A method for synthesizing nitrogen oxides using aniline

Abstract

The present invention discloses a method for synthesizing nitrogen oxides from aniline. Using a micro-droplet reaction device, an aqueous solution of an aniline compound of a certain concentration is sprayed. The resulting target product is collected in a round-bottom flask and separated to obtain nitrogen oxides. This method solves the problem of harsh reaction conditions and the need for catalysts in the prior art of preparing nitrogen oxides from aromatic amines. Furthermore, the method is green, mild, catalyst-free, rapid, and has a high yield.

Description

Technical Field

[0001] The present invention relates to the field of green synthetic chemistry, and in particular to a method for synthesizing nitrogen oxides by utilizing aniline. Background Art

[0002] Small, high-electric-field microdroplets possess unique chemical properties, such as the ability to accelerate chemical reactions or enable reactions that would be impossible in the liquid phase. Recent studies have shown that even without high voltage, some microdroplets exhibit electrochemical cell phenomena, generating reactive species such as electrons, hydroxyl radicals, and water radical cations, which can further induce spontaneous oxidation or reduction reactions. Due to the ultrahigh electric field at the air-water interface of the microdroplet reaction, dimers of hydroxyl radicals and water radical cations can form. These dimers readily decompose to produce reactive oxygen species such as protonated water and hydroxyl radicals, which in turn trigger multiple oxidation reactions within the microdroplet.

[0003] N,N-dimethylaniline (DMA) is commonly used in medicine as a raw material for the synthesis of pharmaceutical intermediates. In the food industry, it can be used to synthesize vanillin. Currently, research on this type of substance mainly focuses on quantitative detection, and there is little research on its oxidation reaction and gas phase dissociation reaction mechanism. Some scholars have reported that a transient intermediate DMA with a half-life of less than 1 microsecond was detected using electrochemical mass spectrometry. +· , the intermediate is produced by the electrochemical oxidation process. In addition, Zhang Xinxing's research group explored DMA +· CH / NH cross-coupling reaction with phenoxazines.

[0004] Amine N-oxide (R3N + -O - ) were first described by Dunston and Goulding in 1899 and named "oxamines." For example, they synthesized triethylamine oxide, with the chemical formula (C2H5)3NO, from hydroxylamine and ethyl iodide. They also published the first method for synthesizing amine N-oxides from tertiary amines using hydrogen peroxide. Meisenheimer conducted further experiments in 1913 and 1919, synthesizing amine N-oxides from tertiary amines using hydrogen peroxide. He described a method for synthesizing N-allyl-N-methylaniline from N-allyl-N-methylaniline and hydrogen peroxide. In the 1960s and 1970s, interest in amine oxides increased due to the discovery that some compounds could be used as detergents and foam stabilizers. During this period, several publications and patents were published on the synthesis, production processes, and applications of amine oxides. Therefore, it is important to develop rapid, catalyst-free, and green methods for preparing nitrogen oxides. Summary of the Invention

[0005] The purpose of the present invention is to solve at least one of the technical problems existing in the prior art and to provide a micro-droplet technical method for rapidly synthesizing nitrogen oxides by spraying an aqueous solution of aniline compounds into micro-droplets. This reaction is rapid, atom-economical, green and pollution-free, and does not require a catalyst, making it a model of green synthetic chemistry.

[0006] N,N-dimethylaniline, as a raw material for pharmaceutical synthesis intermediates, has great application potential in synthesis. We utilized the high electric field effect of microdroplets as a synthesis opportunity. A gas source passing through a metal tube was used to blow the reaction liquid at the capillary mouth to form small droplets with a high electric field. The characteristics of the microdroplets were utilized to induce a free radical reaction, forming N,N-dimethylaniline nitrogen oxide with an m / z of 138.

[0007] A method for synthesizing nitrogen oxides from aniline, using a micro-droplet reaction device, drives an aniline compound aqueous solution to form a tiny spray under the drive of a carrier gas flow, wherein the solute aniline compound forms aniline compound free radicals in the spray, and the solvent water forms hydroxyl free radicals, and the aniline compound free radicals and the hydroxyl free radicals react to generate nitrogen oxides.

[0008] Preferably, the aniline compound includes at least one of N,N-dimethylaniline, N,N-dimethyl-m-hydroxyaniline, N,N-diethylaniline, N,N-dimethyl-p-methoxyaniline, N,N-dimethyl-p-chloroaniline, N,N-dimethyl-p-bromoaniline, and N,N-dimethyl-p-methylaniline.

[0009] Taking N,N-dimethylaniline as an example, the reaction principle is as follows:

[0010]

[0011] Preferably, the carrier gas is air and / or an inert gas.

[0012] Preferably, the concentration of the aqueous solution of the aniline compound is 10-1000 ppm.

[0013] Preferably, the flow rate of the carrier gas is 0.8-1.0 MPa.

[0014] Preferably, the micro-droplet reaction device includes a capillary, a metal outer tube and a tee. The metal outer tube is sleeved on the outer end of the capillary. The cavity formed between the metal outer tube and the capillary is used for gas circulation. The cavity is connected to the gas pipeline. The tee interface is used to connect the metal outer tube and the gas pipeline. It is located outside the capillary, and the front end of the capillary is exposed 0.1-0.3 mm from the outlet of the metal outer tube.

[0015] Preferably, the inlet of the capillary is connected to a sample injector through an injection passage.

[0016] Preferably, the capillary is made of quartz glass.

[0017] Preferably, the method specifically includes the following steps:

[0018] Prepare an aqueous solution of aniline compounds, pass it through the capillary at a certain flow rate, and form microdroplets when reaching the capillary outlet through the impact of the carrier gas. The microdroplets contain intermediate free radical cations and hydroxyl radicals, which react to form nitrogen oxides; use isotope deuterium labeling and isotope 18 O labeling, other conditions remain unchanged, through the corresponding primary mass spectrometry data and secondary mass spectrometry data analysis, it can be known that there are ions of corresponding order of magnitude, which can be determined to be the complex product formed by the reaction of hydroxyl radicals and aniline compounds.

[0019] The present invention has the following beneficial effects:

[0020] By adopting the free radical coupling reaction in the above-mentioned micro-droplets, the present invention avoids the traditional tedious and lengthy reaction processes such as high temperature and high pressure, acid-soluble alkali-soluble, and catalyst. The cost of the spray formed by the present invention is low, air can be used as an air source, and the air source is convenient. In addition, the entire reaction time is extremely short, and the product signal can be clearly seen by mass spectrometry at the moment of forming the spray, indicating that the free radical coupling reaction can occur in an instant. By regulating experimental conditions such as air pressure, flow rate, and distance, the reaction can be efficiently generated. The entire device is simple and has low modification cost. It can not only realize online in-situ analysis, but also realize modification of offline preparation products. The product can be obtained at the moment the spray is formed. The entire process is efficient, fast, green, and environmentally friendly. There are no stringent requirements for the external conditions of the reaction, and it can be carried out at room temperature and pressure. With water as a solvent, the product is clean, with few by-products, and the air source is convenient, green and pollution-free. This provides a new idea for the synthesis reaction of nitrogen oxides, avoids the defects of traditional high dosage and long reaction time, and is of great significance for synthesizing nitrogen oxides. This study used microdroplet reactions to obtain stable intermediate free radical cations that are difficult to capture by other means, which helps to deepen the understanding of the characteristics of water droplet chemistry-promoted oxidation reactions. It is expected that this technical method will be applied to the chemical industry or pharmaceutical fields in the future. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The above advantages of the present invention will become apparent and easily understood in conjunction with the following drawings, wherein;

[0022] Figure 1 This is a schematic structural diagram of the device for synthesizing N,N-dimethylaniline nitrogen oxides of the present invention;

[0023] Figure 2 It is the overall signal comparison of water radical cations before and after injection and the comparison of product signals before and after injection;

[0024] Figure 3 The primary and secondary mass spectra of the radical cation product (m / z 138) formed by the free radical coupling reaction after the spray is formed, as well as the corresponding isotope labeling diagram;

[0025] Figure 4 The results of the optimization of conditions for the generation of hydroxylamine compounds by the reaction of DMA aqueous solution microdroplets are shown. A and B correspond to different optimized conditions, namely, carrier gas pressure (a), distance between the sample outlet and the mass spectrometer port (b), flow rate (c), and sample concentration (d).

[0026] Figure 5 The following are mass spectra of the interaction between aniline compounds with different types of substituents and hydroxyl radicals, where a is DMA (N,N-dimethylaniline), b is meta-hydroxyl substitution (N,N-dimethyl-m-hydroxyaniline), c is N,N-diethylaniline, d is N,N-dimethyl-p-methoxyaniline, e is N,N-dimethyl-p-chloroaniline, f is N,N-dimethyl-p-bromoaniline, and g is N,N-dimethyl-p-methylaniline. DETAILED DESCRIPTION

[0027] To make the objectives, features, and advantages of the present invention more readily apparent, specific embodiments of the benzene invention are described in detail below with reference to the accompanying drawings. The drawings illustrate several reaction examples of the present invention. However, the present invention can be implemented in many different forms and is not limited to the examples described herein. Rather, these reaction examples are provided to enhance the openness and transparency of the present invention.

[0028] In this document, unless otherwise specified or limited, the terms "connect," "fixed," and "connected" are to be understood broadly. For example, they may refer to fixed, detachable, or integral connections; mechanical or non-mechanical connections; direct, through an intermediate medium, or internal communication between components. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0029] See also Figure 1 , a schematic diagram of the structure of an experimental device of the present invention;

[0030] The device includes a capillary tube 2 , a metal outer tube 3 , a tee, a gas path 4 , a sample injection path 6 , and a mass spectrometer 5 .

[0031] The capillary 2 is enclosed in the metal outer tube 3, about 0.2mm protruding from the outer shell, and in a state parallel to it, the capillary 2 is fixed in position by a tee, connected to an injection path 6, and during the specific test, the injection path 6 is connected to a syringe 1, and the syringe is equipped with a DMA aqueous solution. The metal outer tube 3 is connected and fixed on the tee, and is enclosed outside the capillary 2. The space between the metal outer tube 3 and the capillary 2 is a nitrogen source path, and the upper end of the tee is connected and fixed with an air inlet path 4. The nitrogen source can be reached by the metal outer tube 3 through the tee to reach the capillary 2 liquid outlet, and the reaction solution is blown away to form micro-droplets. The effect of the three-necked vertebra bottle is to collect the spray containing the product, and it has three necks, and the middle is used to fix the reaction device. The metal outer tube 3 enclosed with the capillary 2 is fixed on the middle mouth, and the metal outer tube 3 and the capillary 2 liquid outlet are a certain distance from the bottom of the bottle. The other two mouths are respectively used as an air outlet and a liquid taking port, and the solution containing the product collected can be extracted.

[0032] The capillary is a quartz capillary with a diameter of 0.19 mm. The reaction liquid is injected into the capillary from an external injector and passes through the capillary at a certain flow rate, but is not limited thereto.

[0033] The metal outer tube is a metal middle tube with an inner diameter of 0.4 mm, which is sleeved on the outside of the capillary and fixed on the tee. The gas passes through the metal outer tube at a certain pressure and flow rate outside the capillary and reaches the front capillary mouth, blowing away the reaction liquid to form tiny droplets.

[0034] Based on the above device and the functions of each component, a method for synthesizing N,N-dimethylaniline includes:

[0035] The sample is injected into the capillary 2 through the injection passage 6, passes through the capillary 2, and reaches the liquid outlet of the capillary 2 through the tee. The gas path passes through the tee and passes through the metal outer tube 3 to reach the gas outlet. The reaction liquid is blown away at the tube mouth to form microdroplets. Due to the high electric field characteristics of the microdroplets, stable aniline compound free radicals (DMA+·) and water radical cations are generated, which then decompose into hydroxyl radicals. DMA+· and hydroxyl radicals undergo free radical coupling to synthesize N,N-dimethylaniline nitrogen oxides. The gas source is mainly nitrogen, and air can be used as the nitrogen source. The product base peak can be detected by the mass spectrometer 5. Under the same conditions, the product is collected using a three-necked vertebral flask. The collected product is subjected to ESI-MS, and the product peak can also be detected on the mass spectrometer 5. Verification shows that the product can be collected using the three-necked flask.

[0036] In specific applications, it was found that the spray state is related to the gas pressure of the gas source and the injection volume of the reaction liquid, and the spray state directly affects the reaction effect. Through exploration and optimization of reaction conditions, the optimal reaction conditions were found to be a gas pressure of 0.9 MPa and an injection flow rate of 7 μL / min, but these are not limited to these conditions and can also be 0.8-1.0 MPa and an injection flow rate of 6-8 μL / min.

[0037] In specific applications, it was also found that the concentration of the reaction solution has a great influence on the efficiency of the coupling reaction. When the reaction solution concentrations are 1ppm, 10ppm, 100ppm, and 1000ppm, the product signal of 138 of the 100ppm and 1000ppm reaction solutions can be detected in the mass spectrometer as the base peak, and the product signal increases with increasing concentration.

[0038] The airflow in the present method can cause the solvent water to form water radical cations, which then decompose to form hydroxyl radicals. The reactants can also form DMA+ radicals in the microdroplets, which couple to form N,N-dimethylaniline N-oxide. When the reaction solution is replaced with pure water for the spray reaction, the water radical cation signal in the reaction solution is clearly reduced compared to pure water, indicating that the generated hydroxyl radicals participate in the reaction, resulting in a decrease in the mass spectrometer signal.

[0039] The hydroxyl radicals in the method of the present invention come from the solvent, which is 18 O verification, under the condition of ensuring that other conditions are the same, the solvent water is replaced with deuterated water and heavy oxygen water, and the mass spectrometer can show that the signals of 139 and 140 are significantly enhanced. Through secondary and tertiary analysis, it can be determined that the deuterium-labeled hydroxyl free radicals and heavy oxygen-labeled hydroxyl free radicals are +· Coupling product.

[0040] The present invention will be further described below through various embodiments.

[0041] In the following examples, the metal outer tube has an inner diameter of 0.4 mm, and the capillary tube is a quartz capillary tube with a diameter of 0.19 mm. The conditions not specified below are all preferred conditions.

[0042] Example 1

[0043] use Figure 1 The sample was injected into the injection channel through the injection needle, and the carrier gas was turned on. Other conditions were the same (the gas pressure was 0.9 MPa and the injection flow rate was 7 μL / min). Compared with the pure water, the mass spectrometer showed obvious water radical cations (H2O). 2+ The m / z36 signal decreases and the product signal m / z138 increases significantly, such as Figure 2 shown.

[0044] Example 2

[0045] use Figure 1In the device shown, a certain concentration (1ppm, 10ppm, 100ppm, 1000ppm) of N,N-dimethylaniline aqueous solution is introduced into the injection channel, and the microdroplets are blown away by the gas source, thereby forming DMA+ and water free cations, both of which can be observed by the mass spectrometer with corresponding ion signals of m / z121 and m / z36, and a new peak of m / z138 with 17Da added is formed, as shown in FIG. Figure 2 At the same time, it can be observed that the signal of m / z36 is decreasing compared to pure water, which indirectly indicates that the water radical cation of m / z36 is involved in the reaction, reacting with the reactant ion of m / z121 to produce hydroxyl radicals that couple with DMA+· to synthesize the product of m / z138. 18 The O labeling experiment replaced the solvent H2O with D2O and H c 18 O, other conditions remain unchanged, there will be product signals of 18Da and 19Da respectively. Through the corresponding primary and secondary mass spectrometry data analysis, it can be determined that the ion with a mass number of 17Da is the product of the reaction between ·OH from the solvent and DMA+·, such as Figure 3 As shown, further analysis of the secondary and tertiary mass spectrometry data revealed that the product [M+OH]+· mainly lost 17Da after collision cleavage, while the [M+OD]+· product mainly lost 18Da, and [M+ c The main product lost was 19 Da, and all of them obtained a fragment ion of m / z 121. Therefore, it can be determined that the increased amount of 17 Da is from the hydroxyl radical formed by the solvent.

[0046] See Figure 2 , Figure 2 The total ion chromatogram (TIC) and selected ion chromatogram (EIC) obtained under these conditions are shown. A certain amount of pure water is introduced into the injection channel, followed by an N,N-dimethylaniline aqueous solution after a period of time. m / z 36 decreases rapidly after the introduction of the N,N-dimethylaniline aqueous solution, while m / z 138, m / z 121, and m / z 122 increase rapidly. This indicates that m / z 36 is reacted to form m / z 138.

[0047] Example 3

[0048] use Figure 1 The device was used to evaluate the performance of the method. The same method, experimental parameters, and mass spectrometry experimental conditions as in Example 2 were used. Different concentrations of N,N-dimethylaniline aqueous solution (1 ppm, 10 ppm, 100 ppm, 1000 ppm) were sequentially added to the injection channel. A good linear relationship between the different concentrations of N,N-dimethylaniline aqueous solution and the water radical cation coupling product m / z 138 was obtained ( Figure 4d), when the concentration of N,N-dimethylaniline aqueous solution is 10ppm, the ion of m / z 138 can still be detected ( Figure 4 ). The device conditions were optimized and under the best conditions, the signal intensity of m / z138 could reach E4 ( Figure 4 ).

[0049] Example 4

[0050] use Figure 1 The same experiment was conducted on a series of N,N-dimethylaniline compounds, the structures of which are shown in Figure 2. Figure 5 As shown. Using the same method as Example 2, the same experimental parameters and the same mass spectrometry conditions, aqueous solutions of N,N-dimethylaniline compounds with different substituent types are sequentially added to the injection channel shown, and signals of the interaction between various N,N-dimethylaniline compounds and hydroxyl radicals can be obtained ( Figure 2 , 3), which shows that the comparative solution of N,N-dimethylaniline compounds undergoes free radical coupling reaction with hydroxyl radicals to produce a radical cation peak of 17Da. The device can be used to synthesize the corresponding nitrogen oxides of N,N-dimethylaniline compounds, and is particularly suitable for the drug synthesis research of such compounds.

[0051] In summary, the above-mentioned apparatus and method for synthesizing nitrogen oxides utilizes a nitrogen gas source (which can be air) to directly disperse the reaction solution into microdroplets without the need for electricity, thus facilitating convenient raw material supply. By controlling the air pressure and adjusting the spray state, pure water is ensured to generate a water radical cation with m / z 36 to obtain a signal. The water radical cation then forms a hydroxyl radical. The pure water is then replaced with an N,N-dimethylaniline aqueous solution, and a radical coupling reaction is carried out in the microdroplets under the previously adjusted conditions to generate N,N-dimethylaniline nitrogen oxide. The entire apparatus is simple and pollution-free. The reaction time between the water radical cation clusters forming hydroxyl radicals and the interaction with DMA+· is fast, enabling high-throughput analysis. This is of great significance for the synthesis of nitrogen oxides of aniline compounds from a gas source.

[0052] Throughout this specification, reference to terms such as "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" means that a specific feature, structure, material, or characteristic described in conjunction with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0053] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for synthesizing nitrogen oxides using aniline, characterized in that: A micro-droplet reaction device is used to disperse the aqueous solution of aniline compounds into a micro-spray driven by a carrier gas flow. The solute aniline compounds form aniline compound free radicals in the spray, and the solvent water forms hydroxyl free radicals. The aniline compound free radicals react with the hydroxyl free radicals to generate nitrogen oxides. The aniline compound includes at least one of N,N-dimethylaniline, N,N-dimethyl-m-hydroxyaniline, N,N-diethylaniline, N,N-dimethyl-p-methoxyaniline, N,N-dimethyl-p-chloroaniline, N,N-dimethyl-p-bromoaniline, and N,N-dimethyl-p-methylaniline; The micro-droplet reaction device includes a capillary, a metal outer tube and a tee. The metal outer tube is sleeved on the outer end of the capillary. The cavity formed between the metal outer tube and the capillary is used for gas circulation. The cavity is connected to the gas pipeline. The tee interface is used to connect the metal outer tube and the gas pipeline. It is located outside the capillary, and the front end of the capillary is exposed 0.1-0.3 mm from the outlet of the metal outer tube.

2. The method for synthesizing nitrogen oxides using aniline according to claim 1, characterized in that: The carrier gas is air and / or an inert gas.

3. The method for synthesizing nitrogen oxides using aniline according to claim 1, characterized in that: The concentration of the aniline compound aqueous solution is 10-1000 ppm.

4. The method for synthesizing nitrogen oxides using aniline according to claim 1, characterized in that: The flow rate of the carrier gas is 0.8-1.0 MPa, and / or the injection flow rate is 6-8 μL / min.

5. The method for synthesizing nitrogen oxides using aniline according to claim 1, characterized in that: The inlet of the capillary is connected with a sample injector through a sample injection passage.

6. The method for synthesizing nitrogen oxides using aniline according to claim 1, characterized in that: The capillary is made of quartz glass.

7. The method for synthesizing nitrogen oxides using aniline according to claim 1, characterized in that: The specific steps include: Prepare an aqueous solution of aniline compounds, pass it through the capillary at a certain flow rate, and form microdroplets when reaching the capillary outlet through the impact of the carrier gas. The microdroplets contain intermediate free radical cations and hydroxyl radicals, which react to form nitrogen oxides; use isotope deuterium labeling and isotope 18 O labeling, other conditions remain unchanged, through the corresponding primary mass spectrometry data and secondary mass spectrometry data analysis, it can be known that there are corresponding orders of magnitude of ions, which can be determined to be the composite product formed by the reaction of hydroxyl radicals and aniline compound radicals.

Images