Preparation and application of pillararene grafted cyclodextrin double-macrocyclic chiral filler

Abstract

The invention discloses a preparation method of pillararene grafted cyclodextrin double-macrocyclic chiral filler and application of the pillararene grafted cyclodextrin double-macrocyclic chiral filler in chiral pesticide separation. According to the filler, p-brominated pillararene and beta-aminopropyl cyclodextrin are covalently grafted to aminopropyl silica gel, and a double-macrocyclic structure with multiple chiral recognition sites is formed. The preparation process comprises catalytic condensation synthesis of brominated pillararene and double-macrocyclic bonding reaction on the surface of silica gel. The filler has high selectivity, multi-mode compatibility (both normal phase and reverse phase can be used) and excellent stability. The method is particularly suitable for enantiomer resolution of triazole (propiconazole and triazolone) and ester (clodinafop-propargyl) pesticides, and an efficient separation tool is provided for environmental behavior research and safety evaluation of chiral pesticides. The method is simple and convenient in process and low in cost, solves the problems of insufficient selectivity and narrow solvent application range of the existing chiral filler, and has industrial application potential.

Description

Technical Field

[0001] The present invention relates to the technical field of chiral separation materials, and in particular to a preparation method of a pillararene-grafted cyclodextrin bimacrocyclic chiral filler and its application in chiral pesticide separation. Background Art

[0002] Chirality is a fundamental property of life, a unique property in which a substance's geometric shape is asymmetric to its mirror image. Among the numerous chiral substances, chiral drugs, chiral intermediates, and chiral additives are playing an increasingly important role in medicine, agriculture, chemistry, and everyday life. Pesticides are widely used in agricultural production, playing a key role in controlling pests and increasing crop yields, but they also cause serious environmental pollution. Pesticides are frequently detected in various environmental media and have attracted widespread attention due to their environmental persistence and adverse effects on organisms and the environment.

[0003] According to research, approximately 30% of commercial pesticides are chiral compounds, and 93% are sold and used in racemic form. With the continuous advancement of analytical research, macrocyclic molecules, due to their unique structure and excellent performance, are widely used as host molecules for chiral recognition. They can accommodate and recognize a variety of guest molecules through inclusion complexation, leading to rapid development in chiral separation analysis. Chromatographic stationary phases are the "core" of chiral separation analysis, and combining macrocyclic molecules with stationary phases to develop new and efficient chromatographic separation methods is of great significance. Pillarene hydrocarbons, due to their symmetrical "pillar" macrocyclic structure, electron-rich cavity, easy chiral modification, and multi-site chiral recognition, have great potential in the field of chirality research. In view of this, the present invention combines the advantages of pillararenes and further introduces a multi-chiral site cyclodextrin structure to prepare a novel chiral filler with a double macrocyclic structure. The chiral separation of chiral pesticides is evaluated based on this structure, and the influence of multimodal conditions on resolution is explored, providing new ideas for the development of novel chiral fillers with high resolution. Summary of the Invention

[0004] The present invention aims to provide a preparation method of a pillararene-grafted cyclodextrin bimacrocyclic chiral filler and its application in the separation of chiral pesticides.

[0005] 1. Preparation of Chiral Chromatographic Packing (1) Synthesis of brominated pillar arenes: 1,1-dibromophenylene diethyl ether, phenylene dimethyl ether, boron trifluoride etherate, and paraformaldehyde were dissolved in 1,2-dichloroethane at 25-30°C and stirred magnetically for 1-2 h. After the reaction, the reaction was quenched with methanol and purified by column chromatography to obtain brominated pillar arenes. The molar ratio of 1,1-dibromophenylene diethyl ether to phenylene dimethyl ether was 1:3-1:4; the molar ratio of 1,1-dibromophenylene diethyl ether to boron trifluoride ether was 1:4-1:5; and the molar ratio of 1,1-dibromophenylene diethyl ether to paraformaldehyde was 1:4-1:5.

[0006] The synthetic route of brominated pillar aromatics is as follows: (2) Preparation of bimacrocyclic chiral filler: Disperse aminopropyl silica gel in toluene, add para-brominated columnar aromatic hydrocarbon and β -aminopropyl cyclodextrin, reflux reaction at 80~100℃ for 10~12 hours, then add 3,5-dimethylphenyl isocyanate and continue to react for 10~12 hours. After filtration, washing and drying, the pillararene grafted cyclodextrin bimacrocyclic chiral filler is obtained. β -The mass ratio of aminopropyl cyclodextrin and 3,5-dimethylphenyl isocyanate is 4.5~5:1.5~2:1.5~2:1.5~2.

[0007] The synthetic route is as follows: (3) Chromatographic column filling: Disperse the filler in chromatographic methanol and fill it at a pressure of 50-60 MPa for 25-30 min to prepare a chiral chromatographic column.

[0008] 2. Characterization of Chiral Chromatographic Packings The infrared spectrum of pillararene grafted cyclodextrin bimacrocyclic chiral chromatographic packing is as follows Figure 1 As shown, the infrared spectra of aminopropyl silica gel, brominated pillar arene and pillar arene grafted cyclodextrin bimacrocyclic filler were analyzed and it was found that 3442 cm -1 The peaks are derived from the -OH stretching vibration peak, 1450 cm -1 For cyclodextrin a -1,4-glycosidic bond skeleton vibration peaks at 1505 and 1410 cm -1 The peak at 685cm is due to the bending vibration of the benzene ring. -1 The absorption peak at 1097 cm is the skeleton stretching vibration peak of the benzene ring. -1 The broad peaks at 808 and 467 cm-1 are the asymmetric stretching vibrations of Si-O tetrahedron. -1 The peaks appearing at the wavenumbers are the symmetric stretching and bending vibrations of Si-O tetrahedrons. The infrared spectrum confirms the successful preparation of cyclodextrin grafted aromatic bimacrocyclic chiral fillers.

[0009] Thermogravimetric characterization revealed a slow decrease in the mass of the pillararene-grafted cyclodextrin bimacrocyclic chiral chromatographic packing material over a temperature range of 100°C to 300°C. This is due to the release of residues adsorbed on the chiral stationary phase. The material begins to decompose at approximately 300°C, demonstrating its excellent thermal and chemical stability. Based on the mass loss, the pillararene-grafted cyclodextrin bimacrocyclic chiral packing material exhibits a thermogravimetric weight loss of approximately 17.17% from room temperature to 800°C, further demonstrating the successful preparation of the chiral packing material. Figure 2 ).

[0010] Further N2 adsorption / desorption isotherms were used to analyze aminopropyl silica gel and pillar aromatic hydrocarbon grafted cyclodextrin bimacrocyclic chiral fillers. The experimental results showed that the isotherm was type IV ( Figure 3 ). In the low pressure section p / p When 0<0.4, the adsorption amount increases slowly, and the nitrogen molecules are adsorbed on the inner surface of the mesopores in the form of monolayer to multilayer. p / p When 0 < 0.85, the nitrogen capture rate increases rapidly, indicating that the prepared material has a mesoporous structure. The test data show that the specific surface area of aminopropyl silica gel is 249.6 m 2 / g, and the specific surface area of the pillararene-grafted cyclodextrin bimacrocyclic chiral filler is 212.2 m 2 / g, indicating the successful bonding of pillararene grafted cyclodextrin dimacrocyclic to silica gel material, that is, the successful preparation of pillararene grafted cyclodextrin dimacrocyclic chiral filler.

[0011] 3. Evaluation of Chiral Separation In order to study the enantiomeric separation ability of pillararene grafted cyclodextrin bimacrocyclic chiral filler, the separation and evaluation of three chiral pesticide racemates were carried out on the pillararene grafted cyclodextrin bimacrocyclic chiral chromatographic column ( Figure 4 Chiral separation evaluation conditions: The mobile phase was n-hexane:isopropanol (volume ratio), the detection wavelength was 254 nm, and the flow rate was 1.0 mL / min. The chiral separation of propiconazole (a) and triadimefon (b) was evaluated. Experimental results showed that the mobile phase conditions of n-hexane:isopropanol = 85:15 to 90:10 (volume ratio) achieved good chiral separation performance for both propiconazole (a) and triadimefon (b). The chiral separation of clodinafop-propargyl (c) was evaluated using the mobile phase conditions of acetonitrile:water (volume ratio), the detection wavelength was 254 nm, and the flow rate was 1.0 mL / min. Experimental results showed that the mobile phase conditions of acetonitrile:water = 25:75 to 35:65 (volume ratio) achieved good chiral separation performance for clodinafop-propargyl (c). This demonstrates that the pillararomatic grafted cyclodextrin bimacrocyclic chiral packing material has excellent chiral separation performance for chiral pesticide molecules.

[0012] Evaluation of mobile phase ratio: For the target analyte clodinafop-propargyl in reverse phase mode, the effect of acetonitrile volume fraction in the mobile phase (acetonitrile / water) on the chiral separation performance of clodinafop-propargyl was investigated. The experimental results showed that with the increase of acetonitrile volume fraction, the retention time, separation factor, and resolution of clodinafop-propargyl enantiomers gradually decreased. The separation chromatograms affected by different isopropanol volume fractions are shown in Figure 2. Figure 5 shown.

[0013] Flow rate evaluation: The effect of flow rate on the enantiomeric separation of clodinafop-butyl was investigated within the flow rate range of 0.6-1.4 mL / min. Figure 6 As shown in the figure, as the flow rate increases from 0.6 mL / min to 1.4 mL / min, the retention time of clodinafop-butyl decreases, the selectivity factor remains almost unchanged, and the resolution is significantly affected. The overall trend of resolution as the flow rate increases is that it first increases slowly and then gradually decreases. The results indicate that flow rate has a minor effect on the selectivity factor, while retention time and resolution are significantly affected by flow rate. This may be because lower flow rates reduce the mass transfer resistance during enantiomeric separation.

[0014] Temperature evaluation: Clodinafop-butyl was selected as the analyte to investigate the effect of temperature (35-55 ℃) on enantiomeric separation. Figure 7 As shown in the figure, with the continuous increase of temperature, the retention time and separation degree of the analytes gradually decreased, indicating that the enantiomeric separation process on the pillararene-grafted cyclodextrin bimacrocyclic chiral filler is an exothermic process.

[0015] Repeatability test: Figure 8 As shown, six repeated separation performance tests demonstrate that the pillararene-grafted cyclodextrin bimacrocyclic chiral packing material exhibits excellent repeatability and stability for the chiral separation of clodinafop-butyl, with relative standard deviations for retention time and resolution both less than 0.82%. These data demonstrate its practical application in enantiomeric separation analysis.

[0016] In summary, the present invention uses 1,1-dibromophenylene diethyl ether and phenylene dimethyl ether as repeating units, paraformaldehyde as raw material, and boron trifluoride etherate as catalyst in dry 1,2-dichloroethane solvent to react at room temperature and pressure to prepare brominated pillar aromatics, and then add βA pillararomatic-grafted cyclodextrin bimacrocyclic chiral packing was prepared in one step using 1,5-aminopropyl cyclodextrin and 3,5-dimethylphenyl isocyanate. High-pressure packing was used to form a novel chiral chromatographic column for the resolution and evaluation of chiral pesticides. This chiral packing exhibited high selectivity for the resolution of the chiral pesticides propiconazole, triadimefon, and clodinafop-propargyl. The best enantiomeric resolution of propiconazole and triadimefon was achieved using a mobile phase of n-hexane:isopropanol (95:5, by volume) at 254 nm and a flow rate of 1.0 mL / min. The best enantiomeric resolution of clodinafop-propargyl was achieved using a mobile phase of acetonitrile:water (30:70, by volume) at 254 nm and a flow rate of 1.0 mL / min. Temperature-responsive experiments confirmed that the separation of propiconazole, triadimefon, and clodinafop-propargyl on this chiral packing was exothermic. The relative standard deviations of retention time and resolution were all less than 0.82%. The column's aromatic hydrocarbon-grafted cyclodextrin bimacrocyclic chiral filler has strong selectivity and high stability for chiral pesticide racemates.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. Highly selective separation performance Double-ring synergy mechanism: Inclusion complex of electron-rich pillararene cavities: Rigid electron-rich cavities can capture multi-conjugated chiral pesticide molecules through π-π stacking, self-assembly with guest molecules, and hydrophobic interactions; Multi-chiral site recognition of cyclodextrins: β - The hydroxyl groups and glycosidic bonds at positions 1, 2, and 6 of cyclodextrin provide hydrogen bonds and chiral stereo environments, enhancing the differential binding of enantiomers. The two macrocycles synergistically further promote chiral separation (e.g., clodinafop-butyl Rs up to 2.7).

[0018] Broad spectrum applicability: Propiconazole can be split ( Rs =2.1), triadimefon ( Rs =1.9)、clodinafop-butyl( Rs =2.7) and other chiral pesticides with significant polarity differences, covering multiple structural types such as triazoles, ketones, and pyridyl esters.

[0019] 2. Multimodal chromatography compatibility Flexible switching between normal phase and reverse phase: Normal phase conditions (n-hexane / isopropanol) are suitable for non-polar pesticides (such as propiconazole); reverse phase conditions (acetonitrile / water) are suitable for polar pesticides (such as clodinafop-butyl), solving the problem of single filler solvent limitation.

[0020] Polar organic phase potential: infrared spectroscopy ( Figure 3 ) showed the stability of the -Si-O- bond, suggesting that it can be extended to the methanol / acetonitrile system.

[0021] 3. Excellent chemical and thermal stability Thermogravimetric analysis verification ( Figure 4): The initial decomposition temperature is 300℃, which is much higher than the conventional chromatographic operating temperature (≤80℃); the total weight loss at 800℃ is only 17.17%, indicating that the bond is strong and there is no volatile component.

[0022] Reusability: 6 cycles test ( Figure 8 ) showed that the retention time RSD was less than 0.82%, which was better than that of commercial chiral columns (usually RSD>1.5%).

[0023] 4Environmental and Safety Values Pesticide safety evaluation: Precise separation of enantiomers can identify highly toxic isomers (such as triadimefon) R -body insecticidal activity is S -10 times the body), guiding the development of green pesticides; Reduce pollution: Directly separate racemic pesticides, avoiding waste liquids (such as chiral acids / bases) generated by traditional chemical separation.

[0024] 5. Advantages of industrial applications The preparation process is simple, β -Cyclodextrin and pillararomatic hydrocarbons are cheap raw materials, have high filler loading capacity, and are suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Infrared spectrum of pillararene grafted cyclodextrin bimacrocyclic chiral chromatographic packing; Figure 2 Thermogravimetric diagram of pillararene grafted cyclodextrin bimacrocyclic chiral filler; Figure 3 Nitrogen adsorption-desorption spectrum of pillararene-grafted cyclodextrin bimacrocyclic chiral filler; Figure 4 Separation of chiral pesticides: (a) propiconazole, (b) triadimefon, and (c) clodinafop-propargyl; Figure 5 The effect of mobile phase ratio on the separation of clodinafop-butyl; Figure 6 Effect of flow rate on the separation degree of clodinafop-butyl; Figure 7 Effect of temperature on the separation degree of clodinafop-butyl; Figure 8 Evaluation of the reproducible performance of chiral resolution of clodinafop-butyl. DETAILED DESCRIPTION

[0026] The preparation method of the pillararene-grafted cyclodextrin bimacrocyclic chiral filler of the present invention is described in detail below through specific examples. Example

[0027] (1) Synthesis of para-brominated columnar aromatics: 1,1-dibromophenylene diethyl ether (1.5 g, 0.005 mol) was weighed and dissolved in 100 mL of dry 1,2-dichloroethane solution at room temperature and pressure. Then, para-phenylene dimethyl ether (2.5 g, 0.02 mol), boron trifluoride etherate (3.0 g, 0.025 mol), and paraformaldehyde (1.0 g, 0.025 mol) were added. The mixture was stirred magnetically for 1.5 hours. After the reaction was completed, the mixture was poured into 120 mL of dry methanol to quench the reaction. The filtrate was evaporated under reduced pressure to obtain a solid which was purified by column chromatography using a volume ratio of dichloromethane to petroleum ether of 1:10 to obtain para-brominated columnar aromatics. 1 H NMR (400 MHz, CDCl3, rt), δ (ppm): 6.76 (s, 10H), 4.12 (t, 4H), 4.05 (t, 4H), 3.78 (s, 10H), 3.63 (t, 24H).

[0028] (2) Preparation of pillar arene grafted cyclodextrin bimacrocyclic chiral filler: Disperse aminopropyl silica gel (5.0 g) in 150 mL of dry toluene, add p-brominated pillar arene (2.0 g), β -Aminopropyl cyclodextrin (2.0 g) was refluxed at 100 °C for 12 hours, and 3,5-dimethylphenyl isocyanate (1.5 g) was added and the reaction was continued for 10 hours. After the reaction was completed, a yellow solid powder was obtained by filtration. It was washed with 80 ml of acetone and methanol respectively and dried at 50 °C for 20 hours to obtain a pillar aromatic hydrocarbon grafted cyclodextrin bimacrocyclic chiral filler.

[0029] (3) Chiral chromatographic column filling: 3.5 g of the chiral filler material grafted with cyclodextrin (CD) was dispersed in 45 mL of chromatographic methanol, and 350 mL of chromatographic methanol was used as the displacement liquid. The chiral column was filled at a pressure of 55 MPa for 30 min to obtain the chiral chromatographic column grafted with cyclodextrin (CD). The chiral chromatographic column had the best enantiomeric separation of propiconazole and triadimefon under the mobile phase conditions of n-hexane:isopropanol (volume ratio) = 95:5, 254 nm, and a flow rate of 1.0 mL / min. The chiral separation performance of clodinafop-butyl was the best under the mobile phase conditions of acetonitrile:water (volume ratio) = 30:70, 254 nm, and a flow rate of 1.0 mL / min. The relative standard deviations of retention time and resolution were both less than 0.82%.

Claims

1. A method for preparing a pillararene-grafted cyclodextrin bimacrocyclic chiral filler, characterized in that: The method comprises the following steps: (1) synthesis of brominated pillar aromatic hydrocarbons: dissolving 1,1-dibromophenylene diethyl ether, phenylene dimethyl ether, boron trifluoride ethyl ether and paraformaldehyde in 1,2-dichloroethane at 25-30°C and normal pressure, stirring magnetically for 1-2 hours, quenching with methanol after the reaction is completed, and purifying by column chromatography to obtain brominated pillar aromatic hydrocarbons; (2) Preparation of bimacrocyclic chiral filler: Disperse aminopropyl silica gel in toluene, add para-brominated pillar arene and β-aminopropyl cyclodextrin, reflux at 80-100°C for 10-12 hours, then add 3,5-dimethylphenyl isocyanate and continue to react for 10-12 hours. After filtration, washing and drying, the pillar arene grafted cyclodextrin bimacrocyclic chiral filler is obtained.

2. The preparation method according to claim 1, wherein: In step (1), the molar ratio of 1,1-dibromophenylene diethyl ether to phenylene dimethyl ether is 1:3-1:4; the molar ratio of 1,1-dibromophenylene diethyl ether to boron trifluoride ether is 1:4-1:5; and the molar ratio of 1,1-dibromophenylene diethyl ether to paraformaldehyde is 1:4-1:

5.

3. The preparation method according to claim 1, wherein: In step (2), aminopropyl silica gel, para-brominated column aromatic hydrocarbon, β -The mass ratio of aminopropyl cyclodextrin and 3,5-dimethylphenyl isocyanate is 4.5~5:1.5~2:1.5~2:1.5~2.

4. Use of the chiral filler prepared by the method of claim 1 in separating chiral pesticides, characterized in that: The chiral pesticides include propiconazole, triadimefon or clodinafop-propargyl.

5. The use according to claim 4, characterized in that: Chiral pesticides are separated under the following conditions: Normal phase mode: mobile phase: n-hexane / isopropanol (volume ratio of n-hexane to isopropanol: 85:15-90:10), flow rate: 1.0 mL / min, detection wavelength: 254 nm. This method is used for the separation of chiral pesticides such as propiconazole or triadimefon. Reversed-phase mode: the mobile phase is acetonitrile / water (the volume ratio of acetonitrile and water is 25:75~35:65), the flow rate is 1.0 mL / min, and the detection wavelength is 254 nm. It is used for the separation of the chiral pesticide clodinafop-butyl.

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