Preparation method of water-soluble naphthyl nut arene and construction of molecular beaker

Abstract

The invention discloses a preparation method of water-soluble naphthyl nut arene and construction of a molecular beaker. The method comprises the following steps: reacting 2, 7-dibromonaphthalene (compound 1) with 2, 5-dimethoxyphenylboronic acid to generate a compound 2; demethylating through boron tribromide to obtain a compound 3; then reacting with dihaloalkane to generate a compound 4; then carrying out cyclization with methylal to obtain H1; then reacting with trimethylamine to obtain H2; then, H2 and sodium phytate are used for constructing a molecular beaker system; according to the method, a series of water-soluble naphthyl nut arenes with different alkane chain lengths and different halide ions are prepared, and an efficient molecular beaker system is constructed. The molecular beaker system has the advantages of being simple and convenient to synthesize, low in cost, adjustable in height, capable of effectively improving the binding capacity with specific guest molecules and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and application, and relates to the preparation of water-soluble naphthyl nut aromatic hydrocarbons and the construction of a molecular beaker. Background Art

[0002] For host-guest application fields, stronger host-guest binding performance is required. Stronger binding performance means lower detection limit (in the field of fluorescent probes), more precise release (in the field of drug delivery), etc. Therefore, stronger supramolecular macrocycles are urgently needed to achieve super-strong binding.

[0003] Introducing different fragments and derivative structures through synthesis is a useful method. However, constructing a cavity with stronger binding force means doubling the difficulty of synthesis. At the same time, a single macrocycle is not controllable, and its application is limited. Summary of the Invention

[0004] To address the shortcomings of the existing technology, the present invention provides a method for preparing a water-soluble naphthyl nutracene and constructing a molecular beaker. This compound, as a supramolecular macrocyclic aromatic hydrocarbon and molecular beaker assembly, is simple to synthesize, low-cost, and significantly enhances guest binding capacity while also possessing tunable properties.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] A method for preparing quaternary ammonium salt-naphthyl[3]arene.

[0007]

[0008] Wherein, R=-CH2(CH2) n N + (CH3)3X - ; n = 2 ~ 3; X = Br, Cl.

[0009] A method for preparing water-soluble fluorescent naphthyl[3]arene comprises the following steps:

[0010] (1) Synthesis of compound H1

[0011]

[0012] a. Dissolve compound 1, 2,5-dimethoxyphenylboronic acid, and a base in a mixed solvent. Under a nitrogen atmosphere, stir and add tetrakistriphenylphosphine palladium catalyst. Heat and reflux for 6-12 hours. Extract with dichloromethane and dry with anhydrous Na2SO4. Remove the solvent by rotary evaporation and perform column chromatography to obtain compound 2.

[0013]

[0014] b. Under inert gas protection, compound 2 was dissolved in an organic solvent, boron tribromide (BBr3) was added, and the mixture was stirred at 0-35°C for 5-12 hours. After the reaction, ice water was added to precipitate the solid, which was filtered, washed with dichloromethane / water several times, and dried in vacuo to obtain compound 3;

[0015]

[0016] c. Under inert gas protection, add a dihaloalkane and a base to a high-boiling-point solvent, add the solution of compound 3 dropwise at 60-80°C, stir for 2-12 hours, extract with dichloromethane and dry with anhydrous Na2SO4, remove the solvent by rotary evaporation, and obtain fluorescent compound 4 by column chromatography;

[0017]

[0018] d. Dissolve the fluorescent compound 4 in chloroform, add dimethoxymethane and boron trifluoride etherate in sequence, stir for 0.5-1h, extract with dichloromethane and dry with anhydrous Na2SO4, remove the solvent by rotary evaporation, and obtain H1 by column chromatography;

[0019]

[0020] (2) H1 is added to a polar solvent, trimethylamine solution is added, refluxed for 12 h to 24 h, filtered, reprecipitated with ethanol / acetone, and dried under vacuum at 60-80 °C for 12-24 h to obtain H2.

[0021] In the above method, in step a, the mixed solvent includes a toluene / ethanol / water mixed solvent and a tetrahydrofuran / water mixed solvent; the base is potassium carbonate or sodium carbonate; the volume ratio of toluene:ethanol:water in the toluene / ethanol / water mixed solvent is (4-6):(2-3):1; the volume ratio of tetrahydrofuran to water in the tetrahydrofuran / water mixed solvent is 5:1-3:1; and the amount of the catalyst tetrakistriphenylphosphine palladium added is 0.025-0.1 times that of compound 1.

[0022] In the above method, in step b, the organic solvent is dichloromethane or chloroform; the amount of boron tribromide used is 6-10 times that of compound 2.

[0023] In the above method, in step c, the high boiling point solvent includes water, ethanol, acetonitrile, DMF, and acetone; and the base is potassium hydroxide, sodium hydroxide, potassium carbonate, or sodium carbonate.

[0024] In the above method, in step d, the amount of dimethoxymethane added is 5-10 times that of compound 3; the amount of boron trifluoride ether added is 20-30 times that of compound 3.

[0025] In the above method, the concentration of compound 4 should be lower than 2 mol / L.

[0026] In the above method, in step (2), the polar solvent includes ethanol and acetonitrile; and the amount of trimethylamine added is 60-120 times that of compound H1.

[0027] In the above method, the inert gas used is nitrogen or argon.

[0028] The reaction scheme of the present invention is:

[0029]

[0030] A water-soluble naphthyl nutracenyl isocyanate can be combined with phytic acid to form an effective molecular beaker system. Specifically, phytic acid and water-soluble fluorescent naphthyl ring [3] arene are mixed at a molar ratio of 1:2 to 1:1. The concentration of the water-soluble fluorescent naphthyl ring [3] arene in the molecular beaker system is controlled within a range of 0.5 μM to 1 mM. This supramolecular macrocyclic assembly system has the advantages of simple synthesis, low cost, high adjustability, and can effectively enhance the bonding ability with specific guest molecules.

[0031] Compared with the prior art, the present invention has the following advantages:

[0032] (1) The present invention provides a quaternary ammonium salt naphthyl nut aromatic hydrocarbon that is simple and systematic to synthesize, and the strongly conjugated naphthyl macrocycle has a strong fluorescence signal and has a strong binding ability to negatively charged guests, aromatic compound guests, etc.

[0033] (2) The quaternary ammonium salt naphthyl nut aromatic hydrocarbon synthesized by the present invention can combine with phytic acid to form a molecular beaker-shaped assembly system, which can significantly improve the binding ability with the guest, and the method is simple and effective. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the NMR spectrum of the quaternary ammonium salt naphthyl nut aromatic solution configured in Example 2;

[0035] Figure 2 The UV-visible absorption spectrum and fluorescence emission spectrum of the quaternary ammonium salt naphthyl nut aromatic solution prepared in Example 2 are shown;

[0036] Figure 3 The fluorescence titration spectrum and fluorescence titration curve of the quaternary ammonium salt naphthyl nut aromatic solution and phytic acid prepared in Example 2 are shown;

[0037] Figure 4 The fluorescence titration spectrum and fluorescence titration curve in Example 7;

[0038] Figure 5 The fluorescence titration spectrum and fluorescence titration curve in Example 8 are shown. DETAILED DESCRIPTION

[0039] The specific examples of the present invention are further described below with reference to the accompanying drawings and specific embodiments, but the scope of protection claimed by the present invention is not limited to the scope described in the embodiments.

[0040] Example 1

[0041]

[0042] The synthesis steps are as follows:

[0043] (1) Weigh 1 g of 2,7-dibromonaphthalene (Compound 1), 2 g of 2,5-dimethoxyphenylboronic acid, and 10 g of anhydrous potassium carbonate into a 250 ml round-bottom flask. Add toluene / ethanol / water, pump nitrogen three times, add 200 mg of tetrakistriphenylphosphine palladium, pump nitrogen three times again, heat to 90°C, and react for 6 h. After the reaction is complete, extract with water, collect the organic phase, dry over anhydrous sodium sulfate, and spin dry. Chromatography is performed on a 200-300 mesh silica gel column using a 1:1 ratio of petroleum ether to dichloromethane as the eluent. Recrystallization from dichloromethane / methanol yields Compound 2 as white crystals with a yield of 90%.

[0044] (2) 1.2 g of compound 2 was weighed, added to 200 ml of dichloromethane, and the mixture was evacuated with nitrogen three times. 12 ml of a 2 M dichloromethane solution of boron tribromide was added and allowed to react for 24 h. After the reaction, ice water was added to quench the mixture, stirred for 1 h, filtered, and washed alternately with dichloromethane and water three times. The mixture was dried in a vacuum oven at 70°C for 24 h to obtain compound 3 with a yield of 95%.

[0045] (3) Weigh 10 g of potassium carbonate into a three-necked flask, add 200 ml of acetonitrile and 25 ml of 1,4-dibromobutane, dissolve compound 3 in 50 ml of acetonitrile, and add the mixture dropwise to the three-necked flask under nitrogen and reflux conditions. The addition should be complete within 1 hour. The reaction should be allowed to proceed for 24 hours. Filter, extract with dichloromethane, and dry with anhydrous Na2SO4. The solvent should be removed by rotary evaporation. Column chromatography should yield compound 4 in 70% yield.

[0046] (4) 1.6 g of compound 4 was weighed into a two-necked flask, 200 ml of chloroform was added, and the mixture was evacuated and filled with nitrogen three times. 1 ml of methylal and 4 ml of boron trifluoride etherate were added. Stirring was continued at room temperature and the reaction was stopped by a microplate reader until the starting material disappeared. Saturated sodium bicarbonate solution was added. Extraction and separation were performed to obtain compound H1 in a 15% yield.

[0047] (5) Weigh 100 mg of compound H1, add 50 ml of ethanol, add 10 ml of 2M trimethylamine ethanol solution, heat and reflux for 24 h. Spin dry, add ethanol / acetone to reprecipitate. Yield 80%. Figure 1As shown, the H NMR spectrum and C NMR spectrum of H2 were obtained, the NMR integral and NMR shift were consistent with the H2 theory, the carbon spectrum numbers corresponded, and the obtained product was indeed the desired synthesized H2 molecule.

[0048] Example 2

[0049]

[0050] The synthesis steps are as follows:

[0051] (1) Weigh 1 g of 2,7-dibromonaphthalene, 2 g of 2,5-dimethoxyphenylboronic acid, and 10 g of anhydrous potassium carbonate into a 250 ml round-bottom flask, add toluene / ethanol / water, pump nitrogen three times, add 200 mg of tetrakistriphenylphosphine palladium, pump nitrogen three times again, heat to 90°C, and react for 6 h. After the reaction is complete, extract with water, collect the organic phase, dry over anhydrous sodium sulfate, and spin dry. Chromatography is performed on a 200-300 mesh silica gel column with a 1:1 ratio of petroleum ether to dichloromethane as the eluent. Recrystallization from dichloromethane / methanol yields white crystals (Compound 2) with a yield of 90%.

[0052] (2) 1.2 g of compound 2 was weighed, added to 200 ml of dichloromethane, and the mixture was evacuated with nitrogen three times. 12 ml of a 2 M dichloromethane solution of boron tribromide was added and allowed to react for 24 h. After the reaction, ice water was added to quench the mixture, stirred for 1 h, filtered, and washed alternately with dichloromethane and water three times. The mixture was dried in a vacuum oven at 70°C for 24 h to obtain compound 3 with a yield of 95%.

[0053] (3) 1.2 g of compound 3 and 10 g of potassium carbonate were weighed into a three-necked flask. 25 ml of deionized water and 25 ml of 1,4-dichlorobutane were added. The mixture was refluxed under nitrogen for 12 h. The filtrate was filtered, dried, and mixed with silica gel to obtain compound 4 in a 75% yield.

[0054] (4) Weigh 1.6 g of compound 3 into a two-necked flask, add 200 ml of chloroform, and evacuate and refill the flask with nitrogen three times. Then, add 1 ml of methylal and 4 ml of boron trifluoride etherate. Stir at room temperature and track the reaction with a microplate until the starting material disappears. Stop the reaction and add saturated sodium bicarbonate solution. Extract and separate the liquids to obtain compound H1. Yield: 10%.

[0055] (5) Weigh 100 mg of compound H1, add 50 ml of ethanol, add 10 ml of 2M trimethylamine ethanol solution, heat and reflux for 24 h, spin dry, and add ethanol / acetone to reprecipitate to obtain compound H2 with a yield of 80%.

[0056] Example 3

[0057]

[0058] The synthesis steps are as follows:

[0059] (1) Weigh 1 g of 2,7-dibromonaphthalene, 2 g of 2,5-dimethoxyphenylboronic acid, and 10 g of anhydrous potassium carbonate into a 250 ml round-bottom flask, add toluene / ethanol / water, pump nitrogen three times, add 200 mg of tetrakistriphenylphosphine palladium, pump nitrogen three times again, heat to 90°C, and react for 6 h. After the reaction is complete, extract with water, collect the organic phase, dry over anhydrous sodium sulfate, and spin dry. Chromatography is performed on a 200-300 mesh silica gel column with a 1:1 ratio of petroleum ether to dichloromethane as the eluent. Recrystallization from dichloromethane / methanol yields white crystals (Compound 2) with a yield of 90%.

[0060] (2) 1.2 g of compound 2 was weighed, added to 200 ml of dichloromethane, and the mixture was evacuated with nitrogen three times. 12 ml of a 2 M dichloromethane solution of boron tribromide was added and allowed to react for 24 h. After the reaction, ice water was added to quench the mixture, stirred for 1 h, filtered, and washed alternately with dichloromethane and water three times. The mixture was dried in a vacuum oven at 70°C for 24 h to obtain compound 3 with a yield of 95%.

[0061] (3) 1.2 g of compound 3 and 10 g of potassium carbonate were weighed into a three-necked flask. 25 ml of deionized water and 25 ml of 1,3-dichloropropane were added. The mixture was reacted under reflux under nitrogen for 12 h. The filtrate was filtered, dried, and mixed with silica gel to obtain compound 4 in a 60% yield.

[0062] (4) Weigh 1.6 g of compound 4 into a two-necked flask, add 200 ml of chloroform, and evacuate and refill the flask with nitrogen three times. Then, add 1 ml of methylal and 4 ml of boron trifluoride etherate. Stir at room temperature and track the reaction plate until the starting material disappears. Stop the reaction and add saturated sodium bicarbonate solution. Extract and separate the liquids to obtain H1 in a 15% yield.

[0063] (5) Weigh 100 mg of compound H1, add 50 ml of ethanol, add 10 ml of 2M trimethylamine ethanol solution, heat and reflux for 24 h, spin dry, and add ethanol / acetone to reprecipitate to obtain H2 with a yield of 80%.

[0064] Example 4

[0065]

[0066] The synthesis steps are as follows:

[0067] (1) Weigh 1 g of 2,7-dibromonaphthalene, 2 g of 2,5-dimethoxyphenylboronic acid, and 10 g of anhydrous potassium carbonate into a 250 ml round-bottom flask, add toluene / ethanol / water, pump nitrogen three times, add 200 mg of tetrakistriphenylphosphine palladium, pump nitrogen three times again, heat to 90°C, and react for 6 h. After the reaction is complete, extract with water, collect the organic phase, dry over anhydrous sodium sulfate, and spin dry. Chromatography is performed on a 200-300 mesh silica gel column with a 1:1 ratio of petroleum ether to dichloromethane as the eluent. Recrystallization from dichloromethane / methanol yields white crystals (Compound 2) with a yield of 90%.

[0068] (2) 1.2 g of compound 2 was weighed, added to 200 ml of dichloromethane, and the mixture was evacuated with nitrogen three times. 12 ml of a 2 M dichloromethane solution of boron tribromide was added and allowed to react for 24 h. After the reaction, ice water was added to quench the mixture, stirred for 1 h, filtered, and washed alternately with dichloromethane and water three times. The mixture was dried in a vacuum oven at 70°C for 24 h to obtain compound 3 with a yield of 95%.

[0069] (3) 1.2 g of compound 3 and 10 g of potassium carbonate were weighed into a three-necked flask. 25 ml of deionized water and 25 ml of 1,2-dichloroethane were added. The mixture was refluxed under nitrogen for 12 h. The filtrate was filtered, dried, and mixed with silica gel to obtain compound 4 in a 50% yield.

[0070] (4) Weigh 1.6 g of compound 4 into a two-necked flask, add 200 ml of chloroform, and evacuate and refill the flask with nitrogen three times. Then, add 1 ml of methylal and 4 ml of boron trifluoride etherate. Stir at room temperature and track the reaction plate until the starting material disappears. Stop the reaction and add saturated sodium bicarbonate solution. Extract and separate the liquids to obtain H1 in a 15% yield.

[0071] (5) Weigh 100 mg of compound H1, add 50 ml of ethanol, add 10 ml of 2M trimethylamine ethanol solution, heat and reflux for 24 h, spin dry, and add ethanol / acetone to reprecipitate to obtain compound H2 with a yield of 80%.

[0072] Example 5

[0073] Prepare 10μM quaternary ammonium salt H2 solution and measure the UV absorption spectrum and fluorescence emission spectrum. Figure 2 The maximum ultraviolet absorption wavelength of H2 is 305nm, and the strongest fluorescence emission wavelength is 438nm.

[0074] Example 6

[0075] Prepare 0.5mM quaternary ammonium salt H2 solution and measure the fluorescence titration curve with phytic acid solution at pH=3.7. Figure 3The fluorescence titration spectrum and fluorescence titration curve are respectively fitted using the H@G=1:1 and 1:2 models (i.e., the binding ratio of H2 to sodium phytate). It is found that the H@G=1:2 model has a better fitting effect, so the binding constant of H2 to phytic acid K1*K2=6*10 10 Based on this data, a molecular beaker system based on water-soluble fluorescent naphthalene ring can be constructed.

[0076] Example 7

[0077] Prepare an aqueous solution of anthracene at pH = 3.7, 5 μM, and titrate with H2 to obtain the fluorescence titration curve of H2 and anthracene. Figure 4 (a) and (b) are the fluorescence titration spectrum and fluorescence titration curve, respectively. Using the H@G=1:1 and 1:2 models, it is found that the H@G=1:2 model has a better fitting effect, and the complexation constant K of the H2 molecule itself combined with the anthracene molecule is obtained as 3.8*10 11 M -2 Similarly, a solution of 5 μM anthracene and 5 μM sodium phytate was prepared at pH 3.7, and the fluorescence titration curve of H2 and anthracene was measured by titration with H2. Figure 4 (c) and (d) are the fluorescence titration spectrum and fluorescence titration curve respectively. Using H@G=1:1 and 1:2 models, it is found that the H@G=1:2 model has a better fitting effect, and the apparent complexation constant K=3.9*10 12 M -2 ,Through comparison, it was found that the introduction of sodium phytate greatly enhanced the ,ability of H2 binding to anthracene molecules, and the ,molecule beaker system was effective.

[0078] Example 8

[0079] Prepare a 5μM aqueous solution of 2-anthracenecarboxylic acid at pH 3.7 and titrate with H2 to obtain the fluorescence titration curve of H2 and 2-anthracenecarboxylic acid. Figure 5 (a) and (b) are the fluorescence titration spectrum and fluorescence titration curve, respectively. Using the H@G=1:1 and 1:2 models, it is found that the H@G=1:2 model has a better fitting effect, and the complexation constant K of the H2 molecule itself combined with the 2-anthracenecarboxylic acid molecule is obtained as 1.3*10 12 M -2 Similarly, a solution of 5 μM 2-anthracenecarboxylic acid and 5 μM sodium phytate was prepared at pH 3.7, and the fluorescence titration curve of H2 and 2-anthracenecarboxylic acid was measured by titration with H2. Figure 5 (c) and (d) are the fluorescence titration spectra and fluorescence titration curves, respectively. Using the H@G=1:1, 1:2, and 1:3 models, it was found that the H@G=1:3 model had a better fitting effect, and the apparent complexation constant K=7.5*10 18 M -3By comparison, it was found that the introduction of sodium phytate not only enhanced the ability of H2 to bind to 2-anthracenecarboxylic acid, but also increased the number of H2 binding to 2-anthracenecarboxylic acid, indicating that the molecular beaker is effective.

[0080] The present invention is not limited to the above-mentioned optional implementation modes. Anyone can derive other forms of products under the guidance of the present invention. However, no matter what changes are made in the shape or structure, any technical solution that falls within the scope defined by the claims of the present invention falls within the scope of protection of the present invention.

Claims

1. A water-soluble fluorescent naphthyl[3]arene, characterized in that: Its structural formula is: Wherein, R=-CH2(CH2) n N + (CH3)3X - ; n = 2 to 3, X is Br or Cl.

2. The method for preparing a water-soluble fluorescent naphthyl ring [3] aromatic hydrocarbon according to claim 1, characterized in that: The following steps are involved: (1) Synthesis of compound H1 a. Dissolve compound 1, 2,5-dimethoxyphenylboronic acid, and a base in a mixed solvent. Under a nitrogen atmosphere, stir and add tetrakistriphenylphosphine palladium catalyst. Heat and reflux for 6-12 hours. Extract with dichloromethane and dry with anhydrous Na2SO4. Remove the solvent by rotary evaporation and perform column chromatography to obtain compound 2. b. Under inert gas protection, compound 2 was dissolved in an organic solvent, boron tribromide (BBr3) was added, and the mixture was stirred at 0-35°C for 5-12 hours. After the reaction, ice water was added to precipitate the solid, which was filtered, washed with dichloromethane / water several times, and dried in vacuo to obtain compound 3; c. Under inert gas protection, add a dihaloalkane and a base to a high-boiling-point solvent, add the solution of compound 3 dropwise at 60-80°C, stir for 2-12 hours, extract with dichloromethane and dry with anhydrous Na2SO4, remove the solvent by rotary evaporation, and obtain fluorescent compound 4 by column chromatography; d. Dissolve the fluorescent compound 4 in chloroform, add dimethoxymethane and boron trifluoride etherate in sequence, stir for 0.5-1h, extract with dichloromethane and dry with anhydrous Na2SO4, remove the solvent by rotary evaporation, and obtain H1 by column chromatography; (2) H1 is added to a polar solvent, trimethylamine solution is added, refluxed for 12 h to 24 h, filtered, reprecipitated with ethanol / acetone, and dried under vacuum at 60-80 °C for 12-24 h to obtain H2.

3. The method for preparing water-soluble fluorescent naphthyl ring [3] aromatic hydrocarbons according to claim 2, characterized in that: In step a, the mixed solvent includes a toluene / ethanol / water mixed solvent and a tetrahydrofuran / water mixed solvent; the base is potassium carbonate or sodium carbonate; the volume ratio of toluene:ethanol:water in the toluene / ethanol / water mixed solvent is (4-6):(2-3):1; the volume ratio of tetrahydrofuran to water in the tetrahydrofuran / water mixed solvent is 5:1-3:1; and the amount of the catalyst tetrakistriphenylphosphine palladium added is 0.025-0.1 times that of compound 1.

4. The method for preparing water-soluble fluorescent naphthyl ring [3] aromatic hydrocarbons according to claim 2, characterized in that: In step b, the organic solvent is dichloromethane or chloroform; the amount of boron tribromide used is 6-10 times that of compound 2.

5. The method for preparing water-soluble fluorescent naphthyl ring [3] aromatic hydrocarbons according to claim 2, characterized in that: In step c, the high boiling point solvent includes water, ethanol, acetonitrile, DMF, and acetone; and the base is potassium hydroxide, sodium hydroxide, potassium carbonate, or sodium carbonate.

6. The method for preparing water-soluble fluorescent naphthyl ring [3] aromatic hydrocarbons according to claim 2, characterized in that: In step d, the amount of dimethoxymethane added is 5-10 times that of compound 3; the amount of boron trifluoride ether added is 20-30 times that of compound 3.

7. The method for preparing water-soluble fluorescent naphthyl[3]arene according to claim 2, characterized in that: In step (2), the polar solvent includes ethanol and acetonitrile; the amount of trimethylamine added is 60-120 times that of compound H1.

8. The method for preparing water-soluble fluorescent naphthyl[3]arene according to claim 2, characterized in that: The inert gases used were nitrogen or argon.

9. The water-soluble fluorescent naphthyl[3]arene and phytic acid of claim 1 construct an effective molecular beaker system, characterized in that: Phytic acid and water-soluble fluorescent naphthyl ring [3] aromatic hydrocarbon are mixed in a molar ratio of 1:2-1:

1.

10. The system according to claim 9, characterized in that The concentration range of water-soluble fluorescent naphthyl[3]arene in the molecular beaker system was controlled between 0.5 μM and 1 mM.

Images