A process for the preparation of 4,4'-dipyridyl

Abstract

The application belongs to the technical field of chemical synthesis, and discloses a preparation method of 4,4'-bipyridine, characterized in that: under the atmosphere of nitrogen or inert gas, sodium metal is first dissolved in 1,3-dimethyl-2-imidazolidinone, then pyridine is added for reaction, the reaction liquid is cooled to 0-5 DEG C, deionized water is added, and in the case of adding or not adding N,N-dimethylformamide, air is introduced for oxidation reaction to obtain 4,4'-bipyridine. The application takes pyridine as raw material, the raw material is cheap and easy to obtain, and the production cost is low; the application takes green and safe 1,3-dimethyl-2-imidazolidinone as reaction solvent, which has the advantages of low toxicity, small pollution and high stability, and has good solubility to sodium metal, and significantly improves the reaction activity of sodium. Meanwhile, N,N-dimethylformamide with high dielectric constant is used as additive, which effectively promotes the generation of product.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology and relates to a method for preparing 4,4′-bipyridine. Background Technology

[0002] 4,4′-Bipyridine is an important intermediate in organic synthesis and pharmaceutical chemistry, with wide applications in drug molecule synthesis, materials science, and basic chemical research. It is a key intermediate in the synthesis of the non-selective herbicide paraquat; its nitrogen atoms at both ends can coordinate with metal atoms to form excellent bridging ligands, playing a crucial role in catalytic reactions; it can also serve as an indicator for detecting metal ions. Furthermore, 4,4′-bipyridine exhibits luminescent properties and can be used to prepare fluorescent materials.

[0003] Currently, there are four main methods for preparing 4,4′-bipyridine:

[0004] ① 4-Halogenated pyridine method: using 4-chloropyridine or 4-bromopyridine as raw materials, from NaH- t The synthesis of 4,4′-bipyridine is catalyzed by BuONa-Ni(OAc)2-PPh3 catalyst. This method yields good results, but the raw material price is high, resulting in high production costs, making it unsuitable for industrial production.

[0005] ② Hot sodium method and low-temperature sodium method: The hot sodium method uses pyridine and metallic sodium as raw materials, reacting them at 95°C, followed by oxidation with air to obtain 4,4′-bipyridine. This method has low pyridine utilization, low product purity, and generates the highly toxic substance terpyridine, and also poses risks of flammability and explosion. The low-temperature sodium method, pioneered by ICI in the UK, uses pyridine as a raw material, reacting it with a liquid ammonia solution of sodium at -20 to -30°C, followed by oxidation with air to obtain 4,4′-bipyridine. Compared to the hot sodium method, the low-temperature sodium method has higher pyridine utilization and produces a higher purity product. However, this method uses volatile liquid ammonia as a solvent, requiring the reaction to be carried out at consistently low temperatures, making the reaction conditions quite harsh. Furthermore, liquid ammonia is highly corrosive and toxic, posing significant safety hazards.

[0006] ③ Formaldehyde-based pyridine method: Using aluminosilicate or phosphate as catalysts, p-formaldehyde-based pyridine reacts with acetaldehyde and ammonia in a nitrogen stream at a temperature of 300–450℃ to obtain 4,4′-bipyridine. This method uses formaldehyde-based pyridine as a raw material, which is relatively expensive and has high production costs.

[0007] ④ Coupling reactions: These mainly include the palladium-catalyzed Suzuki coupling reaction of 4-chloropyridine and 4-borate pyridine, and the copper-catalyzed photocatalytic coupling reaction of 4-borate pyridine. These methods require expensive metal catalysts, resulting in high production costs and demanding reaction conditions, which limits their industrial production. Summary of the Invention

[0008] The purpose of this invention is to solve the technical problems existing in the above-mentioned synthesis methods and to provide a method for preparing 4,4′-bipyridine.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] A method for preparing 4,4′-bipyridine includes: using pyridine as a raw material, sodium metal as a catalyst, and 1,3-dimethyl-2-imidazolinone as a reaction solvent, under a nitrogen or inert gas atmosphere, first dissolving sodium metal in 1,3-dimethyl-2-imidazolinone, then adding pyridine to react, cooling the reaction solution to 0-5°C, adding deionized water, and then, with or without the addition of N,N-dimethylformamide, purging air to carry out an oxidation reaction to obtain 4,4′-bipyridine.

[0011] The molar ratio of sodium metal to pyridine is 1:1 to 1:5, preferably 1:2 to 1:4, more preferably 1:2 to 1:3, and most preferably 1:2.

[0012] The mass ratio of pyridine to 1,3-dimethyl-2-imidazolinone is 1:2 to 1:8, preferably 1:2 to 1:4.

[0013] Specifically, the mass ratio of pyridine to 1,3-dimethyl-2-imidazolinone can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0014] The mass ratio of deionized water to pyridine is 1:1.5 to 1:5, preferably 1:2 to 1:5, and most preferably 1:3 to 1:3.5.

[0015] The mass ratio of N,N-dimethylformamide to 1,3-dimethyl-2-imidazolinone is 1:2 to 1:5, preferably 1:2 to 1:3.

[0016] The reaction temperature is 20–60°C, preferably 30–50°C, more preferably 30–40°C, even more preferably 35–40°C, and most preferably 40°C; the reaction time is 12–48 h, preferably 20–30 h.

[0017] Preferably, the reaction solution is cooled to 0°C.

[0018] The oxidation reaction is carried out at a temperature of 20–25°C for 10–12 hours.

[0019] As a further preferred technical solution for the preparation method of 4,4′-bipyridine according to the present invention, the method includes: mixing metallic sodium and 1,3-dimethyl-2-imidazolinone under a nitrogen or inert gas atmosphere, and after the sodium is completely dissolved, adding pyridine to react, cooling the reaction solution to 0-5°C, adding deionized water and N,N-dimethylformamide, and then purging air to carry out an oxidation reaction to obtain 4,4′-bipyridine.

[0020] As a further preferred technical solution of the preparation method of 4,4′-bipyridine according to the present invention, the method further includes: after the reaction is completed, water is added to quench the reaction, ethyl acetate is used for extraction, the organic phase is taken, the organic phase is concentrated to remove the solvent, silica gel column chromatography is performed, the eluent is petroleum ether:ethyl acetate = 4:1V / V, and 4,4′-bipyridine is obtained by separation and purification.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] (1) The present invention uses pyridine as raw material, which is cheap and readily available, resulting in low production costs.

[0023] (2) This invention uses 1,3-dimethyl-2-imidazolinone as a green and safe reaction solvent, which has the advantages of low toxicity, low pollution, and high stability. It also has excellent solubility for metallic sodium, significantly improving the reactivity of sodium. Furthermore, the use of N,N-dimethylformamide, with its high dielectric constant, as an additive effectively promotes product formation. The yield of 4,4′-bipyridine in this invention can generally reach over 80%, and in some cases, over 95%.

[0024] (3) The reaction conditions of the present invention are mild, the process is simple and easy to operate, and it has good prospects for industrial application. Attached Figure Description

[0025] Figure 1 The 1H NMR spectrum of 4,4′-bipyridine.

[0026] Figure 2 The carbon NMR spectrum of 4,4′-bipyridine. Detailed Implementation

[0027] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0028] The room temperature in this invention refers to 20–25°C.

[0029] Example 1

[0030] In a pre-dried 250 mL three-necked flask, 47.4 g of 1,3-dimethyl-2-imidazolinone was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (at 800 rpm). After the sodium was completely dissolved, 15.8 g of pyridine was added, and the reaction was carried out at 40 °C with stirring (at 600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C, followed by 23.7 g of... N,N-Dimethylformamide; after the N,N-dimethylformamide was added, air was introduced and the mixture was stirred at room temperature (600 rpm) for 12 h to carry out the oxidation reaction. After the reaction was completed, the mixture was extracted five times with ethyl acetate and the organic phase was collected. The organic phase was concentrated to remove the solvent and then subjected to silica gel column chromatography (200 mesh silica gel). The eluent was petroleum ether:ethyl acetate = 4:1 V / V. The separation and purification yielded 7.57 g of 4,4′-bipyridine (purity 98%), with a yield (based on sodium, the same below) of 97.0% and a selectivity of 98.0%.

[0031] 1 H NMR (300MHz, DMSO-d6) δ8.72 (dd, J=4.2, J=1.8Hz, 4H), 7.82 (dd, J=4.5, 1.5Hz, 4H); 13 C NMR(75MHz,DMSO-d6)δ150.6,144.3,121.3.

[0032] Example 2

[0033] In a pre-dried 250 mL three-necked flask, 47.4 g of 1,3-dimethyl-2-imidazolinone was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (800 rpm). After the sodium was completely dissolved, 15.8 g of pyridine was added, and the reaction was stirred at 50 °C (600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C, followed by 23.7 g of N,N-dimethylformamide. After the N,N-dimethylformamide was added, air was introduced, and the mixture was stirred at room temperature (600 rpm) for 12 h for oxidation. After the reaction was completed, the reaction solution was sampled, and quantitative analysis was performed by liquid chromatography. The yield and selectivity of the product were calculated, and the results are shown in Table 1.

[0034] Example 3

[0035] In a pre-dried 250 mL three-necked flask, 47.4 g of 1,3-dimethyl-2-imidazolinone was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (800 rpm). After the sodium was completely dissolved, 15.8 g of pyridine was added, and the reaction was stirred at 30 °C (600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C, followed by 23.7 g of N,N-dimethylformamide. After the N,N-dimethylformamide was added, air was introduced, and the reaction was stirred at room temperature (600 rpm) for 12 h for oxidation. After the reaction was completed, the reaction solution was sampled, and quantitative analysis was performed by liquid chromatography. The yield and selectivity of the product were calculated, and the results are shown in Table 1.

[0036] Table 1: Effect of reaction temperature on the reaction

[0037] Example 3 30 84.3 95.0 Example 1 40 97.0 98.0 Example 2 50 78.0 75.4

[0038] Table 1 shows that the yield and selectivity of the product 4,4′-bipyridine are good at a reaction temperature of 40℃. When the reaction temperature is 30℃, the product yield decreases, while the product selectivity does not change significantly. When the reaction temperature is 50℃, both the product yield and selectivity decrease, indicating that the formation of byproducts increases at excessively high temperatures. Therefore, the optimal reaction temperature is 40℃.

[0039] Example 4

[0040] In a pre-dried 500 mL three-necked flask, 71.1 g of 1,3-dimethyl-2-imidazolinone was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (800 rpm). After the sodium was completely dissolved, 23.7 g of pyridine was added, and the reaction was stirred at 40 °C (600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C, followed by 35.6 g of N,N-dimethylformamide. After the N,N-dimethylformamide was added, air was introduced, and the reaction was stirred at room temperature (600 rpm) for 12 h for oxidation. After the reaction was completed, the reaction solution was sampled, and quantitative analysis was performed by liquid chromatography. The yield and selectivity of the product were calculated, and the results are shown in Table 2.

[0041] Example 5

[0042] In a pre-dried 500 mL three-necked flask, 94.8 g of 1,3-dimethyl-2-imidazolinone was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (800 rpm). After the sodium was completely dissolved, 31.6 g of pyridine was added, and the reaction was stirred at 40 °C (600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C, followed by 47.4 g of N,N-dimethylformamide. After the N,N-dimethylformamide was added, air was introduced, and the mixture was stirred at room temperature (600 rpm) for 12 h for oxidation. After the reaction was completed, the reaction solution was sampled, and quantitative analysis was performed by liquid chromatography. The yield and selectivity of the product were calculated, and the results are shown in Table 2.

[0043] Table 2: Effect of the molar ratio of sodium metal to pyridine on the reaction

[0044]

[0045]

[0046] As shown in Table 2, the best yield and selectivity are achieved when the molar ratio of sodium to pyridine is 1:2. When the molar ratio of sodium to pyridine is 1:3 or 1:4, both the yield and selectivity of the product decrease. This is because the amount of pyridine far exceeds the amount of metallic sodium required for the reaction, leading to the formation of other byproducts.

[0047] Example 6

[0048] In a pre-dried 250 mL three-necked flask, 47.4 g of 1,3-dimethyl-2-imidazolinone was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (800 rpm). After the sodium was completely dissolved, 15.8 g of pyridine was added, and the reaction was stirred at 40 °C (600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C. After N,N-dimethylformamide was added, air was introduced, and the reaction was stirred at room temperature (600 rpm) for 12 h for oxidation. After the reaction was completed, the reaction solution was sampled, and quantitative analysis was performed by liquid chromatography. The yield and selectivity of the product were calculated, and the results are shown in Table 3.

[0049] Table 3: Effect of additives on the reaction

[0050] Example 6 none 85.0 88.0 Example 1 N,N-Dimethylformamide 97.0 98.0

[0051] As shown in Table 3, when N,N-dimethylformamide is added during the oxidation stage of the reaction, the selectivity and yield of 4,4′-bipyridine are significantly improved. It is speculated that N,N-dimethylformamide is a diluent with a high dielectric constant, which can effectively promote the formation of 4,4′-bipyridine during the oxidation process.

[0052] Comparative Example 1

[0053] In a pre-dried 250 mL three-necked flask, 47.4 g of hexamethylphosphoric triamine was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (800 rpm). After the sodium was completely dissolved, 15.8 g of pyridine was added, and the mixture was stirred at 40 °C (600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C, followed by 23.7 g of N,N-dimethylformamide. After the N,N-dimethylformamide was added, air was introduced, and the mixture was stirred at room temperature (600 rpm) for 12 h for oxidation. After the reaction was completed, the reaction solution was sampled, and quantitative analysis was performed by liquid chromatography. The yield and selectivity of the product were calculated, and the results are shown in Table 4.

[0054] Table 4: Effect of solvent on the reaction

[0055] Example 1 1,3-Dimethyl-2-imidazolinone 97.0 98.0 Comparative Example 1 Hexamethylphosphoric acid triamide 45.0 62.3

[0056] Table 4 shows that when hexamethylphosphoric triamine is used as the reaction solvent, the selectivity and yield of 4,4′-bipyridine are relatively low. The results indicate that 1,3-dimethyl-2-imidazolinone, as a non-protonally polar solvent, has excellent solubility for metallic sodium and improves the reactivity of sodium.

[0057] Example 7

[0058] In a pre-dried 250 mL three-necked flask, 47.4 g of 1,3-dimethyl-2-imidazolinone was added. Under a nitrogen atmosphere, 2.3 g of metallic sodium was added, and stirring was started (at 800 rpm). After the sodium was completely dissolved, 15.8 g of pyridine was added, and the reaction was carried out at 40 °C with stirring (at 600 rpm) for 30 h. After the reaction was completed, the reaction solution was cooled to 0 °C in an ice-water bath, and then 50 g of deionized water was slowly added at 0 °C, followed by the addition of 15.8 g of... N,N-Dimethylformamide; after the N,N-dimethylformamide was added, air was introduced, and the mixture was stirred at room temperature (600 rpm) for 12 h to carry out the oxidation reaction. After the reaction was completed, the mixture was extracted five times with ethyl acetate, and the organic phase was collected. The organic phase was concentrated, the solvent was removed, and then silica gel column chromatography (200 mesh silica gel) was performed. The eluent was petroleum ether:ethyl acetate = 4:1 V / V. The separation and purification yielded 7.43 g of 4,4′-bipyridine (purity 98%), with a yield of 95.2% and a selectivity of 97.20%.

[0059] The optional embodiments of the present invention have been described above to teach those skilled in the art how to implement and reproduce the invention. Unless otherwise specified, the raw materials and equipment used in this invention are commonly used in the art; the methods used in this invention, unless otherwise specified, are conventional methods in the art. For the purpose of teaching the present invention, some conventional technical aspects have been simplified and omitted. Those skilled in the art should understand that variations derived from these aspects are within the scope of protection of this invention.

Claims

1. A method for preparing 4,4'-bipyridine, characterized in that: include: Using pyridine as a raw material, sodium metal as a catalyst, and 1,3-dimethyl-2-imidazolinone as a reaction solvent, under a nitrogen or inert gas atmosphere, sodium metal is first dissolved in 1,3-dimethyl-2-imidazolinone, and then pyridine is added to carry out the reaction. The reaction temperature is 40 °C, and the reaction time is 20–30 h. The reaction solution is cooled to 0–5 °C, deionized water is added, and an oxidation reaction is carried out by purging air with N,N-dimethylformamide to obtain 4,4'-bipyridine. The molar ratio of sodium metal to pyridine is 1:2; the mass ratio of N,N-dimethylformamide to 1,3-dimethyl-2-imidazolinone is 1:2 to 1:3; the oxidation reaction temperature is 20–25 °C, and the oxidation reaction time is 10–12 h.

2. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: The mass ratio of pyridine to 1,3-dimethyl-2-imidazolinone is 1:2 to 1:

8.

3. The method for preparing 4,4'-bipyridine according to claim 2, characterized in that: The mass ratio of pyridine to 1,3-dimethyl-2-imidazolinone is 1:2 to 1:

4.

4. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: Also includes: After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected, concentrated to remove the solvent, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 4:1 V / V as the eluent. The resulting product was 4,4'-bipyridine.

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