Preparation and application of a pillararene-grafted cyclodextrin double macrocycle chiral packing material

Abstract

This invention discloses a method for preparing a column aromatics-grafted cyclodextrin bicyclic chiral packing material and its application in the separation of chiral pesticides. This packing material separates brominated column aromatics from... β -Aminopropyl cyclodextrin is covalently grafted onto aminopropyl silica gel to form a bicyclic macrocyclic structure with multiple chiral recognition sites. The preparation process includes the catalytic condensation synthesis of brominated columnar aromatics and the bicyclic macrocyclic bonding reaction on the silica gel surface. This packing material exhibits high selectivity, multi-mode compatibility (can be used in both normal and reverse phases), and excellent stability. It is particularly suitable for the enantiomeric resolution of triazoles (propiconazole, triadimefon) and esters (clodinafop-propargyl), providing an efficient separation tool for the environmental behavior study and safety evaluation of chiral pesticides. This invention features a simple process and low cost, solving the problems of insufficient selectivity and narrow solvent applicability of existing chiral packing materials, and has the potential for industrial application.

Description

Preparation and Application of a Column Aromatic Hydrocarbon Grafted Cyclodextrin Bimacyclic Chiral Filler Technical Field

[0001] This invention relates to the field of chiral separation materials technology, specifically to a method for preparing a columnar aromatic hydrocarbon-grafted cyclodextrin bicyclic chiral packing and its application in the separation of chiral pesticides. Background Technology

[0002] Chirality is a fundamental attribute of life, referring to substances with a unique property of geometric shape asymmetry with its mirror image. Among numerous chiral substances, chiral drugs, chiral intermediates, and chiral additives play an increasingly important role in medicine, agriculture, chemistry, and daily life. Pesticides are widely used in agricultural production, playing a crucial role in controlling pests and increasing crop yields, but at the same time, they also cause serious environmental pollution. Pesticides are frequently detected in various environmental media, and their environmental persistence and adverse effects on organisms and the environment have attracted widespread attention.

[0003] Studies show that approximately 30% of commercial pesticides are chiral compounds, and 93% are sold and used in racemic form. With the deepening of research in the analytical field, macrocyclic molecules, due to their unique structure and excellent performance, are widely used as host molecules for chiral recognition. They accommodate and recognize various guest molecules through inclusion complexation, thus leading to rapid development in chiral separation analysis. As the "core" of chiral separation analysis, the chromatographic stationary phase plays a crucial role in developing novel and efficient chromatographic separation methods by combining macrocyclic molecules with the stationary phase. Columnar aromatics, due to their symmetrical "column"-shaped macrocyclic structure, electron-rich cavities, ease of chiral modification, and multi-site chiral recognition, possess great potential in the field of chiral research. Therefore, this invention combines the advantages of columnar aromatics by further introducing a multi-chiral site cyclodextrin structure to prepare a novel bi-macrocyclic chiral packing material. The chiral separation of chiral pesticides was evaluated based on this structure, and the influence of multiple modes on the resolution was explored, providing new ideas for developing novel chiral packing materials with high resolution. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing columnar aromatic hydrocarbon-grafted cyclodextrin bicyclic chiral packing material and its application in the separation of chiral pesticides.

[0005] I. Preparation of Chiral Chromatographic Packing Material

[0006] (1) Synthesis of p-bromophenylene columnar aromatics: Under normal pressure and temperature of 25-30℃, 1,1-dibromophenylene diethyl ether, terephthalic acid dimethyl ether, boron trifluoride diethyl ether, and paraformaldehyde were dissolved in 1,2-dichloroethane and magnetically stirred for 1-2 h. After the reaction was completed, the mixture was quenched with methanol and purified by column chromatography to obtain p-bromophenylene columnar aromatics. The molar ratio of 1,1-dibromophenylene diethyl ether to terephthalic acid dimethyl ether was 1:3-1:4; the molar ratio of 1,1-dibromophenylene diethyl ether to boron trifluoride diethyl ether was 1:4-1:5; and the molar ratio of 1,1-dibromophenylene diethyl ether to paraformaldehyde was 1:4-1:5.

[0007] The synthetic route for brominated aromatic hydrocarbons is as follows:

[0008]

[0009] (2) Preparation of bicyclic chiral filler: Aminopropyl silica gel was dispersed in toluene, p-bromoaryl columnar hydrocarbon and β-aminopropylcyclodextrin were added, and the mixture was refluxed at 80-100℃ for 10-12 h. Then, 3,5-dimethylphenyl isocyanate was added and the reaction was continued for 10-12 h. After filtration, washing and drying, the bicyclic chiral filler grafted with cyclodextrin and aryl columnar hydrocarbon was obtained. The mass ratio of aminopropyl silica gel, p-bromoaryl columnar hydrocarbon, β-aminopropylcyclodextrin and 3,5-dimethylphenyl isocyanate was 4.5-5:1.5-2:1.5-2:1.5-2.

[0010] The synthesis route is as follows:

[0011]

[0012] (3) Column packing: Disperse the packing material in chromatographic methanol and pack it for 25-30 min under a pressure of 50-60 MPa to obtain a chiral chromatographic column.

[0013] II. Characterization of Chiral Chromatographic Packing Materials

[0014] The infrared spectra of the column aromatics-grafted cyclodextrin bicyclic chiral chromatographic packing material are shown in Figure 1. Analysis of the infrared spectra of aminopropyl silica gel, p-brominated column aromatics, and column aromatics-grafted cyclodextrin bicyclic chiral packing material revealed a value at 3442 cm⁻¹. -1 The peak values ​​everywhere originate from the -OH stretching vibration peak, 1450 cm⁻¹. -1 These are the α-1,4-glycosidic bond skeletal vibration peaks in cyclodextrin, at 1505 and 1410 cm⁻¹. -1 The peak at 685 cm⁻¹ is caused by the bending vibration of the benzene ring. -1 The absorption peak at 1097 cm⁻¹ is the skeletal stretching vibration peak of the benzene ring. -1 The broad peaks appearing at 808 and 467 cm⁻¹ represent the asymmetric stretching vibrations of the Si-O tetrahedron.-1 The peaks appearing at the wavenumbers are the symmetric stretching and bending vibrations of the Si-O tetrahedron. The infrared spectrum confirmed the successful preparation of the cyclodextrin-grafted pillararene double macrocyclic chiral packing material.

[0015] Thermogravimetric characterization showed that within the temperature range of 100 °C to 300 °C, the mass of the pillararene-grafted cyclodextrin double macrocyclic chiral chromatographic packing material decreased slowly, which was the result of the escape of the residues adsorbed on the chiral stationary phase. The material began to decompose at about 300 °C, indicating their excellent thermal stability and chemical stability. According to the mass loss, from room temperature to 800 °C, the thermogravimetric weight loss rate of the pillararene-grafted cyclodextrin double macrocyclic chiral packing material was about 17.17%, further proving the successful preparation of the chiral packing material (Figure 2).

[0016] Further, the aminopropyl silica gel and the pillararene-grafted cyclodextrin double macrocyclic chiral packing material were analyzed by N2 adsorption / desorption isotherms. The experimental results all showed type IV isotherms (Figure 3). At the low pressure section where p / p0 < 0.4, the adsorption amount increased gently, and at this time, nitrogen molecules were adsorbed on the inner surface of the mesopores from monolayer to multilayer. When 0.4 < p / p0 < 0.85, the nitrogen capture rate increased rapidly, indicating that the prepared material had a mesoporous structure. The test data showed that the specific surface area of the aminopropyl silica gel was 249.6 m 2 / g, and the specific surface area of the pillararene-grafted cyclodextrin double macrocyclic chiral packing material was 212.2 m 2 / g, indicating the successful bonding of the pillararene-grafted cyclodextrin double macrocycle to the silica gel material, that is, the successful preparation of the pillararene-grafted cyclodextrin double macrocyclic chiral packing material.

[0017] III. Enantiomeric Resolution Evaluation

[0018] In order to study the enantiomeric separation ability of the pillararene-grafted cyclodextrin double macrocyclic chiral packing material, the pillararene-grafted cyclodextrin double macrocyclic chiral chromatographic column was evaluated for resolution using three chiral pesticide racemates as the targets (Figure 4). Conditions for enantiomeric resolution evaluation: The mobile phase was n-hexane: isopropanol (volume ratio), the detection wavelength was 254 nm, and chiral resolution evaluation of propiconazole (a) and triadimefon (b) was carried out at a flow rate of 1.0 mL per minute. The experiments showed that good chiral resolution performance for both propiconazole (a) and triadimefon (b) was achieved when the mobile phase conditions were n-hexane: isopropanol = 85:15 to 90:10 (volume ratio). Chiral resolution evaluation of clodinafop-propargyl (c) was carried out at the conditions of mobile phase being acetonitrile: water (volume ratio), detection wavelength being 254 nm, and flow rate being 1.0 mL per minute. The experimental results showed that good chiral resolution performance for clodinafop-propargyl (c) was achieved when the mobile phase was acetonitrile: water = 25:75 to 35:65 (volume ratio). It was proved that the pillararene-grafted cyclodextrin double macrocyclic chiral packing material had good chiral separation performance for chiral pesticide molecules.

[0019] Evaluation of mobile phase ratio: For the target analyte clodinafop-propargyl in reversed-phase mode, the effect of varying the volume fraction of acetonitrile in the mobile phase (acetonitrile / water) on the chiral resolution performance of clodinafop-propargyl was investigated. Experimental results showed that with increasing acetonitrile volume fraction, the retention time, separation factor, and resolution of the enantiomers of clodinafop-propargyl gradually decreased. The separation chromatograms showing the effect of different isopropanol volume fractions are shown in Figure 5.

[0020] Flow rate evaluation: The effect of flow rate on the enantiomeric separation of clodinafop-propargyl was investigated within the flow rate range of 0.6–1.4 mL / min. As shown in Figure 6, when the flow rate increased from 0.6 mL / min to 1.4 mL / min, the retention time of clodinafop-propargyl continuously decreased, the selectivity remained almost unchanged, while the resolution was significantly affected. The overall trend of resolution as the flow rate increased was initially slow and then gradually decreased. The results indicate that the flow rate has a relatively small effect on the selectivity, while the retention time and resolution are significantly affected by the flow rate. This may be because lower flow rates result in lower mass transfer resistance during enantiomeric separation.

[0021] Temperature evaluation: The effect of temperature (35-55 ℃) on enantiomeric separation was investigated using clodinafop-propargyl as the analyte. As shown in Figure 7, the retention time and resolution of the analyte gradually decreased with increasing temperature, indicating that the enantiomeric separation process on the column aromatic-grafted cyclodextrin bicyclic chiral packing material is an exothermic process.

[0022] Repeatability test: As shown in Figure 8, six repeated separation performance tests demonstrate that the column-grown aromatic cyclodextrin bicyclic chiral packing material exhibits excellent repeatability and stability for the chiral separation of clodinafop-propargyl, with relative standard deviations of retention time and resolution both less than 0.82%. These data indicate its practical application value in enantiomeric separation analysis.

[0023] In summary, this invention uses 1,1-dibromo-terephthalic diethyl ether and terephthalic dimethyl ether as repeating units, paraformaldehyde as a raw material, and boron trifluoride ethyl ether as a catalyst to react in a dry 1,2-dichloroethane solvent at room temperature and pressure to prepare p-bromo-coated aromatics. Then, β-aminopropyl cyclodextrin and 3,5-dimethylphenyl isocyanate are added to prepare a column aromatics-grafted cyclodextrin bicyclic chiral packing material in one step. High-pressure packing is used to form a novel chiral chromatographic column, which is applied to the resolution and evaluation of chiral pesticides. This type of chiral packing material exhibits high resolution selectivity for the chiral pesticides propiconazole, triadimefon, and clodinafop-propargyl. Under mobile phase conditions of hexane:isopropanol (95:5 v / v), at a flow rate of 1.0 mL / min and 254 nm, the enantiomeric separation of propiconazole and triadimefon is optimal. Under mobile phase conditions of acetonitrile:water (30:70 v / v), at a flow rate of 1.0 mL / min and 254 nm, the chiral resolution of clodinafop-propargyl is optimal. Temperature response experiments confirm that the separation process of propiconazole, triadimefon, and clodinafop-propargyl on this chiral packing material is exothermic. The relative standard deviations of retention time and resolution are both less than 0.82%. This column, with aromatics grafted cyclodextrin dual macrocyclic rings, demonstrates strong selectivity and high stability for racemic chiral pesticides.

[0024] The advantages of this invention compared to existing technologies are as follows:

[0025] 1. High selective separation performance

[0026] Dual-ring synergy mechanism:

[0027] Electron-rich cavity encapsulation in columnar aromatics: 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: The hydroxyl groups and glycosidic bonds at the 1, 2, and 6 positions of β-cyclodextrin provide hydrogen bonds and a chiral steric environment, enhancing enantiomeric recognition and differential binding. The synergistic effect of the two macrocycles further promotes chiral separation (e.g., Rs of clodinafop-propargyl reaches 2.7).

[0028] Broad-spectrum applicability: It can separate chiral pesticides with significant polarity differences, such as propiconazole (Rs=2.1), triadimefon (Rs=1.9), and clodinafop-propargyl (Rs=2.7), covering multiple structural types of triazole alcohols, ketones, and pyridyl esters.

[0029] 2. Multimode chromatography compatibility

[0030] Flexible switching between normal and reverse phases: 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-propargyl), solving the problem of limited solvents for single fillers.

[0031] Potential for polar organic phases: Infrared spectroscopy (Figure 3) shows the stability of the -Si-O- bonds, suggesting that it can be extended to methanol / acetonitrile systems.

[0032] 3. Excellent chemical and thermal stability

[0033] Thermogravimetric analysis verification (Figure 4): The initial decomposition temperature was 300℃, which is much higher than the conventional chromatographic operating temperature (≤80℃); the total weight loss at 800℃ was only 17.17%, indicating that the bond is strong and there are no volatile components.

[0034] Reusability: Six-cycle testing (Figure 8) showed a retention time RSD of <0.82%, which is superior to commercial chiral columns (typically RSD >1.5%).

[0035] 4. Environmental and Safety Value

[0036] Pesticide safety evaluation: Precise enantiomer separation can identify highly toxic isomers (such as the R-form of triadimefon, which has 10 times the insecticidal activity of the S-form), guiding the development of green pesticides;

[0037] Reduce pollution: Directly separate racemic pesticides, avoiding waste liquids (such as chiral acids / bases) generated by traditional chemical separation.

[0038] 5. Advantages of industrial application

[0039] The preparation process is simple, the raw materials β-cyclodextrin and columnar aromatics are inexpensive, and the packing loading is high, making it suitable for large-scale production. Attached Figure Description

[0040] Figure 1. Infrared spectrum of the column containing aromatic-grafted cyclodextrin bicyclic chiral chromatographic packing material;

[0041] Figure 2. Thermogravimetric analysis of column aromatic-grafted cyclodextrin bicyclic chiral packing;

[0042] Figure 3. Nitrogen adsorption-desorption spectrum of column aromatics-grafted cyclodextrin bicyclic chiral packing.

[0043] Figure 4. Separation of chiral pesticides: (a) propiconazole, (b) triadimefon and (c) clodinafop-propargyl;

[0044] Figure 5. Effect of mobile phase ratio on the separation degree of clodinafop-propargyl;

[0045] Figure 6. Effect of flow rate on the separation degree of clodinafop-propargyl;

[0046] Figure 7. Effect of temperature on the separation degree of clodinafop-propargyl;

[0047] Figure 8. Evaluation of the chiral resolution repeatability of clodinafop-propargyl. Detailed Implementation

[0048] The preparation method of the columnar aromatic hydrocarbon-grafted cyclodextrin bicyclic chiral filler of the present invention will be described in detail below through specific embodiments. Examples

[0049] (1) Synthesis of p-bromoarene: Under normal pressure and temperature, 1,1-dibromo-terephthalic diethyl ether (1.5 g, 0.005 mol) was weighed and dissolved in 100 mL of dry 1,2-dichloroethane solution. Then, terephthalic dimethyl ether (2.5 g, 0.02 mol), boron trifluoride ethyl ether (3.0 g, 0.025 mol), and paraformaldehyde (1.0 g, 0.025 mol) were added. The mixture was magnetically stirred for 1.5 hours. After the reaction was completed, the mixture was poured into 120 mL of dry methanol to quench the reaction. The solid obtained after vacuum distillation of the filtrate was purified by column chromatography with a volume ratio of dichloromethane:petroleum ether = 1:10 to obtain p-bromoarene. 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).

[0050] (2) Preparation of column aromatics-grafted cyclodextrin bicyclic chiral filler: 5.0 g of aminopropyl silica gel was dispersed in 150 mL of dry toluene, 2.0 g of p-bromopropyl column aromatics and 2.0 g of β-aminopropyl cyclodextrin were added, and the mixture was refluxed at 100 °C for 12 hours. 1.5 g of 3,5-dimethylphenyl isocyanate was added and the reaction was continued for 10 hours. After the reaction was completed, a yellow solid powder was obtained by filtration. The powder was washed with 80 mL of acetone and methanol and dried at 50 °C for 20 hours to obtain the column aromatics-grafted cyclodextrin bicyclic chiral filler.

[0051] (3) Chiral column packing: 3.5 g of aromatic-grafted cyclodextrin bicyclic chiral packing material was dispersed in 45 mL of chromatographic methanol, with 350 mL of chromatographic methanol as the displacement solvent. The column was packed at 55 MPa for 30 min to obtain an aromatic-grafted cyclodextrin bicyclic chiral chromatographic column. Under the conditions of a mobile phase of hexane:isopropanol = 95:5 (v / v), a flow rate of 254 nm, and 1.0 mL / min, the chiral column showed the best enantiomeric resolution for propiconazole and triadimefon. Under the conditions of a mobile phase of acetonitrile:water (v / v) = 30:70, a flow rate of 254 nm, and 1.0 mL / min, the column showed the best chiral resolution for clodinafop-propargyl. The relative standard deviations of retention time and resolution were both less than 0.82%.

Claims

1. A method for preparing a columnar aromatic hydrocarbon-grafted cyclodextrin bicyclic chiral filler, characterized in that, The process includes the following steps: (1) Synthesis of p-bromopillar aromatics: Under normal pressure at 25-30℃, 1,1-dibromophenyl diethyl ether, p-phenylenedimethyl ether, boron trifluoride ethyl ether and paraformaldehyde are dissolved in 1,2-dichloroethane and magnetically stirred for 1-2 hours. After the reaction is completed, the mixture is quenched with methanol and purified by column chromatography to obtain p-bromopillar aromatics; (2) Preparation of bicyclic chiral packing material: aminopropyl silica gel is dispersed in toluene, p-bromopillar aromatics and β-aminopropyl cyclodextrin are added, and the mixture is refluxed at 80-100℃ for 10-12 hours. Then, 3,5-dimethylphenyl isocyanate is added and the reaction is continued for 10-12 hours. After filtration, washing and drying, the p-bromopillar aromatics grafted with cyclodextrin bicyclic chiral packing material is obtained.

2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of 1,1-dibromo-terephthalic diethyl ether to terephthalic dimethyl ether is 1:3 to 1:4; the molar ratio of 1,1-dibromo-terephthalic diethyl ether to boron trifluoride ethyl ether is 1:4 to 1:5; and the molar ratio of 1,1-dibromo-terephthalic diethyl ether to paraformaldehyde is 1:4 to 1:

5.

3. The preparation method according to claim 1, characterized in that: In step (2), the mass ratio of aminopropyl silica gel, p-bromopropyl aromatic hydrocarbon, β-aminopropyl cyclodextrin and 3,5-dimethylphenyl isocyanate is 4.5~5:1.5~2:1.5~2:1.5~2.

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

5. The application according to claim 4, characterized in that: Chiral pesticides were separated under the following conditions: Normal-phase mode: the mobile phase was hexane / isopropanol, with a volume ratio of hexane to isopropanol of 85:15 to 90:10, a flow rate of 1.0 mL / min, and a detection wavelength of 254 nm, for the separation of chiral pesticides propiconazole or triadimefon; Reversed-phase mode: the mobile phase was acetonitrile / water, with a volume ratio of acetonitrile to water of 25:75 to 35:65, a flow rate of 1.0 mL / min, and a detection wavelength of 254 nm, for the separation of chiral pesticide clodinafop-propargyl.

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