37 mmol) was dissolved in 10 ml CH2Cl2, and POCl3 (0.45 ml, 0.47 mmol) was added dropwise at 0 ºC. The solution was warmed to room temperature slowly and stirred for 6 h. The mixture was cooled to 0 ºC. Et3N
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(0.28 ml, 2.0 mmol) was added dropwise. After stirring for 15 min, BF3·Et2O (0.5 ml, 4.0 mmol) was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 6 h. Water was added, and the mixture was stirred at room temperature overnight (to decompose excess
SC
BF3·Et2O and other impurities). The organic layer was washed with water, brine and dried over Na2SO4. The solvent was removed under reduced
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pressure and the residue was purified by column chromatography on silica gel (n-hexane : CH2Cl2 = 1 : 2), and followed by recrystallization from CH2Cl2/n-hexane to afford 5 (94.2 mg, 47%) as coppery solids. M.p.: 170.0–171.0 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.95 (d, 3J = 8.0 Hz, 2H), 7.91 (d, 3J = 8.0 Hz, 2H), 7.41-753 (m, 14H), 7.29 (d, 3J = 8.0 Hz,
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2H), 6.74 (s, 1H), 6.73 (s, 1H), 2.52 (s, 3H). HRMS-MALDI (m/z): [M]+ calcd for C34H25BF2N2S: 542.17941; found: 542.17969.
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Synthesis of BODIPY 6 (Scheme S5)
Under N2, Pyrrole 1 (100 mg, 0.37 mmol) and pyrrole-2-carbaldehyde 7 (108
AC C
mg, 0.37 mmol) was dissolved in 10 ml CH2Cl2, and POCl3 (0.45 ml, 0.47 mmol) was added dropwise at 0 ºC. The solution was warmed to room temperature slowly and stirred for 6 h. The mixture was cooled to 0 ºC. Et3N (0.14 ml, 1.0 mmol) was added dropwise. After stirring for 15 min, BF3·Et2O (0.2 ml, 1.6 mmol) was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 6 h. Water was added, and the mixture was stirred at room temperature overnight (to decompose excess BF3·Et2O and other impurities). The organic layer was washed with water, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel
ACCEPTED MANUSCRIPT (n-hexane : CH2Cl2 = 1 : 2), and followed by recrystallization from CH2Cl2/n-hexane to afford 6 (137 mg, 63%) as coppery solids. M.p.: 225.0–225.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.90 (d, 3J = 8.0 Hz, 4H), 7.51 (t, 3J = 8.0 Hz, 4H), 7.46 (d, 3J = 8.0 Hz, 4H), 7.43 (s, 1H),
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7.42 (t, 3J = 8.0 Hz, 2H), 7.30 (d, 3J = 8.0 Hz, 4H), 6.73 (s, 2H), 2.53 (s, 6H). HRMS-MALDI (m/z): [M]+ calcd for C35H27BF2N2S2: 588.16713; found: 588.16736.
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3. Results and Discussion
By the artful selection of methylthioacetophenone, the methylthio-substituted
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pyrrole was successfully prepared in 47% yield by the typical method (Scheme 1) [13]. The methylthio-containing pyrrole 1 showed a typical hydrogen signal (δ = 8.41 (br s, 1HN-H)) in the 1H NMR spectrum (see ESI), which is in agreement with that (δ = 8.3-9.9 (br s, 1HN-H)) of the reported pyrroles [14]. Moreover, the chemical shift of the methyl group (δ = 2.45 (s, 3H) of the –SMe
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group in pyrrole 1 locates at the high field (see ESI), comparing to that (δ = 2.90 (s, 3H)) of the –OMe group in the reported pyrroles in the low field [14a], just due to the electron-riching sulphur atom. Next, such pyrrole 1 was found to
EP
be able to synthesize the aesthetic symmetric aza-BODIPY 2 in 46% yield under AcOH, Ac2O and NaNO2, followed by the complexation with
AC C
Et3N–BF3·Et2O [15].
Methylthio-substituted pyrrole 1 is also suited to synthesize unsymmetrical aza-BODIPY 3 which was not previously obtainable (Figure 2 and Scheme S1).
ACCEPTED MANUSCRIPT And, the corresponding aldehyde was dissolved in pyrrole 1, followed by the oxidation with DDQ and complexation, to also give the symmetric BODIPY 4 in 31% yield (Figure 2 and Scheme S2). Moreover, methylthio-substituted BODIPY dyes 5 and 6 without an 8-substituent could be obtained via
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condensation of the pyrrole-2-carbaldehyde 7 with another pyrrole (Figure 2 and Scheme S3-5). So, the methylthio-substituted pyrrole 1 was suitable to synthesize symmetric/symmetric BODIPYs and aza-BODIPYs.
Next, to severely compare with the photophysical properties of aza-BODIPY
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2 bearing the –SMe groups, the known aza-BODIPY 8 bearing the –OMe groups was also prepared [8]. The spectra of absorption and fluorescence of
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aza-BODIPYs 2 and 8 are outlined and shown in Figure 3 and Table1. Surprisingly, the maxima absorption and emission between 2 and 8 are obviously different. In comparison with the maxima emission of aza-BODIPY 8 bearing the –OMe groups (λem = 715 nm in CHCl3) [8], a mere substituent change from a –OMe to a –SMe group in dye 2 (λem = 746 nm in CHCl3) leads
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to be 31 nm of dramatically bathochromic shift. Especially, aza-BODIPY 2 has the high extinction coefficients (105000 M-1 cm-1) and a large Stokes’ shift (840 cm-1), comparing to those (78500 M-1 cm-1, 549 cm-1) of dye 8. The full width
EP
half maximum (Fwhm = 68 nm) of 2 was broader than that (52 nm) of dye 8. Because the introduction of the electron-riching methylthioether substituent easily results in the ICT effect [16], the fluorescence quantum yield (Φf = 0.06)
AC C
of aza-BODIPY 2 is lower than that (Φf = 0.36) of aza-BODIPY 8. So, the introduction
of
the
electron-donating
methylthio
substituent
into
BODIPY/aza-BODIPY dyes could reduce the quantum yields, red-shift its emission spectra, provide higher extinction coefficients, larger Stokes’ shift and broader Fwhm (Table 1). In addition, MO calculations between 2 (HOMO/LUMO (eV) = −5.35/−3.36) and 8 (HOMO/LUMO (eV) = −5.33/−3.27) well supported and explained the difference of their absorption maxima (Figure 4 and ESI).
S0143-7208(17)31105-1
DOI:
10.1016/j.dyepig.2017.07.038
Reference:
DYPI 6127
To appear in:
Dyes and Pigments
Received Date: 15 May 2017 Revised Date:
30 June 2017
Accepted Date: 16 July 2017
Please cite this article as: Jiang X-D, Liu X, Fang T, Sun C, Synthesis and application of methylthiosubstituted BODIPYs/aza-BODIPYs, Dyes and Pigments (2017), doi: 10.1016/j.dyepig.2017.07.038. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Synthesis and application of methylthio-substituted BODIPYs/aza-BODIPYs Xin-Dong Jiang, a,b* Xin Liu,a Tao Fanga and Changliang Sunc a
M AN U
SC
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College of Applied Chemistry, Shenyang University of Chemical Technology, Shenyang, 110142, China. E-mail: [email protected]; Tel: +86 024 89387219. b State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China. c Center of Physical and Chemistry Test, Shenyang University of Chemical Technology, Shenyang 110142, China Corresponding author: Tel: +86 024 89387219. Fax: +86 024 89388211 E-mail: [email protected]
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Abstract: A series of new BODIPYs/aza-BODIPYs with a methylthio group were Herein prepared. Introduction of the electron-donating methylthio substituent into such dyes could reduce the fluoresecence quantum yield, red-shift its emission spectra,
EP
provide higher extinction coefficients and larger Stokes’ shift. Oxidation of the thioether of BODIPY 4 into the corresponding electron-withdrawing sulfoxide by
AC C
HClO can restore the quantum yield and blue-shift its emission spectra, and dye 4 was highly sensitive and selective to HClO. Keywords: Aza-BODIPY • NIR • Fluorescent dye • Methylthio • Oxidation
1. Introduction
Borondipyrromethenes
(BODIPYs)
and
aza-borondipyrromethenes
(aza-BODIPYs) in the family of dyes, are well-known to be highly fluorescent, stable, and have tunable emission wavelengths, and therefore such dyes have been attracting increasing interest [1]. Such dyes and their derivatives
ACCEPTED MANUSCRIPT widespreadly acted as good candidates for biological labeling applications and fluorescent materials and so forth [2]. To enrich the functionalization of BODIPY/aza-BODIPY dyes, the structure innovation and modification are the key content. So, many groups devote their attention to design and synthesize
To
date,
some
reviews
almost
showed
all
RI PT
the new structures of BODIPYs/aza-BODIPYs [3]. the
structures
of
BODIPYs/aza-BODIPYs [2,4]. However, methylthio-substituted BODIPYs were found to be so rare (Figure 1) [5], and no aza-BODIPY with a methylthio group
SC
was recorded. Inspired by the aforementioned reports, it urges us to explore to design the platform of BODIPYs/aza-BODIPYs bearing a –SMe group. In
M AN U
comparision with the introduction of a –SMe group into BODIPY [5], the creation of a methylthio-substituted pyrrole as a modular unit is of great importance. Our group has been working on pyrroles [6]. Therefore, the new pyrrole bearing a –SMe group was herein prepared and applied to synthesize a series of new BODIPYs/aza-BODIPYs 2-6. Moreover, a near-infrared (NIR)
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BODIPY 4 as a probe was highly sensitive and selective to HClO.
AC C
General:
EP
2. Experimental methods
1-(4-(Methylthio)phenyl)ethanone (98%) were purchased from Energy Chemical & Technology (Shanghai) Co. Ltd. All other chemicals and solvents used in this work were of analytical grade, purchased from Energy Chemical & Technology (Shanghai) Co. Ltd and used without further purification. 1H NMR spectra were recorded on a VARIAN Mercury 500 MHz spectrometer. 1H NMR chemical shifts (δ) are given in ppm downfield from Me4Si, determined by residual chloroform (δ = 7.26 ppm).
13
C NMR spectra were recorded on a VARIAN Mercury 125 MHz
spectrometer in CDCl3, all signals are reported in ppm with the internal chloroform
ACCEPTED MANUSCRIPT signal at δ 77.0 ppm as standard. Fluorescence spectra were recorded on an F-4600 spectrophotometer and are reported as cm−1. UV/Vis spectra were recorded on a UV-2550 spectrophotometer at room temperature. All pH measurements were performed with a PHS-3E pH meter. The refractive index of
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the medium was measured by 2 W Abbe’s refractometer at 20 °C.
The fluorescence quantum yields (Φf) of the BODIPY/aza-BODIPY systems were calculated using the following relationship (equation 1): Φf = Φref Fsampl Aref n2sampl/Fref Asampl n2ref
SC
(1)
Here, F denotes the integral of the corrected fluorescence spectrum, A is the
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absorbance at the excitation wavelength, and n is the refractive index of the medium, ref and sampl denote parameters from the reference and unknown experimental samples, respectively.
The reference systems used were Nile blue as standard [Φf = 0.27, λex = 625 nm, 0.5% (v/v) 0.1 M HCl in ethanol] [7] for 4-6, and aza-BODIPY 8 as
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standard (Φf = 0.36 in chloroform, λabs = 688 nm) [8] for 2 and 3. The MO calculations were performed at the DFT level, and the frontier molecular
orbitals
of
aza-PODIPY
2
and
aza-BODIPY
8
at
the
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B3LYP/6-31G(d) level with Gaussian 09 [9].
AC C
Preparation of ROS and RNS Various ROS and RNS were prepared according to published methods [10]. Various ROS and RNS including ClO−, · OH, H2O2, 1O2, NO2−, NO, ONOO−, O2−, and tBuOOH were prepared according to the following methods. NaClO obtained commercially from Energy Chemical & Technology (Shanghai) Co. Ltd.
The hydroxyl radical (· OH) was generated by Fenton reaction on mixing Fe(NH4)2(SO4)2·6H2O with 10 equivalents of H2O2; the concentration of · OH was
estimated from the concentration of Fe2+. The concentration of the commercially available stock H2O2 solution was estimated by optical absorbance
ACCEPTED MANUSCRIPT at 240 nm. Singlet oxygen (1O2) was generated by the addition of NaOCl and H2O2 according to the literature [11]. The sources of NO2− were NaNO2. Nitric oxide (NO) was generated from sodium nitroferricyanide(III) dihydrate. Peroxynitrite (ONOO−) was prepared according to the reported method [12]; the concentration of
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peroxynitrite was estimated by using an extinction coefficient of 1670 M−1 cm−1 (302 nm). Superoxide (O2−) was prepared from KO2. tBuOOH was obtained commercially from Energy Chemical & Technology (Shanghai) Co. Ltd.
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Preparation of metal ion titration solutions
Stock solutions (4 × 10−4 M) of the salts of NaCl, HgCl2, MgCl2, AgNO3, CrCl3,
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FeCl3, NiCl2 and CdCl2 in MeCN/PBS (1 : 9, v/v; pH = 7.4) were prepared. BODIPY 4 (1 × 10−4 M) was also prepared in MeCN/PBS (1 : 9, v/v; pH = 7.4). Test solutions were prepared by placing 40 µL of the sensor stock solution into a test tube, then adding an appropriate aliquot of each metal stock (0−1.0 mL),
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and diluting the solution to 4 mL with MeCN/PBS (1 : 9, v/v; pH = 7.4). Synthesis of pyrrole 1
EP
Under N2, 1-(4-(methylthio)phenyl)ethanone (200.0 mg, 1.2 mmol) was added to NaH (115.4 mg, 4.79 mmol) in DMSO (20 ml) at 20 °C and stirred for 10 min.
AC C
Then, 3-phenyl-2H-azirine (131.3 mg, 1.1 mmol) in THF (5 ml) was added and the resulting mixture was stirred for 2 h at the same temperature. It was quenched with water, neutralized with dilute HCl to a pH about 7. The mixture was extracted with CH2Cl2 (2 × 50 ml), and the organic layer was washed with brine (2 × 50 ml) and dried over anhydrous MgSO4. After removal of the solvents by evaporation, the resulting crude mixture was separated by column chromatography (n-hexane : CH2Cl2 = 1 : 3) to afford 1 as green solids (149.5 mg, 47%). M.p.: 176.5–177.3 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 8.41 (br s, 1H), 7.55 (d, 3J = 8.0 Hz, 2H), 7.43 (d, 3J = 8.0 Hz, 2H), 7.35
ACCEPTED MANUSCRIPT (t, 3J = 8.0 Hz, 2H), 7.29 (d, 3J = 8.0 Hz, 2H), 7.19 (t, 3J = 8.0 Hz, 1H), 7.13 (m, 1H), 6.78 (m, 1H), 2.51 (s, 3H). HRMS-MALDI (m/z): [M + H]+ calcd for C17H16NS: 266.09980; found: 266.09988.
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Synthesis of pyrrole-2-carbaldehyde 7 (Scheme S3) Under N2, POCl3 (0.18 ml, 1.9 mmol) was added dropwise to DMF (0.14 ml, 1.8 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 15 min. The ice bath was replaced to cool the mixture back to 0 °C, then 10
SC
ml of ClCH2CH2Cl was added to the mixture. A solution of pyrrole 1 (200 mg, 0.75 mmol) in 5 ml of ClCH2CH2Cl was added dropwise over 1 min at 0 °C.
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The reaction mixture was refluxed for 30 min and then cooled to room temperature. A solution of K2CO3 (0.5 g, 3.6 mmol) in 10 ml of water was added. The reaction mixture was again refluxed for 20 min. The organic layer was washed with brine (2 × 50 ml) and dried over anhydrous MgSO4. After removal of the solvents by evaporation, the resulting crude mixture was
TE D
separated by column chromatography (n-hexane : CH2Cl2 = 1 : 2) to afford 7 as light green solids (138.4 mg, 63%). M.p.: 162.1–162.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 9.62 (s, 1H), 9.54 (br s, 1H), 7.56 (d, 3J = 8.0 Hz, 2H), 7.54 (d, 3J = 8.0 Hz, 2H), 7.46 (t, 3J = 8.0 Hz, 2H), 7.41 (d, 3J = 8.0 Hz,
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1H), 7.31 (d, 3J = 8.0 Hz, 2H), 6.70 (s, 1H), 2.53 (s, 3H). HRMS-MALDI (m/z):
AC C
[M + H]+ calcd for C18H16NSO: 294.09471; found: 294.09457. Synthesis of aza-BODIPY 2 Sodium nitrite (13 mg, 0.18 mmol) was added to a suspension of pyrrole 1 (100 mg, 0.37 mmol) in a mixture of acetic acid/anhydride (1 ml/0.4 ml) at 0 °C, and was stirred for 15 min. The color changed from colorless to brown, then green, and finally dark green was observed. After 0.5 h stirring at room temperature, the mixture was heated at 70 °C for 0.5 h. Crushed ice was added to the mixture, the resulted dark green dye was filtered, washed with
ACCEPTED MANUSCRIPT water. The dark green dye was dissolved in CH2Cl2, filtered through a pad of alumina (activity III). Solvent was removed under reduced pressure, and the residue was dissolved in dry 1,2-dichloroethane. Triethylamine (0.12 ml, 0.86 mmol) was added, followed by dropwise addition of BF3·Et2O (0.13 ml, 1.05
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mmol) with stirring at room temperature. The mixture was stirred for 0.5 h, then heated in 80 °C for 0.5 h. The reaction was quenched with crushed ice, extracted with CH2Cl2. The resulting crude mixture was separated by column chromatography on silica gel (n-hexane : CH2Cl2 = 1 : 2), and followed by
SC
recrystallization from CH2Cl2/n-hexane to afford 2 (48.7 mg, 46%) as coppery solids. M.p.: 275.6–276.5 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm)
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8.07 (d, 3J = 8.0 Hz, 4H), 8.01 (d, 3J = 8.0 Hz, 4H), 7.46 (t, 3J = 8.0 Hz, 4H), 7.42 (t, 3J = 8.0 Hz, 2H), 7.32 (d, 3J = 8.0 Hz, 4H), 7.06 (s, 2H), 2.54 (s, 6H). 13
C NMR (125 MHz, CDCl3): δ (ppm) 158.1, 145.6, 143.5, 143.4, 132.3, 129.8,
129.3, 129.2, 128.5, 127.6, 125.4, 118.8, 46.8. HRMS-MALDI (m/z): [M + H]+ calcd for C34H27BF2N3S2: 590.17020; found: 590.17041.
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Synthesis of aza-BODIPY 3 (Scheme S1) Sodium nitrite (31.4 mg, 0.45 mmol) was added to a suspension of
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2,4-diphenyl-1H-pyrrole (100 mg, 0.45 mmol) in acetic acid (1 ml) at 0 °C, and was stirred for 10 min. The color changed from colorless to brown, then green,
AC C
and finally brown was observed. The second pyrrole 1 (120.9 mg, 0.45 mmol) was added, followed by addition of acetic anhydride (0.4 ml). The mixture turned blue immediately. After 0.5 h stirring, the mixture was heated at 80 °C for 0.5 h. Crushed ice was added to the mixture, the resulted blue dye was filtered, washed with water. The blue dye was dissolved in CH2Cl2, filtered through a pad of alumina (activity III). Solvent was removed under reduced pressure, and the residue was dissolved in dry 1,2-dichloroethane. Triethylamine (0.28 ml, 2.0 mmol) was added, followed by dropwise addition of BF3·Et2O (0.50 ml, 4.0 mmol) with stirring at room temperature. The mixture was stirred for 0.5 h, then heated in 80 °C for 0.5 h. The reaction was
ACCEPTED MANUSCRIPT quenched with crushed ice, extracted with CH2Cl2, and purified by chromatography
on
silica
gel
followed
by
recrystallization
from
CH2Cl2/n-hexane to afford 3 (151.5 mg, 62%) as coppery solids. M.p.: 198.0–198.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 8.07 (d, 3J =
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8.0 Hz, 4H), 8.02 (d, 3J = 8.0 Hz, 4H), 7.42-750 (m, 9H), 7.32 (d, 3J = 8.0 Hz, 2H), 7.08 (s, 1H), 7.02 (s, 1H), 2.54 (s, 3H). HRMS-MALDI (m/z): [M+H]+ calcd for C33H25BF2N3S: 544.18248; found: 544.18213.
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Synthesis of BODIPY 4 (Scheme S2)
Under N2, pyrrole 1 (100 mg, 0.37 mmol) and 4-nitrobenzaldehyde (22.8 mg,
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0.15 mmol) was dissolved in CH2Cl2 (10 ml) and 2 drops of trifluoroacetic acid (TFA) were added. The reaction was allowed to proceed for 1 h at room temperature
and
directly
oxidized
with
a
solution
of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 85.6 mg, 0.37 mmol) in CH2Cl2 (20 ml) at room temperature. The reaction was allowed to proceed for
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4 h at room temperature. Et3N (0.14 ml, 1.0 mmol) was added to the solution, which was stirred for 30 min. BF3·Et2O (0.2 ml, 1.6 mmol) was added, and stirring was maintained for 1 h. The reaction mixture was washed with H2O (2
EP
× 50 ml), and the aqueous solution was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude
AC C
product was purified by silica gel column chromatography (CH2Cl2/n-hexane = 1:1) to afford 4 (32.9 mg, 31%) as coppery solids. M.p.: 296.0–296.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.87 (d, 3J = 8.0 Hz, 4H), 7.31 (d, 3J = 8.0 Hz, 4H), 7.28 (d, 3J = 8.0 Hz, 2H), 6.96 (d, 3J = 8.0 Hz, 2H), 6.92 (t, 3
J = 8.0 Hz, 2H), 6.84 (t, 3J = 8.0 Hz, 4H), 6.71 (d, 3J = 8.0 Hz, 4H), 6.56 (s, 2H),
2.53 (s, 6H). HRMS-MALDI (m/z): [M]+ calcd for C41H31BF2N3O2S2: 709.18351; found: 709.18359. Synthesis of BODIPY 5 (Scheme S4)
ACCEPTED MANUSCRIPT 2,4-Diphenyl-1H-pyrrole (82 mg, 0.37 mmol) and pyrrole-2-carbaldehyde 7 (108 mg, 0.37 mmol) was dissolved in 10 ml CH2Cl2, and POCl3 (0.45 ml, 0.47 mmol) was added dropwise at 0 ºC. The solution was warmed to room temperature slowly and stirred for 6 h. The mixture was cooled to 0 ºC. Et3N
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(0.28 ml, 2.0 mmol) was added dropwise. After stirring for 15 min, BF3·Et2O (0.5 ml, 4.0 mmol) was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 6 h. Water was added, and the mixture was stirred at room temperature overnight (to decompose excess
SC
BF3·Et2O and other impurities). The organic layer was washed with water, brine and dried over Na2SO4. The solvent was removed under reduced
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pressure and the residue was purified by column chromatography on silica gel (n-hexane : CH2Cl2 = 1 : 2), and followed by recrystallization from CH2Cl2/n-hexane to afford 5 (94.2 mg, 47%) as coppery solids. M.p.: 170.0–171.0 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.95 (d, 3J = 8.0 Hz, 2H), 7.91 (d, 3J = 8.0 Hz, 2H), 7.41-753 (m, 14H), 7.29 (d, 3J = 8.0 Hz,
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2H), 6.74 (s, 1H), 6.73 (s, 1H), 2.52 (s, 3H). HRMS-MALDI (m/z): [M]+ calcd for C34H25BF2N2S: 542.17941; found: 542.17969.
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Synthesis of BODIPY 6 (Scheme S5)
Under N2, Pyrrole 1 (100 mg, 0.37 mmol) and pyrrole-2-carbaldehyde 7 (108
AC C
mg, 0.37 mmol) was dissolved in 10 ml CH2Cl2, and POCl3 (0.45 ml, 0.47 mmol) was added dropwise at 0 ºC. The solution was warmed to room temperature slowly and stirred for 6 h. The mixture was cooled to 0 ºC. Et3N (0.14 ml, 1.0 mmol) was added dropwise. After stirring for 15 min, BF3·Et2O (0.2 ml, 1.6 mmol) was added dropwise to the solution. The reaction mixture was warmed to room temperature and stirred for 6 h. Water was added, and the mixture was stirred at room temperature overnight (to decompose excess BF3·Et2O and other impurities). The organic layer was washed with water, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel
ACCEPTED MANUSCRIPT (n-hexane : CH2Cl2 = 1 : 2), and followed by recrystallization from CH2Cl2/n-hexane to afford 6 (137 mg, 63%) as coppery solids. M.p.: 225.0–225.8 ºC (decomp.). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.90 (d, 3J = 8.0 Hz, 4H), 7.51 (t, 3J = 8.0 Hz, 4H), 7.46 (d, 3J = 8.0 Hz, 4H), 7.43 (s, 1H),
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7.42 (t, 3J = 8.0 Hz, 2H), 7.30 (d, 3J = 8.0 Hz, 4H), 6.73 (s, 2H), 2.53 (s, 6H). HRMS-MALDI (m/z): [M]+ calcd for C35H27BF2N2S2: 588.16713; found: 588.16736.
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3. Results and Discussion
By the artful selection of methylthioacetophenone, the methylthio-substituted
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pyrrole was successfully prepared in 47% yield by the typical method (Scheme 1) [13]. The methylthio-containing pyrrole 1 showed a typical hydrogen signal (δ = 8.41 (br s, 1HN-H)) in the 1H NMR spectrum (see ESI), which is in agreement with that (δ = 8.3-9.9 (br s, 1HN-H)) of the reported pyrroles [14]. Moreover, the chemical shift of the methyl group (δ = 2.45 (s, 3H) of the –SMe
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group in pyrrole 1 locates at the high field (see ESI), comparing to that (δ = 2.90 (s, 3H)) of the –OMe group in the reported pyrroles in the low field [14a], just due to the electron-riching sulphur atom. Next, such pyrrole 1 was found to
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be able to synthesize the aesthetic symmetric aza-BODIPY 2 in 46% yield under AcOH, Ac2O and NaNO2, followed by the complexation with
AC C
Et3N–BF3·Et2O [15].
Methylthio-substituted pyrrole 1 is also suited to synthesize unsymmetrical aza-BODIPY 3 which was not previously obtainable (Figure 2 and Scheme S1).
ACCEPTED MANUSCRIPT And, the corresponding aldehyde was dissolved in pyrrole 1, followed by the oxidation with DDQ and complexation, to also give the symmetric BODIPY 4 in 31% yield (Figure 2 and Scheme S2). Moreover, methylthio-substituted BODIPY dyes 5 and 6 without an 8-substituent could be obtained via
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condensation of the pyrrole-2-carbaldehyde 7 with another pyrrole (Figure 2 and Scheme S3-5). So, the methylthio-substituted pyrrole 1 was suitable to synthesize symmetric/symmetric BODIPYs and aza-BODIPYs.
Next, to severely compare with the photophysical properties of aza-BODIPY
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2 bearing the –SMe groups, the known aza-BODIPY 8 bearing the –OMe groups was also prepared [8]. The spectra of absorption and fluorescence of
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aza-BODIPYs 2 and 8 are outlined and shown in Figure 3 and Table1. Surprisingly, the maxima absorption and emission between 2 and 8 are obviously different. In comparison with the maxima emission of aza-BODIPY 8 bearing the –OMe groups (λem = 715 nm in CHCl3) [8], a mere substituent change from a –OMe to a –SMe group in dye 2 (λem = 746 nm in CHCl3) leads
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to be 31 nm of dramatically bathochromic shift. Especially, aza-BODIPY 2 has the high extinction coefficients (105000 M-1 cm-1) and a large Stokes’ shift (840 cm-1), comparing to those (78500 M-1 cm-1, 549 cm-1) of dye 8. The full width
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half maximum (Fwhm = 68 nm) of 2 was broader than that (52 nm) of dye 8. Because the introduction of the electron-riching methylthioether substituent easily results in the ICT effect [16], the fluorescence quantum yield (Φf = 0.06)
AC C
of aza-BODIPY 2 is lower than that (Φf = 0.36) of aza-BODIPY 8. So, the introduction
of
the
electron-donating
methylthio
substituent
into
BODIPY/aza-BODIPY dyes could reduce the quantum yields, red-shift its emission spectra, provide higher extinction coefficients, larger Stokes’ shift and broader Fwhm (Table 1). In addition, MO calculations between 2 (HOMO/LUMO (eV) = −5.35/−3.36) and 8 (HOMO/LUMO (eV) = −5.33/−3.27) well supported and explained the difference of their absorption maxima (Figure 4 and ESI).