4-nitrobenzoic acid imidazole quaternary ammonium salt, its preparation method and application

Abstract

The application discloses 4-nitrobenzoic acid imidazole quaternary ammonium salt and a preparation method and application thereof. The 4-nitrobenzoic acid imidazole quaternary ammonium salt provided by the application has a structure as shown in formula (I), is in a single crystal form, is in a triclinic crystal system, and belongs to a P-1 space group. The 4-nitrobenzoic acid imidazole quaternary ammonium salt has a significant bacteriostatic effect, good thermal stability, and can be applied to preparation of antibacterial materials as an antibacterial agent.

Description

Technical Field

[0001] This invention belongs to the field of antibacterial materials technology, and relates to a 4-nitrobenzoic acid imidazole quaternary ammonium salt, its preparation method and application. Background Technology

[0002] Common microorganisms such as Escherichia coli, Candida albicans, and Staphylococcus aureus can easily cause dysfunction in the human body and induce diseases; a significant number of malignant infectious diseases are caused by microorganisms. Quaternary ammonium salt antibacterial agents are inexpensive and highly practical, and have become one of the most widely used and promising cationic antibacterial agents. The N-terminus of quaternary ammonium salts... + Positively charged bacteria can adhere to the negatively charged bacterial cell membranes via Coulomb attraction, disrupting the cell membrane structure, causing the cell contents to leak out, and ultimately killing the bacteria. However, the widespread use of quaternary ammonium compounds has led to a large number of drug-resistant bacteria, making bacterial resistance a significant issue. Finding safe, highly effective, and residue-free bactericides is a new development trend. The preparation of quaternary ammonium compounds also needs to evolve towards enhanced efficacy, improved biocompatibility, and expanded applicability.

[0003] Mao Huilin prepared an imidazole-m-nitrobenzoic acid eutectic using evaporation crystallization, cooling crystallization, and solvent dropwise grinding methods. Its molecular formula is C2. 10 H9N3O4; The imidazole-m-nitrobenzoic acid eutectic contains 3 NH···O hydrogen bonds. The carboxyl group in m-nitrobenzoic acid is connected to the NH bond in the imidazole ring, and the OH bond is connected to the N atom in the imidazole ring through NH···O hydrogen bonds. The resulting imidazole-m-nitrobenzoic acid eutectic has a monoclinic crystal system, space group P2(1) / c, and the cell parameters are: α = 90.00°, β = 106.38(5)°, γ = 90.00°, Z = 4, cell volume The imidazole-m-nitrobenzoic acid cocrystal has certain antibacterial properties, but its antibacterial effect still needs to be improved (Mao Huilin. Preparation and analysis of drug cocrystals [D]. Tianjin University, 2009. DOI:10.7666 / d.y1675622.). Summary of the Invention

[0004] The purpose of this invention is to provide a 4-nitrobenzoic acid imidazole quaternary ammonium salt, its preparation method, and its application.

[0005] According to one aspect of the present invention, an imidazole quaternary ammonium salt of 4-nitrobenzoic acid is provided, which has 4-nitrobenzoic acid as an anion and imidazole as a cation, and has a chemical structure as shown in formula (I):

[0006]

[0007] The present application provides 4-nitrobenzoic acid imidazole quaternary ammonium salt, as shown in the formula (I). Figure 1 The anion and the cation are connected by 4 C-H···O and 1 C-H···N hydrogen bonds, wherein the nitro group in the 4-nitrobenzoic acid is connected with the imidazole ring by C-H···O and C-H···N, the carboxyl group in the 4-nitrobenzoic acid is connected with the imidazole ring by C-H···O, and there are 5 hydrogen bonds in total; the obtained 4-nitrobenzoic acid imidazole quaternary ammonium salt is in a single crystal form, the crystal form is triclinic, the space group is P-1, and the cell parameters are as follows: α = 103.033 (4) °, β = 100.165 (5) °, γ = 90.725 (5) °, the number of molecules in the cell Z = 2, and the cell volume V = 1 1 1 1. 1 (3) A3.

[0008] According to another aspect of the present application, a preparation method of the above-mentioned 4-nitrobenzoic acid imidazole quaternary ammonium salt is provided, and the method comprises the following steps:

[0009] 4-nitrobenzoic acid and imidazole are dissolved in a first solvent, and then the reaction is carried out at room temperature for 2-6 hours; the filter residue is washed with the first solvent and then dried to obtain a white solid powder reaction product A.

[0010] The reaction product A is dissolved in a second solvent, and then the reaction is carried out at room temperature for 1-3 weeks; the filter residue is washed with the second solvent and then dried to obtain the colorless crystal material, which is the 4-nitrobenzoic acid imidazole quaternary ammonium salt of the present application.

[0011] In some embodiments, the molar ratio of 4-nitrobenzoic acid and imidazole can be 1:(0.8-1.2).

[0012] In some embodiments, the first solvent can be at least one selected from the group consisting of methanol, ethanol, chloroform, isopropanol and acetone. Preferably, the first solvent is methanol.

[0013] In some embodiments, the second solvent can be at least one selected from the group consisting of methanol, ethanol, chloroform, isopropanol and acetone. Preferably, the second solvent is methanol.

[0014] In some embodiments, the molar volume ratio of the reaction product A and the second solvent can be (2-5) mmol:(10-15) mL.

[0015] In some embodiments, the drying method can adopt vacuum drying, and specifically can comprise the following steps: placing the material to be dried in a vacuum drying box, and drying at 0.08-0.1 Mpa and 45-60 °C for 10-15 h.

[0016] The preparation method of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid provided by the application can be carried out at room temperature throughout, is simple to operate, has high yield, requires simple instrument equipment, is easy to operate, requires less solvent consumption, saves cost, and is beneficial to industrial production.

[0017] The beneficial effects of the application include:

[0018] The preparation method of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid provided by the application can be carried out at room temperature throughout, has simple reaction conditions, fast reaction speed, simple operation, and low cost, the prepared imidazole quaternary ammonium salt of 4-nitrobenzoic acid has significant bacteriostatic effect and good thermal stability, and can be widely applied to the preparation of various antibacterial materials as a bacteriostatic agent.

[0019] In addition, the imidazole quaternary ammonium salt of 4-nitrobenzoic acid provided by the application has an absorption cutoff wavelength of 421 nm and an optical band gap of 2.95 eV, indicating that it has a certain absorption capacity for visible light, and the corresponding optical band gap belongs to the range of typical semiconductor materials, and is comparable to the values of other organic nonlinear optical materials studied as potential solar ultraviolet absorbers, and can be applied as an ultraviolet absorber. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 It is a hydrogen bond diagram of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0021] Figure 2 It is a crystal structure schematic diagram of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0022] Figure 3 It is a cation mass spectrum of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0023] Figure 4 It is an anion mass spectrum of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0024] Figure 5 It is an infrared spectrum of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0025] Figure 6 It is a solid ultraviolet-visible diffuse reflectance spectrum of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0026] Figure 7 It is an energy gap diagram of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0027] Figure 8 It is a thermogravimetric-thermal differential analysis diagram of the imidazole quaternary ammonium salt of 4-nitrobenzoic acid of the application;

[0028] Figure 9Inhibition zone diagram of 4-nitrobenzoic acid imidazole quaternary ammonium salt and solvent DMSO on Staphylococcus aureus and Escherichia coli;

[0029] Figure 10 MIC determination diagram of 4-nitrobenzoic acid complex quaternary ammonium salt ([IM][4NO2BA]), 4-nitrobenzoic acid (4NO2BA), imidazole (IM), imidazole-m-nitrobenzoic acid co-crystal (IM-m-nitrobenzoic acid) on Staphylococcus aureus and Escherichia coli. DETAILED DESCRIPTION

[0030] The application will be further described in detail below in conjunction with the embodiments. The examples are only used for explanation and do not limit the application in any way. If not otherwise specified, the raw materials and reagents used in the examples are conventional products that can be commercially available; the experimental methods not specified in the examples are usually carried out according to the conventional conditions in the art or according to the conditions recommended by the manufacturers.

[0031] Example 1

[0032] The preparation method of 4-nitrobenzoic acid imidazole quaternary ammonium salt comprises the following steps:

[0033] (1) 2 mmol of 4-nitrobenzoic acid and 2 mmol of imidazole were weighed in a 30 mL wide-mouth bottle, dissolved in 20 mL of methanol, stirred at room temperature for 6 hours, white precipitate was generated, vacuum filtration was performed under reduced pressure, the precipitate was washed with a small amount of methanol for 3 times, vacuum drying was performed at 0.08 Mpa and 60℃ for 12 hours, and white solid powder was obtained as the reaction product A;

[0034] (2) 2 mmol of the above reaction product A was taken in a 50 mL beaker, 15 mL of methanol was added as a solvent, the reaction product A was fully dissolved, and then the solution was placed at room temperature for natural evaporation, colorless crystals were precipitated after one week, vacuum filtration was performed under reduced pressure, the precipitate was washed with a small amount of methanol for 3 times, vacuum drying was performed at 0.08 Mpa and 60℃ for 12 hours, and 4-nitrobenzoic acid imidazole quaternary ammonium salt was obtained, the crystal structure schematic diagram thereof is shown in Figure 2 , and the main crystallographic data thereof is shown in Table 1.

[0035] Table 1 Main crystallographic data of 4-nitrobenzoic acid imidazole quaternary ammonium salt of the application

[0036]

[0037] The electrospray mass spectrum of the 4-nitrobenzoic acid imidazole quaternary ammonium salt ([IM][4NO2BA]) prepared by the application is shown in Figures 3-4 . It can be seen from the diagram that the cation [IM] + The measured molecular weight is 69.2, which is consistent with the theoretical value 68.0, and the anion [4NO2BA]- The measured molecular weight was 166.0, which is close to the theoretical value of 166.2.

[0038] The infrared spectrum of the 4-nitrobenzoic acid complex quaternary ammonium salt is shown in the figure. Figure 5 3167cm -1 The nearby absorption peak is caused by the stretching vibration of the NH group on the imidazole ring; 3097 cm⁻¹ -1 and 3008cm -1 The main vibration is the stretching vibration of CH in the imidazole five-membered hybrid ring; at 1712 cm⁻¹ -1 The nearby absorption peak is due to the C=O stretching vibration in carboxylic acids; 1554 cm⁻¹ -1 The nearby absorption peaks all belong to the C-S stretching vibration of the benzene ring; 1514 cm⁻¹ -1 and 1342cm -1 The nearby absorption peaks belong to the asymmetric and symmetric stretching vibrations of the nitro NO2 group on the benzene ring; 1187 cm⁻¹ -1 and 1104cm -1 The nearby absorption peaks are all caused by the in-plane bending vibration of the CH group of the benzene ring; 764 cm⁻¹ -1 and 702cm -1 The nearby absorption peaks all belong to the out-of-plane bending vibration of the CH group of the benzene ring.

[0039] Solid UV absorption spectroscopy was performed on 4-nitrobenzoic acid complex quaternary ammonium salt. The solid UV-Vis diffuse reflectance spectrum and bandgap diagram are shown below. Figure 6 and Figure 7 As shown in the figure, the absorption cutoff wavelength of the 4-nitrobenzoic acid composite quaternary ammonium salt provided by this invention is 421 nm, and the corresponding optical band gap is 2.95 eV. This indicates that the 4-nitrobenzoic acid composite quaternary ammonium salt provided by this invention has a certain absorption capacity for visible light. This band gap is within the range of typical semiconductor materials and is comparable to the values ​​of other organic nonlinear optical materials studied as potential solar ultraviolet absorbers, making it a potential optical material.

[0040] Thermogravimetric analysis and differential thermal analysis (TG / DTG) for the detection of 4-nitrobenzoic acid complex quaternary ammonium salts are shown in [reference needed]. Figure 8 The TG curves show that from room temperature to the initial weight loss point, the compound experiences slight weight loss with increasing temperature, primarily between 168.4 and 257.1 °C, with a weight loss rate of 97.06% of the initial mass. When the temperature reaches 799.1 °C, the residual mass of the material is measured to be 2.94%. The TG / DTG curves indicate that the 4-nitrobenzoic acid composite quaternary ammonium salt provided by this invention is stable at 168.4 °C, exhibiting strong thermal stability.

[0041] Antibacterial test of test cases

[0042] (1)Antibacterial activity determination

[0043] An appropriate amount of 4-nitrobenzoic acid complex quaternary ammonium salt crystals prepared in Example 1 was dissolved with dimethyl sulfoxide (DMSO) to prepare a 0.1 g·mL -1 of drug solution, and a 6 mm diameter circular filter paper was soaked in the drug solution and used as a control. At the same time, a 6 mm diameter circular filter paper was soaked in DMSO as a blank control. In the vicinity of an alcohol lamp, 100 μL of 6.0 x 10 6 CFU·mL -1 of Staphylococcus aureus bacterial solution and 100 μL of 2.0 x 10 7 CFU·mL -1 of Escherichia coli bacterial solution were uniformly coated on LB solid medium, and the filter paper soaked in the drug solution / DMSO was placed on the medium, and the culture dish was sealed with a sealing film. After incubation at 37°C for 24 h, the diameter of the inhibition zone was measured, and the results are shown in Figure 9 .

[0044] The results show that the 4-nitrobenzoic acid complex quaternary ammonium salt provided by the present application has an inhibition zone size of 1.4 cm and 1.3 cm for Staphylococcus aureus and Escherichia coli, respectively. It can be seen that the 4-nitrobenzoic acid complex quaternary ammonium salt exhibits good antibacterial activity for Staphylococcus aureus and Escherichia coli at the same dose.

[0045] (2) Minimum inhibitory concentration (MIC) determination

[0046] Imidazole-m-nitrobenzoic acid co-crystals were prepared by the method of "evaporative crystallization" described in "Mao Hui-lin. Preparation and analysis of drug co-crystals [D]. Tianjin University, 2009. DOI: 10.7666 / d.y1675622." with deionized water as the solvent, and the MIC of the co-crystals for Escherichia coli and Staphylococcus aureus was determined.

[0047] The MIC value was determined by the double dilution method. First, 100 μL of LB liquid medium was transferred to the required wells of a 96-well plate, and then 4-nitrobenzoic acid complex quaternary ammonium salt ([IM][4NO2BA]), 4-nitrobenzoic acid (4NO2BA), imidazole (IM), and imidazole-m-nitrobenzoic acid co-crystals (IM-m-nitrobenzoic acid) were dissolved in DMSO to prepare a drug solution with a concentration of 0.01 mol·L -1 , and 100 μL of the drug solution was added to the first well on the left side of each row of the 96-well plate. Then, by the double dilution method, the solution was diluted in gradient, and 100 μL of Staphylococcus aureus with a concentration of 6.0 x 10 6 CFU·mL -1 (or 100 μL of Escherichia coli with a concentration of 2.0 x 10 7 CFU·mL-1 The E. coli was added to each sample, and 3 groups of samples were parallel. A negative control (adding the bacterial solution and kanamycin), a positive control (only adding the bacterial solution), a solvent control (adding the bacterial solution and the solvent DMSO), and a blank control (only adding the LB medium) were additionally set. After being cultured in a thermostat at 37℃ for 18h, 50μL of 2,3,5-chlorinated triphenyl tetrazolium (TTC) with a concentration of 2g·L -1 The minimum concentration without red color was observed as the minimum inhibitory concentration of the sample, and Table 2, Figure 10 .

[0048] Table 2 MIC values of each sample

[0049]

[0050] The results show that the 4-nitrobenzoic acid complex quaternary ammonium salt provided by the application has more significant antibacterial effect.

[0051] The above only describes some embodiments of the application. For those skilled in the art, without departing from the concept of the application, several modifications and improvements can be made, which are all within the protection scope of the application.

Claims

1. Use of 4-nitrobenzoic acid imidazolium quaternary salt as an antibacterial agent in the preparation of an antibacterial material, characterized in that, The structure of the 4-nitrobenzoic acid imidazole quaternary ammonium salt is shown in the following formula (I): （I）。 2. Use according to claim 1, characterized in that, The 4-nitrobenzoic acid imidazole quaternary ammonium salt is in a single crystal form, which is in a triclinic crystal system, P -1 space group, with a unit cell parameter of: a = 5.9604(8) Å, b = 7.5354(8) Å, c = 11.8174(16) Å, α = 103.033(4) , β = 100.165(5) , γ = 90.725(5) , Z = 2, with a unit cell volume of 508.22(11) Å 3 .

3. Use according to claim 1 or 2, characterized in that, The preparation method of the 4-nitrobenzoic acid imidazole quaternary ammonium salt comprises the following steps: Take 4-nitrobenzoic acid and imidazole, dissolve them in a first solvent, and react at room temperature for 2-6 hours, then perform vacuum filtration, wash the filter residue with the first solvent, and dry to obtain a reaction product A; Dissolve the reaction product A in a second solvent, and place it at room temperature for 1-3 weeks, then perform vacuum filtration, wash the filter residue with the second solvent, and dry to obtain the 4-nitrobenzoic acid imidazole quaternary ammonium salt.

4. Use according to claim 3, characterized in that, The molar ratio of the 4-nitrobenzoic acid and the imidazole is 1:(0.8-1.2).

5. Use according to claim 3, characterized in that, The first solvent is at least one selected from methanol, ethanol, chloroform, isopropyl alcohol, and acetone.

6. Use according to claim 5, characterized in that, The second solvent is at least one selected from methanol, ethanol, chloroform, isopropyl alcohol, and acetone.

7. Use according to claim 6, characterized in that, The molar volume ratio of the reaction product A and the second solvent is (2-5) mmol:(10-15) mL.

8. Use according to claim 3, characterized in that, The drying is vacuum drying.

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