Application of fat-soluble ring-opened cucurbituril in identification of organic compounds

Abstract

The invention discloses an application of fat-soluble ring-opened cucurbituril in specific recognition of organic compounds in organic solvents, the fat-soluble ring-opened cucurbituril is composed of glycoluril tetramer and terminal aromatic ring, the terminal aromatic ring is modified by phosphate side chain, and the terminal aromatic ring has good solubility in various organic solvents; according to the invention, the C-shaped adjustable cavity of the fat-soluble ring-opened cucurbituril is matched with the size of a guest molecule, and is matched with hydrogen bonds, pi-pi interaction and the like, so that efficient molecular recognition of organic matters in an organic solvent is realized; the application of the supramolecular macrocyclic main body in organic solvents is expanded by utilizing fat-soluble ring-opening cucurbituril, and the supramolecular macrocyclic main body is expected to be applied to the fields of medicine, chemical industry, environment and the like.

Description

Technical Field

[0001] This invention belongs to the field of supramolecular chemistry technology, specifically relating to the application of a lipid-soluble open-ring cucurbitaurea in the specific recognition of organic compounds in organic solvents. Background Technology

[0002] Currently, analytical techniques for determining the content of small molecule organic compounds in organic solvents mainly include chromatography, spectrometry, and electrochemical methods. However, these techniques often require specialized personnel and cumbersome sample preparation and analysis procedures. In recent years, supramolecular fluorescence sensors based on the interaction between supramolecular macrocyclic host and guest molecules have been developed into an ideal tool for the quantitative detection of small molecules.

[0003] The development of novel supramolecular macrocyclic hosts has played a crucial role in the advancement of the sensing and detection field. In 2010, Isaacs et al. first reported the design and synthesis of open-ring cucurbituril, a novel supramolecular macrocyclic host. J. Org. Chem. 2010, 75 , (4786-4795) laid the foundation for the basic structure of open-ring cucurbitacins, and various other types of open-ring cucurbitacins have been developed since then. However, the reported open-ring cucurbitacins are mainly highly water-soluble molecules modified with sulfonate groups, and therefore can only be used in aqueous solutions. To date, the application of open-ring cucurbitacins in organic solvents has not been realized.

[0004] In 2024, Liu Hui et al. published a patent for "open-ring cucurbita phosphate compound and its preparation and application in drug solubilization" (China: CN114539318, 2022.05.27). However, this open-ring cucurbita derivative is a water-soluble compound and is only applicable to applications in the aqueous phase. Summary of the Invention

[0005] This invention provides a novel application of lipophilic open-ring cucurbituril, namely its application in the identification of organic compounds in organic solvents. This invention utilizes fluorescence spectrometry titration to study the molecular recognition of lipophilic open-ring cucurbituril with organic compounds such as retinoic acid, 1,5-glutaric acid, N,N'-bis-(2,2,6,6-tetramethyl-4-piperidinyl)-1,6-hexanediamine, and 1,5-pentanediol in organic solvents such as chloroform. The results show that it has high binding constants for all four organic compounds, and it holds promise for the efficient separation and recovery of such organic compounds from organic wastewater.

[0006] We synthesized two lipid-soluble open-ring cucurbitacins (D1 and D2) and determined their solubility in different organic solvents, confirming their excellent solubility in a variety of commonly used organic solvents. This lays the foundation for the detection of their organic compound content in different solvents.

[0007] The chemical structures of the two lipid-soluble open-ring cucurbitacins (D1 and D2) are as follows:

[0008] D1

[0009] D2 The lipid-soluble open-ring cucurbituril described in this invention consists of a glycourea tetramer unit and a terminal aromatic ring modified with a phosphate ester side chain. This structure endows them with a C-shaped cavity with a certain degree of tunability, the size of which can be finely adjusted according to the size of the guest molecule. Its terminal aromatic ring can interact with the guest molecule in a π-π manner, and the multi-carbonyl structure can form multiple hydrogen bonds with the guest, thus exhibiting a strong recognition ability for guest molecules containing hydrogen bond donors.

[0010] The lipid-soluble open-ring cucurbitacin described in this invention differs from previously reported water-soluble open-ring cucurbitacins, exhibiting excellent solubility in a variety of commonly used organic solvents. It can specifically recognize guest molecules (G1-G4) in organic solvents through host-guest molecule recognition, and can efficiently achieve quantitative detection of small molecule compounds in organic solvents by detecting changes in fluorescence intensity. Methods for molecular recognition of the aforementioned four organic compounds in organic solvents have not yet been reported.

[0011] The lipid-soluble open-ring cucurbituril disclosed in this invention can achieve molecular recognition of guest molecules in organic solvents through host-guest recognition. By utilizing the fluorescence changes generated by supramolecular host-guest molecular recognition, the content of specific small molecule organic compounds in organic solvents can be detected. This invention enriches the types of open-ring cucurbituril and expands its applications, which can be applied to fields such as medicine, chemistry, and environmental monitoring. Detailed Implementation

[0012] The methods described in this invention are further illustrated below through examples. However, the scope of protection of this invention is not limited by the examples. Unless otherwise specified, the reagents used in these examples are all commercially available reagents or reagents prepared by conventional methods, and the methods used are all conventional methods unless otherwise specified.

[0013] Example 1: Preparation of open-ring cucurbituril D1 (1) Preparation of methylated glycourea 10.4 g of urea was dissolved in hydrochloric acid (0.3 mol / L, 30 mL), and then 5 g of 1,3-butanedione was added to it. The reaction solution was stirred at room temperature for 12 h and then filtered to obtain a white crude product. The crude product was washed twice with water (500 mL × 2), filtered, and the filter cake was dried under vacuum to obtain 9.5 g of white solid methylated urea (yield 92%). 1 H NMR (600MHz, DMSO-)d 6, ppm): d 7.18(s, 4H), 1.36 (s, 6H). ; (2) Preparation of etherified methylated glycourea 5 g of methylated glycyrrhizin was dissolved in hydrochloric acid (9 mol / L, 25 mL), and 4.5 g of paraformaldehyde was slowly added. The reaction solution was stirred at room temperature for 24 h and then filtered to obtain a white crude product. The crude product was washed with water three times (500 mL × 3), filtered, and the filter cake was vacuum dried to obtain 5.5 g of white solid (yield 67%). 1 H NMR (600MHz, DMSO-) d 6, ppm): d 5.25 (d, J =10.8 Hz, 4H), 5.03 (d, J = 10.8 Hz, 4H), 1.83 (s, 6H). ; (3) Preparation of dimers 10 g of glycyrrhizin was dissolved in hydrochloric acid (8 mol / L, 30 mL), and 2.1 g of paraformaldehyde was slowly added. The reaction solution was reacted at 50 °C for 48 h and then filtered to obtain a white crude product. The crude product was washed with water several times until neutral, filtered, and the filter cake was dried under vacuum to obtain 4.7 g of white solid (yield 43%). 1 H NMR (600MHz, DMSO-d6, ppm): d 7.66 (d, J =2.2Hz, 4H), 5.59 (d, J =14.5 Hz, 2H), 5.36 (d, J = 8.5 Hz, 2H), 5.24 (dt, J = 8.4, 2.1 Hz, 2H), 4.04 (d, J = 14.5 Hz, 2H). ; (4) Preparation of tetramer 2.2 g of dimer and 7.6 g of etherified methylated glycourea were added to 15 mL of anhydrous methanesulfonic acid. The reaction solution was reacted at 50 °C for 3 h. Then the reaction solution was cooled to room temperature and added dropwise to 150 mL of acetone and stirred for 2 h. The mixture was filtered, and the filter cake was washed twice with acetone (100 mL × 2) and twice with water (100 mL × 2). The mixture was filtered again, and the filter cake was dried under vacuum to obtain 4 g of white solid (yield 80%).1 H NMR (600MHz, DMSO-) d 6, ppm): d 5.72-5.40 (m, 10H), 5.15 (d, J = 10.6 Hz, 4H), 4.82 (d, J =10.8 Hz, 4H), 4.24 (dd, J = 14.7, 9.5 Hz, 6H), 1.8 (s, 6H), 1.62 (s, 6H). ; (5) Preparation of the B1 sidewall of the benzene ring First, weigh out 1,4-bis(2-hydroxyethoxy)benzene (10.0 g, 50.4 mmol) and triphenylphosphine (31.5 g, 50.4 mmol) respectively. 120 mmol) was added to a round-bottom flask, followed by 250 mL of anhydrous acetonitrile. After the solid was completely dissolved, the mixture was stirred vigorously in an ice bath. Carbon tetrabromide (39.8 g, 120 mmol) was added in portions. The reaction mixture was stirred at room temperature for 4 h. After the reaction was complete, 200 mL of cold water was added to the reaction mixture, resulting in a white precipitate. The precipitate was collected and washed with methanol / water (volume ratio 3:2, 3 × 100 mL). The precipitate was then recrystallized in methanol and dried under vacuum to give a white solid B1 (12.66 g, yield: 78%). 1 H NMR (600 MHz, CDCl3): d 6.86 (s, 4H), 4.24 (t, J = 6.3 Hz, 4H), 3.62 (t, J = 6.2Hz, 4H). ; (6) Preparation of C1 sidewall of benzene ring B1 (6.6 g, 2.02 mmol) and triethyl phosphite (35 mL, 202.2 mmol) were added to a round-bottom flask, followed by 55 mL of xylene. The mixture was stirred until homogeneous at room temperature, and then refluxed under N2 protection with stirring and heating to 140 °C for 72 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, volume ratio 1:100) to obtain pure pale yellow liquid C1 (8.1 g, yield: 91%). 1 H NMR (600 MHz, DMSO-d6): d 6.86 (d, J = 1.8 Hz, 4H), 4.13 –3.90(m, 12H), 2.24 (dt,J = 18.4, 7.1 Hz, 4H), 1.23 (t, J = 7.0 Hz, 12H); 13 CNMR (150 MHz, DMSO-d6) d 152.57, 115.54, 65.56, 61.81, 61.77, 21.07, 26.08, 16.41, 16.37. ; (7) Preparation of open-ring cucurbituril D1 C1 (12.5 g, 28.5 mmol) and tetramer (5.6 g, 7.2 mmol) were added to a round-bottom flask, followed by 40 mL of acetic anhydride and 40 mL of trifluoroacetic acid. The mixture was stirred at room temperature and reacted at 70 °C for 6 h. After the reaction was completed, the reaction solution was quenched dropwise in 200 mL of methanol, concentrated under reduced pressure, and after cooling, 80 mL of diethyl ether or isopropyl ether was added to the concentrate. A pale yellow precipitate was precipitated. The precipitate was filtered, and the solid was washed with diethyl ether or isopropyl ether (200 mL × 3). After vacuum drying, a pale yellow solid D1 (8.4 g, yield: 72%) was obtained. 1 H NMR (600 MHz, D2O): d 6.88 (d, 4H), 5.90 – 5.38 (m, 14H), 4.22– 4.11 (m, 34H), 2.31 (t, J = 81.4, 38.2 Hz, 8H), 1.68 (t, J = 7.1 Hz, 12H), 1.31 (s, 24H); 13 C NMR (150 MHz, D2O): d 156.81, 155.74, 149.72, 128.37,115.36, 78.55, 77.36, 72.35, 71.84, 64.13, 63.31, 63.27, 62.86, 62.81, 48.79,42.19, 34.71, 25.12, 24.21, 10.31; HR-MS(ESI) m / z : calcd for C 66 H 96 N 16 O 24 P4[M+H] + : 1621.5807, found: 1621.5833. IR (cm -1): 3449, 2985, 2932, 1730, 1469,1382, 1315, 1229, 1021, 1026, 963, 823, 798, 759, 667, 537, 456. .

[0014] Example 2: Preparation of open-ring cucurbituril D2 (1) The preparation of methylated glycourea, etherified methylated glycourea, dimer and tetramer are the same as steps 1-4 in Example 1; (2) Preparation of naphthalene ring sidewall B2 First, weigh 1,4-naphthoquinone A1 (10.0 g, 63 mmol) into a 1 L round-bottom flask, and add 250 mL of the solution. Dissolve in ethyl acetate, then add the prepared sodium dithionite aqueous solution (50 g, 287 mmol, dissolved in 350 mL). (Prepared in water), the reaction was carried out under N2 protection at 30°C with vigorous stirring for 3 h. The reaction system became colorless and clear. After the reaction was completed, the aqueous phase was extracted with ethyl acetate and the organic phases were combined. The mixture was then evaporated to dryness at 30°C to obtain pure 1,4-naphthol as a brown solid (9.5 g, yield: 94%). To prevent oxidation of the product, it was immediately added to the next reaction step. 55 mL of acetonitrile was added to a round-bottom flask, followed by 1,4-naphthol A2 (9.5 g, 59.5 mmol), anhydrous potassium carbonate (34.0 g, 246.1 mmol), and 18-crown ether-6 (0.783 g, 2.9 mmol). 1,2-dibromoethane (55 mL, 638.1 mmol) was added to a dropping funnel. The reaction mixture was slowly added under N2 protection and refluxed at 70 °C for 4 days. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrated solution was slowly added dropwise to 100 mL of stirred acetone, and after stirring for 1 hour, it was filtered to obtain a brown solid. The solid was washed and filtered in 200 mL of acetone to obtain pure product B2 as a brown solid (9.5 g, yield: 43%). 1 H NMR (600 MHz, CDCl3): d 8.26 (dd, J =6.4, 3.3 Hz, 2H), 7.54 (dd, J = 6.4, 3.3 Hz, 2H), 6.69 (s, 2H), 4.42 (d, J =6.1 Hz, 4H), 3.77 (t, J = 6.1 Hz, 4H). ; (3) Preparation of C2 on the side wall of the naphthalene ring Add B2 (9.0 g, 24.2 mmol) and triethyl phosphite (43.2 mL, 301.2 mmol) to a round-bottom flask, and then... Then add 80 mL of xylene, stir to dissolve at room temperature, and after stirring evenly, reflux at 140 °C for 72 h under N2 protection. After the reaction is completed, concentrate under reduced pressure and use 200-300 mesh silica gel column chromatography (MeOH / DCM = 1:150) to obtain a pure product as a pale yellow liquid (8.1 g, yield: 69%). 1 H NMR (600 MHz, DMSO-d6): d 8.17 (dd, J = 6.4, 3.3 Hz, 2H), 7.53 (dd, J = 6.4, 3.3 Hz, 2H), 6.86 (s, 2H), 4.27 (dt, J =16.1, 6.7Hz, 4H), 4.09–3.95 (m, 8H), 2.42 (dt, J = 17.9, 6.7 Hz, 4H), 1.23 (t, J = 7.0Hz, 12H); 13 C NMR (150 MHz, DMSO-d6): d 148.29, 126.33, 125.94, 121.78, 104.45, 62.55, 61.88, 61.84, 27.11, 26.17, 16.46, 16.42. ; (4) Synthesis of open-ring cucurbituril D2 C2 (8.1 g, 16.6 mmol) and tetramer (4.0 g, 5.1 mmol) were added to a round-bottom flask, followed by 30 mL of acetic anhydride and 30 mL of trifluoroacetic acid. The mixture was stirred at room temperature and reacted at 70 °C for 6 h. After the reaction was completed, the reaction solution was quenched dropwise in 400 mL of methanol, concentrated under reduced pressure, and after cooling, 80 mL of diethyl ether was added dropwise to the concentrate, resulting in a brown precipitate. The precipitate was filtered, and the solid was washed with diethyl ether or isopropyl ether (200 mL × 3). After filtration, the solid was dried under vacuum to obtain pure P2 intermediate 1 as a yellow solid (6.9 g, yield: 77%). 1 H NMR (600 MHz, DMSO-d6): d 8.22 (d, J= 15.9 Hz, 4H), 7.54(s, 4H), 5.56–5.13 (m, 14H), 4.24–4.05 (m, 34H), 2.74–2.25 (m, 8H), 1.78 (d, J = 64.6Hz, 12H), 1.34 (s, 24H); 13 C NMR (150 MHz, D2O): δ 156.56, 156.40,148.33, 128.04, 127.13, 126.54, 117.16, 115.23, 78.25, 77.16, 70.83, 69.27,63.14, 62.97, 62.38, 57.38, 48.63, 35.87, 26.31, 25.38, 15.10, 14.74; HR-MS(ESI) m / z : calcd for C 74 H 100 N 16 O 24 P4 [M+H] + : 1721.6120, found: 1721.6128. IR (cm -1 ): 3446, 2986, 2930, 1732, 1465, 1380, 1350, 1314, 1228, 1185, 1083, 1027,977, 884, 825, 800, 729, 664. .

[0015] Example 3: Determination of the solubility of lipid-soluble open-ring cucurbituril D1 and D2 in organic solvents Excessive amounts of open-ring cucurbituril D1 or D2 were added to different organic solvents. After thorough stirring at 25°C, the mixture was filtered to obtain a clear solution. The solvent was evaporated from the solution and the solution was weighed. The solubility of open-ring cucurbituril D1 and D2 in different organic solvents was determined. The results are shown in the table below. Solubility of lipid-soluble open-ring cucurbituril D1 and D2 in different organic solvents (25℃)

[0016] The above results indicate that the lipid-soluble open-ring cucurbituril D1 and D2 disclosed in this invention exhibit good solubility in a variety of organic solvents, which lays the foundation for their efficient identification of organic compounds in different organic solvents.

[0017] Example 4: Determination of the binding constants of lipid-soluble open-ring cucurbituril D1 and D2 with guests G1-G4 This experiment used fluorescence spectroscopy to determine the binding constants of open-ring cucurbituril D1 and D2 with the guest, i.e. K a First, prepare a solution with a concentration of 2×10⁻⁶ using chloroform (or methanol). -6 A bulk open-ring cucurbita solution of mol / L was prepared, and a 2×10⁻⁶ concentration was prepared using the bulk solution as the solvent. -6 A guest solution of mol / L was prepared. Different volumes of guest solution (1, 2, 3, 5, 7, 10, 15, 20, 30, 40, 60, 80, 100, 150, 200, 300, 600, 900, 1500, 2000 μL) were added dropwise to 2 mL of the host solution, and the mixture was carefully shaken until homogeneous. The fluorescence intensity at the maximum emission wavelength was measured. This process was repeated three times. The concentration of the guest in the mixed solution was calculated, and its binding constant was obtained by fitting the data on the supramolecular website (supramolecular.org). K a The table below shows G1 as retinoic acid, G2 as 1,5-glutaric acid, G3 as N,N'-bis-(2,2,6,6-tetramethyl-4-piperidinyl)-1,6-hexanediamine, and G4 as 1,5-pentanediol. Binding constants of lipid-soluble open-ring cucurbituril D1 and D2 with guest molecules G1-G4 in chloroform (25℃) ; Binding constants of lipid-soluble open-ring cucurbituril D1 and D2 with guest molecules G1-G4 in methanol (25℃) .

[0018] Example 5: Determination of the detection limit of lipid-soluble open-ring cucurbituril for guest molecules in chloroform or methanol Keeping the concentrations of the main components D1 and D2 constant, the concentrations of the guest component were gradually changed to 2.5 μM, 5 μM, 7.5 μM, 10 μM, 12.5 μM, and 15 μM. The fluorescence intensity at different guest component concentrations was recorded, and a linear regression equation was obtained. The detection limit was calculated using the following formula: DL = 3 × σ / S, where S is the slope of the calibration curve and σ is the standard deviation of the y-intercept of the regression line.

[0019] Limits of detection (25℃) of lipid-soluble open-ring cucurbiturils D1 and D2 for guest molecules G1-G4 in chloroform. ; Limits of detection (25℃) of lipid-soluble open-ring cucurbiturils D1 and D2 for guest molecules G1-G4 in methanol. ; The results show that the lipid-soluble open-ring cucurbitacins D1 and D2 disclosed in this invention have good molecular recognition capabilities for all four organic compounds G1-G4. Furthermore, both open-ring cucurbitacins D1 and D2 have relatively low detection limits for these four guests. This allows for efficient quantitative detection of small molecule organic compounds in organic solvents through changes in fluorescence intensity. This technology holds promise for applications in pharmaceuticals, chemistry, and environmental monitoring.

Claims

1. Application of a liposoluble open-loop cucurbituril with the chemical structure shown in the following formula in specific recognition of organic compounds in organic solvents; ； 。 2. Use according to claim 1, characterized in that: The organic solvents are chloroform, dichloromethane, methanol, and ethanol, and the organic compounds are tretinoin, 1,5-pentanedioic acid, N,N'-bis-(2,2,6,6-tetramethyl-4-piperidyl)-1,6-hexanediamine, and 1,5-pentanediol.

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