CN114874257B - Carbazole reaction type fluoride ion fluorescent probe based on aralkenyl nitrile and preparation method and application thereof - Google Patents

Carbazole reaction type fluoride ion fluorescent probe based on aralkenyl nitrile and preparation method and application thereof Download PDF

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CN114874257B
CN114874257B CN202210552197.4A CN202210552197A CN114874257B CN 114874257 B CN114874257 B CN 114874257B CN 202210552197 A CN202210552197 A CN 202210552197A CN 114874257 B CN114874257 B CN 114874257B
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carbazole
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CN114874257A (en
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刘晟溥
邹英
乐意
鄢龙家
刘力
马婷婷
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Guizhou Renwei Biotechnology Co ltd
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Abstract

The invention relates to the technical field of detection, in particular to a carbazole reaction type fluoride ion fluorescent probe based on aromatic acrylonitrile, and a preparation method and application thereof. According to the invention, carbazole is taken as a fluorophore, a silicon-oxygen bond is taken as an identification group, and 2-methyl cyanoacetate is introduced through Knoevenagel condensation reaction to synthesize a compound, namely 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-yl) -2-methyl cyanoacrylate. The fluorine ions induce Si-O bond to break through Lewis acid-base reaction to form O ‑ The ortho-aryl allyldinitrile group is attacked to carry out intramolecular cyclization, so that the conjugation area of the probe is greatly increased, the quantum yield is improved, the fluorescence intensity is obviously changed to realize the detection of the fluoride ion, and the introduction of the ester group enhances the permeability of the cell membrane of the probe molecule, so that the probe has a good imaging effect on the fluoride ion in the cell.

Description

Carbazole reaction type fluoride ion fluorescent probe based on aralkenyl nitrile and preparation method and application thereof
Technical Field
The invention relates to the technical field of detection, in particular to a carbazole reaction type fluoride ion fluorescent probe based on aromatic acrylonitrile, and a preparation method and application thereof.
Background
Fluorine is an essential element of the human body, is one of main components constituting bones and teeth of the human body, plays an important role in the formation of bone tissues and enamel, and participates in metabolic processes by activating or inhibiting activities of various enzymes, and fluorine deficiency or excessive fluorine intake is disadvantageous to the health of the human body. Insufficient fluorine intake can cause caries, bone malnutrition, long bone stopping development and other large bone diseases, and small cell anemia can also occur; excessive fluorine intake can cause dental fluorosis and osteofluorosis, damage brain function, and cause damage to reproductive system function. China is one of the most popular and serious countries with drinking water type local fluorosis in the world. The fluorine poisoning seriously damages the health of people, and an efficient fluorine ion detection method is researched, so that the method has practical value for fluorine pollution and environmental evaluation.
Because the atomic radius of fluorine is small, electronegativity is large, hydrogen bonds are easily formed with hydrogen bond donors in water environment, and great difficulty is brought to the detection of fluorine ions. The probe as in patent CN111039972a is only suitable for detecting fluoride ions in nonpolar solvents, has low sensitivity and long response time, is not suitable for rapid quantitative detection of fluoride ions in large polar solutions, and is greatly limited in practical application.
Therefore, the ratio type fluorescent probe with rapid response and high sensitivity to the fluoride ions is sought, the detection limit reaches the nM level, and the ratio type fluorescent probe can be used for rapidly and quantitatively detecting the trace fluoride ions in the water sample, and is a problem which needs to be solved rapidly at present.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a carbazole reaction type fluoride ion fluorescent probe based on aromatic acrylonitrile, and a preparation method and application thereof.
Carbazole-based reactive fluoride ion fluorescent probe based on aralkenyl nitrile, namely 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-yl) -2-cyanoacrylate, which is abbreviated as SCC, has the following specific structural formula:
the preparation method of the carbazole reaction type fluoride ion fluorescent probe based on the aromatic vinyl nitrile comprises the following steps:
(a) 2-methoxy-9H-carbazole and iodopropane are subjected to substitution reaction to generate 2-methoxy-9-propyl-9H-carbazole:
the molar ratio of the substitution reagent to the 2-methoxy-9H-carbazole is 2-5:1, the molar ratio of the alkali to the 2-methoxy-9H-carbazole is 2-5:1, and the reaction temperature is 60-70 ℃;
(b) Formylation of 2-methoxy-9-propyl-9H-carbazole with DMF and phosphorus oxychloride to produce 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde:
The molar ratio of the reactant to the 2-methoxy-9-propyl-9H-carbazole is 2-5:1, and the reaction temperature is 55-65 ℃;
(c) Hydrolyzing the 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde to generate 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde:
the feeding mole ratio of the reaction reagent to the 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde is 2-5:1, and the reaction temperature is room temperature;
(d) 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde and tert-butyl dimethyl chlorosilane undergo substitution reaction to obtain 2- ((tert-butyl dimethyl silicon based) oxy) -9-propyl-9H-carbazole-3-formaldehyde:
the molar ratio of the reaction reagent to the 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde is 2-5:1, the molar ratio of the catalyst to the 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde is 1-2:1, the molar ratio of the alkali to the compound 4 is 2-5:1, and the reaction temperature is-10 ℃;
(e) 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde was reacted with methyl 2-cyanoacetate to give the title compound methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate:
the feeding mole ratio of the reactant to the 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-formaldehyde is 1.5-2.5:1, the ratio of the catalyst to the 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-formaldehyde is 0.005-0.015:1, and the reaction temperature is-10 ℃.
Further, in the step (a), the solvent is dimethyl sulfoxide (DMSO) or N, N-Dimethylformamide (DMF), the substitution reagent is iodopropane, and the base is sodium hydroxide or potassium hydroxide.
Further, in the step (b), the solvent is anhydrous N, N-Dimethylformamide (DMF), and the reaction reagent is phosphorus oxychloride.
Further, in the step (c), the solvent is anhydrous dichloromethane, anhydrous 1, 2-dichloroethane or anhydrous 1, 1-dichloroethane, and the reaction reagent is aluminum trichloride.
Further, in the step (d), the solvent is dichloromethane, 1, 2-dichloroethane or 1, 1-dichloroethane, the reaction reagent is tert-butyldimethyl chlorosilane, the catalyst is 4-dimethylaminopyridine, and the base is triethylamine or diethylamine.
Further, in the step (e), the solvent is anhydrous Tetrahydrofuran (THF), the reaction reagent is methyl 2-cyanoacetate, and the catalyst is tetrahydropyrrole.
The carbazole reaction type fluoride ion fluorescent probe based on the aromatic vinyl nitrile is applied to fluoride ion detection. Further, the fluoride ion detection aspect is the fluoride ion detection aspect in the water sample.
The carbazole reaction type fluoride ion fluorescent probe based on the aromatic vinyl nitrile is applied to living cell imaging.
Compared with the prior art, the invention has the technical effects that:
according to the invention, carbazole is taken as a fluorophore, a silicon-oxygen bond is taken as an identification group, and 2-methyl cyanoacetate is introduced through Knoevenagel condensation reaction to synthesize a compound, namely 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-yl) -2-methyl cyanoacrylate. The fluorine ions induce Si-O bond to break through Lewis acid-base reaction to form O - The ortho-aryl allyldinitrile group is attacked to carry out intramolecular cyclization, so that the conjugation area of the probe is greatly increased, the quantum yield is improved, the fluorescence intensity is obviously changed to realize the detection of the fluoride ion, and the introduction of the ester group enhances the permeability of the cell membrane of the probe molecule, so that the probe has a good imaging effect on the fluoride ion in the cell. Experiments prove that: in isopropyl alcohol (IPA), the recognition of fluoride ions by probe SCC produces a significant change in fluorescence signal. The fluorescence intensity of SCC is very weak before reaction with fluoride ions in IPA; the solution after the addition of fluoride ions exhibits yellowish green fluorescence. [ F - ]In the interval of 0-5 mu M, the fluorescence intensity of SCC is lambda Em The detection limit was 25.9nM in linear relation to fluoride ion concentration at =504 nM. Quinine sulfate (phi) 350nm =0.456) was used as a reference, and the quantum yield of the SCC after reaction with fluoride ions in THF-HEPES/NaOH (50 mm,7.4,9:1, v/v) was tested to be 0.287. SCC (1. Mu.M) and fluoride ion in IPA solution The son (20. Mu.M) reached saturation in fluorescence intensity within 40 min. And (3) performing a standard adding recovery experiment on the fluoride ions in river water, wherein the recovery rate of the fluoride ions reaches 109.3%. Cell imaging showed that under the green channel, the fluorescence change was evident after the probe SCC reacted with fluoride ions. In conclusion, the SCC is a ratio type fluorescent probe with rapid response to fluoride ions and high sensitivity, the detection limit reaches the nM level, and the SCC can be used for rapid quantitative detection of trace fluoride ions in a water sample and has a good application prospect.
Drawings
FIG. 1 is a flow chart of the preparation of carbazole-based reactive fluoride fluorescent probe based on aralkenylnitrile in the present application.
FIG. 2 is a spectrum of SCC (a) and SCC-F (b) coexisting with fluoride in IPA.
FIG. 3 is a spectrum of a fluoride ion (0.about.10. Mu.M) titrating SCC (0.5. Mu.M).
Fig. 4 is a graph of the response time (ex=383 nm, em=525 nm) of SCC (1 μm) to fluoride ions (20 μm).
FIG. 5 is a fluorescence image of HepG2 cells treated with SCC (1. Mu.M) and fluoride (5. Mu.M).
Detailed Description
The technical scheme of the present application is further defined below in conjunction with the specific embodiments, but the scope of the claimed application is not limited to the description.
Example 1
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (5.91 g,30 mmol) and sodium hydroxide (4.2 g,105 mmol) were added and dissolved in DMSO (60 mL) and iodopropane (10.2 g,60 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the vacuum is pumped for three times, and the temperature is raised to 65 ℃ for reaction for 12 hours. After the reaction was completed, cooled to room temperature and diluted with 60mL of water, dichloromethane (60 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (100 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 5.83g of 2-methoxy-9-propyl-9H-carbazole as a white solid, yield 81.3%.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (8 mL) was added first, phosphorus oxychloride (4.59 g,30 mmol) was added dropwise to the three-necked flask at 0℃under argon protection, and stirred for 15min, then 2-methoxy-9-propyl-9H-carbazole (2.39 g,10 mmol) was dissolved in anhydrous DMF (16 mL), and then added dropwise to the three-necked flask, the temperature was raised to 60℃to stir the reaction for 4.5H, ice water (25 mL) was added after the reaction solution cooled to room temperature, stirring was continued for 0.5H, extraction was performed with dichloromethane (25 mL. Times.3), the organic phase was combined and washed with saturated NaCl solution, anhydrous sodium sulfate was added to stand for 15min, and the dichloromethane was evaporated under reduced pressure to obtain the crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 2.21g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 82.7%.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (3.19 g,24 mmol) and anhydrous 1, 1-dichloroethane (16 mL) are added into a 100mL round bottom flask, anhydrous 1, 1-dichloroethane (16 mL) is dissolved 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde (3.2 g,12 mmol) and then added dropwise into the round bottom flask, stirring is carried out at room temperature for 10H, after the reaction is finished, 2M HCl solution (12 mL) is added dropwise and stirring is continued for 0.5H, and 1, 1-dichloroethane in the reaction solution is evaporated under reduced pressure. Ethyl acetate (30 ml×3) was extracted, the organic phases were combined and washed with saturated NaCl solution (60 ml×2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 0.94g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 31.1%.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.77 g,7 mmol), 4-dimethylaminopyridine (0.85 g,7 mmol), triethylamine (1.41 g,14 mmol) and 1, 1-dichloroethane (10 mL) were added, stirred and protected with argon, t-butyldimethylchlorosilane (2.11 g,14 mmol) was dissolved in 1, 1-dichloroethane (10 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 9 hours, saturated sodium carbonate solution (20 mL, purified water) was added to the reaction mixture, extracted with dichloromethane (20 mL. Times.3), the organic phase was combined and washed with saturated NaCl solution (40 mL. Times.2, purified water), anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 0.82g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 31.79% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (0.74 g,2 mmol), methyl 2-cyanoacetate (0.3 g,3 mmol), tetrahydropyrrole (0.0014 g,0.02 mmol) and anhydrous THF (8 mL) were added to a 100mL round bottom flask and reacted with argon protection at-10℃for 9H under stirring, and anhydrous THF in the reaction solution was evaporated under reduced pressure to give crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow solid 0.2g in 22.3% yield.
Example 2
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (4.93 g,25 mmol) and sodium hydroxide (4.0 g,100 mmol) were added and dissolved in DMSO (50 mL) and iodopropane (10.6 g,62.5 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the vacuum is pumped for three times, and the temperature is raised to 65 ℃ for reaction for 14 hours. After the reaction was completed, cooled to room temperature and diluted with 50mL of water, dichloromethane (50 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (100 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 5.15g of 2-methoxy-9-propyl-9H-carbazole as a white solid, yield 86.1%.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (9 mL) was added first, phosphorus oxychloride (11.47 g,75 mmol) was added dropwise to the three-necked flask under the protection of argon at 0℃and stirred for 15min, 2-methoxy-9-propyl-9H-carbazole (3.59 g,15 mmol) was dissolved in anhydrous DMF (26 mL) and then added dropwise to the three-necked flask, the temperature was raised to 60℃and stirred for 4H, ice water (35 mL) was added after the reaction solution cooled to room temperature and stirring was continued for 0.5H, extraction was performed with dichloromethane (35 mL. Times.3 mL), the organic phases were combined and washed with saturated NaCl solution, anhydrous sodium sulfate was added and allowed to stand for 15min, and the dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 3.38g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 84.5%.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (3.99 g,30 mmol) and anhydrous dichloromethane (14 mL) are added into a 100mL round-bottomed flask, anhydrous dichloromethane (13 mL) is added dropwise into the round-bottomed flask after 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde (2.67 g,10 mmol) is dissolved, stirring is carried out at room temperature for 10H, after the reaction is finished, 2M HCl solution (15 mL) is added dropwise for continuous stirring for 0.5H, and dichloromethane in the reaction solution is evaporated under reduced pressure. Ethyl acetate (27 mL x 3) was extracted, the organic phases were combined and washed with saturated NaCl solution (54 mL x 2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 0.85g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 33.8%.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.52 g,6 mmol), 4-dimethylaminopyridine (0.73 g,6 mmol), diethylamine (0.88 g,12 mmol) and 1, 1-dichloroethane (7 mL) were added, stirred and protected with argon, t-butyldimethylchlorosilane (1.81 g,12 mmol) was dissolved in 1, 1-dichloroethane (8 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 9 hours, saturated sodium carbonate solution (15 mL, pure water) was added to the reaction mixture, extracted with dichloromethane (15 mL. Times.3), the organic phase was combined and washed with saturated NaCl solution (30 mL. Times.2, pure water), anhydrous sodium sulfate was added and allowed to stand for 15 minutes, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 0.74g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 33.72% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (1.1 g,3 mmol), methyl 2-cyanoacetate (0.59 g,6 mmol), tetrahydropyrrole (0.0021 g,0.03 mmol) and anhydrous THF (10 mL) were added to a 100mL round bottom flask and reacted with argon protection at-10℃for 12H under stirring, and anhydrous THF in the reaction solution was evaporated under reduced pressure to give crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow solid 0.35g in 25.7% yield.
Example 3
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (5.91 g,30 mmol) and potassium hydroxide (8.4 g,150 mmol) were added and dissolved in DMSO (60 mL) and iodopropane (15.3 g,90 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the vacuum is pumped for three times, and the temperature is raised to 60 ℃ for reaction for 16 hours. After the reaction was completed, cooled to room temperature and diluted with 60mL of water, dichloromethane (60 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (100 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 6.31g of 2-methoxy-9-propyl-9H-carbazole as a white solid in 88% yield.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (8 mL) was added first, phosphorus oxychloride (6.9 g,45 mmol) was added dropwise to the three-necked flask under the protection of argon at 0℃and stirred for 15min, 2-methoxy-9-propyl-9H-carbazole (2.4 g,10 mmol) was dissolved in anhydrous DMF (16 mL) and then added dropwise to the three-necked flask, the temperature was raised to 65℃and stirred for 3H, ice water (25 mL) was added after the reaction solution cooled to room temperature and stirring was continued for 0.5H, extraction was performed with dichloromethane (25 mL. Times.3 mL), the organic phases were combined and washed with saturated NaCl solution, anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to obtain a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 2.22g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 83.1%.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (4.79 g,36 mmol) and anhydrous 1, 1-dichloroethane (16 mL) are added into a 100mL round-bottomed flask, anhydrous 1, 1-dichloroethane (16 mL) is dissolved 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde (3.2 g,12 mmol) and then added dropwise into the round-bottomed flask, stirring is carried out at room temperature for 12H, after the reaction is completed, 2M HCl solution (18 mL) is added dropwise and stirring is continued for 0.5H, and 1, 1-dichloroethane in the reaction solution is evaporated under reduced pressure. Ethyl acetate (30 ml×3) was extracted, the organic phases were combined and washed with saturated NaCl solution (60 ml×2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 1.32g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 43.5%.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.77 g,7 mmol), 4-dimethylaminopyridine (0.85 g,7 mmol), triethylamine (1.41 g,14 mmol) and 1, 2-dichloroethane (10 mL) were added, stirred and protected with argon, t-butyldimethylchlorosilane (3.16 g,21 mmol) was dissolved in 1, 2-dichloroethane (10 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 9 hours, saturated sodium carbonate solution (20 mL, purified water) was added to the reaction mixture, extracted with dichloromethane (20 mL. Times.3), the organic phase was combined and washed with saturated NaCl solution (40 mL. Times.2, purified water), anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 0.92g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 35.65% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (0.73 g,2 mmol), methyl 2-cyanoacetate (0.5 g,5 mmol), tetrahydropyrrole (0.0014 g,0.02 mmol) and anhydrous THF (8 mL) were added to a 100mL round bottom flask and reacted with argon protection at-10℃for 16H under stirring, and the anhydrous THF in the reaction solution was evaporated under reduced pressure to give the crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow solid 0.26g in 28.4% yield.
Example 4
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (4.93 g,25 mmol) and sodium hydroxide (3 g,75 mmol) were added and dissolved in DMF (50 mL) and iodopropane (14.9 g,87.5 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the vacuum is pumped for three times, and the temperature is raised to 65 ℃ for reaction for 14 hours. After the reaction was completed, cooled to room temperature and diluted with 50mL of water, dichloromethane (50 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (80 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 5.4g of 2-methoxy-9-propyl-9H-carbazole as a white solid, yield 90.4%.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (9 mL) was added first, phosphorus oxychloride (9.18 g,60 mmol) was added dropwise to the three-necked flask at 0℃under argon protection, stirred for 15min, 2-methoxy-9-propyl-9H-carbazole (3.6 g,15 mmol) was dissolved in anhydrous DMF (26 mL) and then added dropwise to the three-necked flask, the temperature was raised to 55℃and stirred for 5H, ice water (35 mL) was added after the reaction solution cooled to room temperature, stirring was continued for 0.5H, extraction was performed with dichloromethane (35 mL. Times.3 mL), the organic phase was combined and washed with saturated NaCl solution (70 mL. Times.2 mL), anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 3.06g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with 76.5% yield.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (3.99 g,30 mmol) and anhydrous 1, 2-dichloroethane (14 mL) are added into a 100mL round-bottomed flask, anhydrous 1, 2-dichloroethane (13 mL) is dissolved 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde (2.7 g,10 mmol) and then added dropwise into the round-bottomed flask, stirring is carried out at room temperature for 14H, after the reaction is completed, 2M HCl solution (15 mL) is added dropwise and stirring is continued for 0.5H, and 1, 2-dichloroethane in the reaction solution is evaporated under reduced pressure. Ethyl acetate (25 mL x 3) was extracted, the organic phases were combined and washed with saturated NaCl solution (50 mL x 2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 1.12g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 44.2%.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.52 g,6 mmol), 4-dimethylaminopyridine (0.88 g,7.2 mmol), triethylamine (1.82 g,18 mmol) and methylene chloride (7 mL) were added, stirred and protected with argon, tert-butyldimethylsilyl chloride (2.71 g,18 mmol) was dissolved in methylene chloride (8 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 12 hours, a saturated sodium carbonate solution (15 mL, prepared with pure water) was added to the reaction mixture, extracted with methylene chloride (15 mL. Times.3), the organic phase was combined and washed with a saturated NaCl solution (30 mL. Times.2, prepared with pure water), and dried sodium sulfate was added and allowed to stand for 15 minutes, and the methylene chloride was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 0.83g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 37.58% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (1.1 g,3 mmol), methyl 2-cyanoacetate (0.45 g,4.5 mmol), tetrahydropyrrole (0.0021 g,0.03 mmol) and anhydrous THF (11 mL) were added to a 100mL round bottom flask and reacted with argon under stirring at room temperature for 12H and the anhydrous THF in the reaction solution was evaporated under reduced pressure to give the crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow-green solid 0.29g in 21.5% yield.
Example 5
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (5.91 g,30 mmol) and sodium hydroxide (2.4 g,60 mmol) were added and dissolved in DMSO (60 mL) and iodopropane (20.4 g,120 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the temperature is raised to 70 ℃ for reaction for 10 hours after three times of vacuumizing. After the reaction was completed, cooled to room temperature and diluted with 60mL of water, dichloromethane (60 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (100 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 6.51g of 2-methoxy-9-propyl-9H-carbazole as a white solid, yield 90.8%.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (8 mL) was added first, phosphorus oxychloride (5.36 g,35 mmol) was added dropwise to the three-necked flask at 0℃under argon protection, stirred for 15min, 2-methoxy-9-propyl-9H-carbazole (2.39 g,10 mmol) was dissolved in anhydrous DMF (16 mL) and then added dropwise to the three-necked flask, the temperature was raised to 60℃to stir the reaction for 4H, ice water (25 mL) was added after the reaction solution cooled to room temperature, stirring was continued for 0.5H, extraction was performed with dichloromethane (25 mL. Times.3 mL), the organic phase was combined and saturated NaCl solution (50 mL. Times.2 mL) was washed, anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 2.11g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with 79% yield.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (6.38 g,48 mmol) and anhydrous 1, 2-dichloroethane (16 mL) were added to a 100mL round-bottomed flask, anhydrous 1, 2-dichloroethane (16 mL) was dissolved 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde (3.2 g,12 mmol) and then added dropwise to the round-bottomed flask, stirring was carried out at room temperature for 10 hours, after the reaction was completed, 2M HCl solution (24 mL) was added dropwise and stirring was continued for 0.5 hour, and 1, 2-dichloroethane in the reaction solution was evaporated under reduced pressure. Ethyl acetate (30 ml×3) was extracted, the organic phases were combined and washed with saturated NaCl solution (60 ml×2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 1.27g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 41.8%.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.77 g,7 mmol), 4-dimethylaminopyridine (1.37 g,11.2 mmol), diethylamine (2.3 g,32 mmol) and methylene chloride (10 mL) were added, stirred and protected with argon, t-butyldimethylsilyl chloride (3.16 g,21 mmol) was dissolved in methylene chloride (10 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 14H, a saturated sodium carbonate solution (20 mL, prepared with pure water) was added to the reaction mixture, extracted with methylene chloride (20 mL. Times.3), the organic phase was combined and washed with a saturated NaCl solution (40 mL. Times.2, prepared with pure water), and dried sodium sulfate was added and allowed to stand for 15min, followed by evaporation of methylene chloride under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 1.02g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 39.51% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (0.74 g,2 mmol), methyl 2-cyanoacetate (0.4 g,4 mmol), tetrahydropyrrole (0.0014 g,0.02 mmol) and anhydrous THF (8 mL) were added to a 100mL round bottom flask and reacted with argon protection at-10℃for 12H under stirring, and anhydrous THF in the reaction solution was evaporated under reduced pressure to give crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow-green solid 0.22g in 24.6% yield.
Example 6
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (4.93 g,25 mmol) and sodium hydroxide (4 g,100 mmol) were added and dissolved in DMSO (50 mL) and iodopropane (19.1 g,112.5 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the vacuum is pumped for three times, and the temperature is raised to 65 ℃ for reaction for 14 hours. After the reaction was completed, cooled to room temperature and diluted with 50mL of water, dichloromethane (60 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (80 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 5.54g of 2-methoxy-9-propyl-9H-carbazole as a white solid, yield 92.7%.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (9 mL) was added first, phosphorus oxychloride (6.9 g,45 mmol) was added dropwise to the three-necked flask under the protection of argon at 0℃and stirred for 15min, 2-methoxy-9-propyl-9H-carbazole (3.59 g,15 mmol) was dissolved in anhydrous DMF (26 mL) and then added dropwise to the three-necked flask, the temperature was raised to 60℃and stirred for 4H, ice water (35 mL) was added after the reaction solution cooled to room temperature and stirring was continued for 0.5H, extraction was performed with dichloromethane (35 mL. Times.3 mL), the organic phases were combined and saturated NaCl solution (70 mL. Times.2 mL) was washed, anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 3.13g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with 78.3% yield.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (5.32 g,40 mmol) and anhydrous 1, 1-dichloroethane (14 mL) are added into a 100mL round-bottomed flask, anhydrous 1, 1-dichloroethane (13 mL) is dissolved 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde (2.67 g,10 mmol) and then added dropwise into the round-bottomed flask, stirring is carried out at room temperature for 12H, after the reaction is completed, 2M HCl solution (20 mL) is added dropwise and stirring is continued for 0.5H, and 1, 1-dichloroethane in the reaction solution is evaporated under reduced pressure. Ethyl acetate (25 mL x 3) was extracted, the organic phases were combined and washed with saturated NaCl solution (50 mL x 2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 1.13g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 44.6%.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.52 g,6 mmol), 4-dimethylaminopyridine (0.73 g,6 mmol), triethylamine (1.21 g,12 mmol) and 1, 1-dichloroethane (7 mL) were added, stirred and protected with argon, t-butyldimethylchlorosilane (4.52 g,30 mmol) was dissolved in 1, 1-dichloroethane (8 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 12 hours, saturated sodium carbonate solution (15 mL, pure water) was added to the reaction mixture, extracted with dichloromethane (15 mL. Times.3), the organic phase was combined and washed with saturated NaCl solution (30 mL. Times.2, pure water), anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 0.91g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 41.44% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (1.1 g,3 mmol), methyl 2-cyanoacetate (0.74 g,7.5 mmol), tetrahydropyrrole (0.0021 g,0.03 mmol) and anhydrous THF (10 mL) were added to a 100mL round bottom flask and reacted with argon under stirring at room temperature for 12H and the anhydrous THF in the reaction solution was evaporated under reduced pressure to give the crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow-green solid 0.37g in 27.7% yield.
Example 7
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (5.91 g,30 mmol) and sodium hydroxide (6 g,150 mmol) were added and dissolved in DMSO (60 mL) and iodopropane (25.5 g,150 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the vacuum is pumped for three times, and the temperature is raised to 60 ℃ for reaction for 16 hours. After the reaction was completed, cooled to room temperature and diluted with 60mL of water, dichloromethane (60 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (100 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 6.66g of 2-methoxy-9-propyl-9H-carbazole as a white solid, yield 92.9%.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (8 mL) was added first, phosphorus oxychloride (3.83 g,25 mmol) was added dropwise to the three-necked flask at 0℃under argon protection, stirred for 15min, 2-methoxy-9-propyl-9H-carbazole (2.4 g,10 mmol) was dissolved in anhydrous DMF (16 mL) and then added dropwise to the three-necked flask, the temperature was raised to 65℃and stirred for 3H, ice water (25 mL) was added after the reaction solution cooled to room temperature, stirring was continued for 0.5H, extraction was performed with dichloromethane (25 mL. Times.3 mL), the organic phase was combined and saturated NaCl solution (50 mL. Times.2 mL) was washed, anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 2.1g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 78.7%.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (6.65 g,50 mmol) and anhydrous 1, 2-dichloroethane (14 mL) are added into a 100mL round-bottomed flask, anhydrous 1, 2-dichloroethane (13 mL) is dissolved 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde (2.67 g,10 mmol) and then added dropwise into the round-bottomed flask, stirring is carried out at room temperature for 14H, after the reaction is completed, 2M HCl solution (25 mL) is added dropwise and stirring is continued for 0.5H, and 1, 2-dichloroethane in the reaction solution is evaporated under reduced pressure. Ethyl acetate (25 mL x 3) was extracted, the organic phases were combined and washed with saturated NaCl solution (50 mL x 2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 1.2g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid with a yield of 47.3%.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.77 g,7 mmol), 4-dimethylaminopyridine (1.02 g,8.4 mmol), triethylamine (2.12 g,21 mmol) and 1, 2-dichloroethane (10 mL) were added, stirred and protected with argon, t-butyldimethylchlorosilane (5.27 g,35 mmol) was dissolved in 1, 2-dichloroethane (10 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 14 hours, a saturated sodium carbonate solution (20 mL, purified water) was added to the reaction mixture, extracted with dichloromethane (20 mL. Times.3), the organic phase was combined and washed with a saturated NaCl solution (40 mL. Times.2, purified water), anhydrous sodium sulfate was added and allowed to stand for 15 minutes, and the dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 1.12g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 43.37% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (0.73 g,2 mmol), methyl 2-cyanoacetate (0.4 g,4 mmol), tetrahydropyrrole (0.0007 g,0.01 mmol) and anhydrous THF (8 mL) were added to a 100mL round bottom flask and reacted with argon protection at-10℃under stirring for 12H, and anhydrous THF in the reaction solution was evaporated under reduced pressure to give crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow solid 0.21g in 23.7% yield.
Example 8
A preparation method of carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile comprises the following steps:
(a) Preparation of 2-methoxy-9-propyl-9H-carbazole
In a 100mL round bottom flask, 2-methoxy-9H-carbazole (4.93 g,25 mmol) and potassium hydroxide (7 g,125 mmol) were added and dissolved in DMSO (50 mL) and iodopropane (12.8 g,75 mmol) was added with stirring. After all the raw materials are added, a condensing tube and an Ar balloon are placed above the round-bottom flask, the vacuum is pumped for three times, and the temperature is raised to 65 ℃ for reaction for 14 hours. After the reaction was completed, cooled to room temperature and diluted with 50mL of water, dichloromethane (50 ml×3) was added for extraction, and after the organic phase was combined and washed with saturated NaCl solution (80 ml×2), anhydrous sodium sulfate was added for standing for 15min, and the dichloromethane was dried under reduced pressure to give crude product, which was subjected to column chromatography (PE: ea=10:1) to give 5.34g of 2-methoxy-9-propyl-9H-carbazole as a white solid, yield 89.3%.
(b) Preparation of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde
In a 250mL three-necked flask, anhydrous DMF (9 mL) was added first, phosphorus oxychloride (4.59 g,30 mmol) was added dropwise to the three-necked flask at 0℃under argon protection, and stirred for 15min, then 2-methoxy-9-propyl-9H-carbazole (3.59 g,15 mmol) was dissolved in anhydrous DMF (26 mL), and then added dropwise to the three-necked flask, the temperature was raised to 60℃to stir the reaction for 4H, ice water (35 mL) was added after the reaction solution cooled to room temperature, stirring was continued for 0.5H, extraction was performed with dichloromethane (35 mL. Times.3 mL), the organic phase was combined and washed with saturated NaCl solution (70 mL. Times.2 mL), anhydrous sodium sulfate was added and allowed to stand for 15min, and dichloromethane was evaporated under reduced pressure to obtain a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 3.1g of 2-methoxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 77.43% yield.
(c) Preparation of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde
Anhydrous aluminum trichloride (7.98 g,60 mmol) and anhydrous dichloromethane (16 mL) are added into a 100mL round-bottomed flask, anhydrous dichloromethane (16 mL) is added dropwise into the round-bottomed flask after dissolving 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde (3.2 g,12 mmol), stirring is carried out at room temperature for 12H, after the reaction is finished, 2M HCl solution (30 mL) is added dropwise for continuous stirring for 0.5H, and dichloromethane in the reaction solution is evaporated under reduced pressure. Ethyl acetate (30 ml×3) was extracted, the organic phases were combined and washed with saturated NaCl solution (60 ml×2), anhydrous sodium sulfate was added and left to stand for 15min, and ethyl acetate was evaporated under reduced pressure to give a crude product. EA: pe=1: 5 as mobile phase, the crude product was purified by column chromatography to give 1.4g of 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 46% yield.
(d) Preparation of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde
In a 100mL two-necked flask, 2-hydroxy-9-propyl-9H-carbazole-3-carbaldehyde (1.52 g,6 mmol), 4-dimethylaminopyridine (1.17 g,9.6 mmol), triethylamine (3.03 g,30 mmol) and 1, 1-dichloroethane (7 mL) were added, stirred and protected with argon, t-butyldimethylchlorosilane (4.52 g,30 mmol) was dissolved in 1, 1-dichloroethane (8 mL), then the mixture was added dropwise to the two-necked flask at-10℃and stirred for 10 hours, a saturated sodium carbonate solution (15 mL, prepared with pure water) was added to the reaction mixture, extracted with dichloromethane (15 mL. Times.3), the organic phases were combined and washed with a saturated NaCl solution (30 mL. Times.2, prepared with pure water), and anhydrous sodium sulfate was added to stand for 15 minutes, and the dichloromethane was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give 0.89g of 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde as yellow solid in 40.3% yield.
(e) Preparation of methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate
2- ((tert-Butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde (1.1 g,3 mmol), methyl 2-cyanoacetate (0.59 g,6 mmol), tetrahydropyrrole (0.0032 g,0.045 mmol) and anhydrous THF (11 mL) were added to a 100mL round bottom flask, and the reaction was stirred at room temperature under argon for 12H, and anhydrous THF in the reaction solution was evaporated under reduced pressure to give a crude product. EA: pe=1: 20 as mobile phase, the crude product was purified by column chromatography to give methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate as a yellow-green solid 0.28g in 20.8% yield.
The physical properties and the structure of the 2-methoxy-9-propyl-9H-carbazole obtained in the step (a) are as follows:
MP:100.3-101.7℃； 1 H NMR(400MHz,DMSO-d 6 )δ8.00(d,J＝8.8Hz,2H),7.52(s,1H),7.34(d,J＝1.4Hz,1H),7.18–7.10(m,2H),6.80(dd,J＝8.4,2.4Hz,1H),4.34(s,2H),3.88(s,3H),1.79(d,J＝7.2Hz,2H),0.88(t,J＝7.6Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ159.0,141.9,140.7,124.3,123.0,121.1,119.5,118.9,116.8,108.5,106.9,93.3,55.7,44.6,22.2,11.9；ESI-HRMS C 16 H 17 NO([M+H] + ):calcd 240.1382,found 240.1385.
the physical properties and the structure of the 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde obtained in the step (b) are as follows:
MP:104.5-105.9℃； 1 H NMR(400MHz,CDCl 3 )δ10.48(s,1H),8.57(s,1H),8.02(d,J＝7.6Hz,1H),7.49–7.39(m,1H),7.36(d,J＝8.0Hz,1H),7.26(s,1H),6.75(s,1H),4.22(t,J＝7.2Hz,2H),4.03(s,3H),1.93(d,J＝7.2Hz,2H),1.00(t,J＝7.6Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ189.4,161.6,145.8,141.3,125.6,123.5,121.7,120.4,120.2,118.4,116.9,109.0,90.4,55.9,44.8,22.1,11.8；ESI-HRMS C 17 H 17 NO 2 ([M+H] + ):calcd 268.1331,found 268.1331.
the physical properties and the structure of the 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde obtained in the step (c) are as follows:
MP:115.1-116.7℃； 1 H NMR(400MHz,CDCl 3 )δ11.52(s,1H),9.91(s,1H),8.14(s,1H),7.99(d,J＝8.8Hz,1H),7.49–7.40(m,1H),7.36(d,J＝8.4Hz,1H),7.30–7.25(m,1H),6.80(s,1H),4.17(t,J＝7.2Hz,2H),1.90(h,J＝7.6Hz,2H),0.98(t,J＝7.6Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ195.0,161.2,146.4,141.6,127.2,125.9,123.1,120.6,119.8,117.3,114.9,109.2,95.1,44.9,21.9,11.7；ESI-HRMS C 16 H 15 NO 2 ([M+H] + ):calcd 254.1175,found 245.1177.
the physical properties and the structure of the 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-formaldehyde obtained in the step (d) are as follows:
MP:80.1-81.7℃； 1 H NMR(400MHz,CDCl 3 )δ10.48(s,1H),8.57(s,1H),8.03(d,J＝7.6Hz,1H),7.48–7.40(m,1H),7.36(d,J＝8.0Hz,1H),7.26(s,1H),6.72(s,1H),4.19(t,J＝6.8Hz,2H),1.91(h,J＝7.2Hz,2H),1.07(s,9H),0.98(t,J＝7.6Hz,3H),0.33(s,6H)； 13 CNMR(101MHz,CDCl 3 )δ189.77,158.05,145.77,141.51,125.82,123.46,121.16,120.56,120.35,120.34,118.17,108.99,98.71,44.86,25.80,22.12,18.47,11.91,-4.18；ESI-HRMS C 22 H 29 NO 2 Si([M+H] + ):calcd 368.2040,found 368.2035.
methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate obtained by the step (e) has the following physical properties and structure:
MP:158.4-159.8℃；IR:υ2952.60,2923.26,2849.92,2210.33,1723.31,1494.46,1459.26,1356.57,1233.35,1095.45cm -1 ； 1 H NMR(400MHz,CDCl 3 )δ9.23(s,1H),8.92(s,1H),8.10(d,J＝7.6Hz,1H),7.44(s,1H),7.36(s,1H),7.27(d,J＝4.0Hz,1H),6.76(s,1H),4.18(t,J＝6.8Hz,2H),3.93(s,3H),1.91(d,J＝7.2Hz,2H),1.10(s,9H),0.98(t,J＝7.6Hz,3H),0.31(s,6H)； 13 C NMR(101MHz,DMSO-d 6 )δ163.90,155.86,150.23,145.65,141.71,126.77,122.47,121.13,121.01,120.13,118.12,117.40,115.24,110.63,100.04,96.34,53.46,44.35,26.01,22.11,18.51,11.81,-4.15；ESI-HRMS C 26 H 32 N 2 O 3 Si([M+H] + ):calcd 449.2254,found449.2247.
fluoride fluorescent probe function test was performed on methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate (SCC) prepared in example 1-8 above:
methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate (SCC) was tested for changes in fluorescence of IPA solution before and after reaction with fluoride ions, see FIG. 2 for spectra of the coexistence of SCC with fluoride ions and SCC-F fluorescence spectra in IPA. FIG. 2 (a) shows the excitation spectrum (Ex) and emission spectrum (Em) of SCC and SCC in the presence of fluorine ions, [ SCC ]]＝1μM，[F - ]The spectra measured when the excitation spectrum was at a fixed emission wavelength (em=525 nm) and the emission spectrum was at a fixed excitation wavelength (ex=386 nm) are consistent with the SCC-F fluorescence spectrum measured in fig. 2 (b), which illustrates the formation of a cyclized product after the reaction of SCC with fluoride ions, confirming the mechanism of the reaction of SCC with fluoride ions. The inset photo shows the SCC or SCC and fluoride ion coexisting solution taken under 365nm UV lamp. It can be seen that at an excitation wavelength of 386nm, the fluorescence intensity emitted by the fluoride-free SCC solution was weak, whereas the fluorescence intensity emitted by the fluoride-containing SCC solution was significantly enhanced, and the solution exhibited yellowish green fluorescence. Experimental results indicate that in IPA, probe SCC produces a significant change in fluorescence signal for fluoride ion recognition.
The effect of fluoride concentration on fluorescence intensity of the solution after the reaction was determined by a fluorescence titration experiment, see FIG. 3 for spectra of fluoride (0-10. Mu.M) titrating SCC (0.5. Mu.M). The solvent was THF-HEPES/NaOH (50 mm,7.4,9:1, v/v) (emission wavelength ex=386 nm); FIG. 3a is a fluorescence titration spectrum of fluoride (0.about.10. Mu.M) of SCC (0.5. Mu.M). As can be seen from the graph, SCC (0.5. Mu.M) emits weak fluorescence at 504nm under 386nm monochromatic light excitation, and as fluoride ions are added, the fluorescence emission at 504nm gradually increases, and when the fluoride ion concentration reaches 5. Mu.M, the fluorescence intensity increases to saturation. The relationship between the fluorescence intensity of SCC at 504nm and the concentration of fluorine ions is fitted (see figure 3 b), and the fluorescence intensity and the concentration of fluorine ions have good linear relationship in the range of 0-5 mu M, so that the quantitative detection of fluorine ions can be realized.
The response time of SCC to detect fluoride ion was determined, see fig. 4, response time of SCC (1 μm) to fluoride ion (20 μm) (ex=3836 nm, em=525 nm). As can be seen from the graph, the fluorescence intensity reached the highest value after 40min of reaction. The probe SCC can thus respond rapidly to fluoride ions.
The imaging ability of probe SCC on HepG2 cells was examined with an Olympus IX71 inverted fluorescence microscope. See FIG. 5 for fluorescence images of HepG2 cells treated with SCC (1. Mu.M) and fluoride (5. Mu.M). Upon incubation of SCC (1 μm) with cells under the Cyan channel, red fluorescence is generated; with the addition of fluoride ions, the red fluorescence is reduced. The experimental result shows that the fluorescence of the probe SCC is obviously changed before and after the probe SCC recognizes fluoride ions in cells, and the probe SCC has good cell imaging capability and can detect the fluoride ions in the cells.
In conclusion, the SCC is a ratio type fluorescent probe with the characteristics of rapid response to fluorine ions, strong anti-interference performance and high sensitivity, can be used for quantitatively detecting fluorine ions in a water sample and imaging living cells, and has a good application prospect.
Finally, it should be noted that the above embodiments are merely representative examples of the present invention. Obviously, the technical solution of the invention is not limited to the above-described embodiments, but many variations are possible. All modifications directly derived or suggested to one skilled in the art from the present disclosure should be considered as being within the scope of the present invention.

Claims (5)

1. Carbazole-based reactive fluoride fluorescent probe based on aromatic acrylonitrile is characterized by comprising the following specific structural formula:
。
2. the method for preparing the carbazole-based reactive fluoride fluorescent probe based on the aralkenyl nitrile as claimed in claim 1, which is characterized by comprising the following steps:
(a) 2-methoxy-9H-carbazole and iodopropane are subjected to substitution reaction to generate 2-methoxy-9-propyl-9H-carbazole:
the molar ratio of the substitution reagent to the 2-methoxy-9H-carbazole is 2-5:1, the molar ratio of the alkali to the 2-methoxy-9H-carbazole is 2-5:1, and the reaction temperature is 60-70 ℃;
(b) Formylation reaction of 2-methoxy-9-propyl-9H-carbazole with N, N-dimethylformamide and phosphorus oxychloride to generate 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde:
the molar ratio of the reactant to the 2-methoxy-9-propyl-9H-carbazole is 2-5:1, and the reaction temperature is 55-65 ℃;
(c) Hydrolyzing the 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde to generate 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde:
the feeding molar ratio of the reaction reagent to the 2-methoxy-9-propyl-9H-carbazole-3-formaldehyde is 2-5:1, and the reaction temperature is room temperature;
(d) 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde and tert-butyl dimethyl chlorosilane undergo substitution reaction to obtain 2- ((tert-butyl dimethyl silicon based) oxy) -9-propyl-9H-carbazole-3-formaldehyde:
the molar ratio of the reaction reagent to the 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde is 2-5:1, the molar ratio of the catalyst to the 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde is 1-2:1, the molar ratio of the alkali to the 2-hydroxy-9-propyl-9H-carbazole-3-formaldehyde is 2-5:1, and the reaction temperature is-10 ℃;
(e) 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-carbaldehyde was reacted with methyl 2-cyanoacetate to give the title compound methyl 3- (2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazol-3-yl) -2-cyanoacrylate:
The feeding molar ratio of the reactant to the 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-formaldehyde is 1.5-2.5:1, the ratio of the catalyst to the 2- ((tert-butyldimethylsilyl) oxy) -9-propyl-9H-carbazole-3-formaldehyde is 0.005-0.015:1, and the reaction temperature is-10 ℃;
the solvent in the step (a) is dimethyl sulfoxide or N, N-dimethylformamide, the substitution reagent is iodopropane, and the alkali is sodium hydroxide or potassium hydroxide;
the solvent in the step (b) is anhydrous N, N-dimethylformamide, and the reaction reagent is phosphorus oxychloride;
the solvent in the step (c) is anhydrous dichloromethane, anhydrous 1, 2-dichloroethane or anhydrous 1, 1-dichloroethane, and the reaction reagent is aluminum trichloride;
the solvent in the step (d) is dichloromethane, 1, 2-dichloroethane or 1, 1-dichloroethane, the reaction reagent is tert-butyl dimethyl chlorosilane, the catalyst is 4-dimethylaminopyridine, and the base is triethylamine or diethylamine;
in the step (e), the solvent is anhydrous tetrahydrofuran, the reaction reagent is 2-cyanomethyl acetate, and the catalyst is tetrahydropyrrole.
3. The use of the carbazole-based reactive fluoride ion fluorescent probe based on aralkenylnitrile according to claim 1 for preparing fluoride ion detection reagent.
4. The use according to claim 3, wherein the fluoride ion detection is of a water sample.
5. The use of the carbazole-reactive fluoride ion fluorescent probe based on aralkenylnitrile according to claim 1 for preparing living cell fluorescence imaging reagent.
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Publication number Priority date Publication date Assignee Title
CN104418875A (en) * 2013-08-28 2015-03-18 苏州罗兰生物科技有限公司 Fluorescent molecular probe for detecting fluoride ions as well as synthesis method and application thereof
CN104610955A (en) * 2014-05-16 2015-05-13 中南大学 Synthesis method and application of ratiometric fluorescent molecular probe for simultaneously detecting fluorine ion and sulfite radical
CN111039972A (en) * 2019-11-29 2020-04-21 华南师范大学 Application of 4-hydroxycarbazole compound as fluorine ion fluorescent probe
CN114014887A (en) * 2021-12-03 2022-02-08 贵州仁威生物科技有限责任公司 Rhodanine fluorescent probe compound for detecting fluorine ions and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104418875A (en) * 2013-08-28 2015-03-18 苏州罗兰生物科技有限公司 Fluorescent molecular probe for detecting fluoride ions as well as synthesis method and application thereof
CN104610955A (en) * 2014-05-16 2015-05-13 中南大学 Synthesis method and application of ratiometric fluorescent molecular probe for simultaneously detecting fluorine ion and sulfite radical
CN111039972A (en) * 2019-11-29 2020-04-21 华南师范大学 Application of 4-hydroxycarbazole compound as fluorine ion fluorescent probe
CN114014887A (en) * 2021-12-03 2022-02-08 贵州仁威生物科技有限责任公司 Rhodanine fluorescent probe compound for detecting fluorine ions and preparation method thereof

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