The invention relates to a method for preparing 2, 2apos; preparation method of-bis (trifluoromethyl) biphenyl
By using a self-coupling reaction with a mixture of oxygen and nitrogen as the oxidant, the problems of high cost and low yield in traditional methods are solved, and a low-cost and high-efficiency synthesis of 2,2'-bis(trifluoromethyl)biphenyl is achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ZHEJIANG WEIHUA NEW MATERIAL CO LTD
- Filing Date
- 2025-12-25
- Publication Date
- 2026-05-01
AI Technical Summary
Traditional methods for synthesizing 2,2'-bis(trifluoromethyl)biphenyl require expensive catalysts and complex reaction conditions, resulting in high production costs and low yields.
A Grignard reagent was prepared using a cheap and readily available mixture of oxygen and nitrogen as an oxidant in the presence of lithium chloride, ethyl magnesium bromide, and bromoethane. Then, a self-coupling reaction was carried out in the presence of ferric chloride to generate 2,2'-bis(trifluoromethyl)biphenyl.
A high-yield (up to 85%) and low-cost synthesis of 2,2'-bis(trifluoromethyl)biphenyl was achieved, with readily available raw materials and an environmentally friendly process.
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Abstract
Description
A method for preparing 2,2'-bis(trifluoromethyl)biphenyl Technical Field
[0001] This invention relates to a method for preparing 2,2'-bis(trifluoromethyl)biphenyl. Background Technology
[0002] 2,2'-Bis(trifluoromethyl)biphenyl is an important organic compound widely used in pharmaceuticals, pesticides, dyes, and polymer materials. For example, it is a crucial intermediate in the synthesis of polyimide (PI) resins. Traditional biphenyl synthesis methods typically require expensive catalysts or complex reaction conditions, resulting in high production costs. Therefore, developing a low-cost, efficient biphenyl synthesis method has significant industrial application value.
[0003] The literature Eur. J. Org. Chem. 2017(10), 1331-1336. reported a method for heterocoupling of aryl Grignard reagents with MnCl2 catalysis and oxygen as oxidant, and the main product is the heterocoupling product.
[0004] The literature Org. Process Res. Dev. 2021, 25, 2442-2446 reports the synthesis of o-trifluoromethylphenyl magnesium chloride Grignard reagent from o-trifluorotoluene as a starting material, followed by a self-coupling reaction to generate 2,2'-bis(trifluoromethyl)biphenyl under a catalyst and oxidant. 1,2-Dichloropropane (DCP) was used as the oxidant in a FeCl3 / DCP / toluene system at a reaction temperature of 50-60 °C. The product was purified by vacuum distillation to a purity > 97% and a yield of 65% (based on o-trifluorotoluene). Summary of the Invention
[0005] The technical problem this invention aims to solve is to overcome the limitations of existing methods for synthesizing biphenyl, which typically require expensive catalysts or complex reaction conditions, resulting in high production costs and low yields. This invention provides a method for preparing 2,2'-bis(trifluoromethyl)biphenyl. The raw materials used in this method are inexpensive and readily available, particularly employing a green, inexpensive, and readily available mixture of oxygen and nitrogen as an oxidant, resulting in high yields and low costs.
[0006] This invention provides a method for preparing 2,2'-bis(trifluoromethyl)biphenyl, which includes the following steps:
[0007] ,
[0008] ;
[0009] Step I: In a solvent, in the presence of lithium chloride, ethyl magnesium bromide, and bromoethane, o-chlorotrifluorotoluene reacts with magnesium to obtain a Grignard reagent;
[0010] Step II: In a mixed atmosphere of oxygen and nitrogen, and in the presence of ferric chloride, the Grignard reagent obtained in Step I undergoes a self-coupling reaction to give 2,2'-bis(trifluoromethyl)biphenyl.
[0011] In some embodiments of the present invention, in step I, the reaction is carried out in an inert gas atmosphere; for example, in a nitrogen atmosphere.
[0012] In some embodiments of the present invention, in step I, the solvent is a conventional solvent in the art, preferably an ether solvent, such as tetrahydrofuran.
[0013] In some embodiments of the present invention, in step I, the mass ratio of the solvent to o-chlorotrifluorotoluene is (2-5):1; preferably (3-4):1; for example, 3.1:1, 3.3:1 or 3.5:1.
[0014] In some embodiments of the present invention, in step I, the molar ratio of lithium chloride and o-chlorotrifluorotoluene is (0.05-0.25):1; preferably (0.1-0.2):1; for example, 0.1:1, 0.125:1 or 0.15:1.
[0015] In some embodiments of the present invention, in step I, the molar ratio of ethyl magnesium bromide to o-chlorotrifluorotoluene is (0.01-0.05):1; preferably (0.02-0.04):1; for example, 0.03:1; the ethyl magnesium bromide is preferably added in the form of an ethyl magnesium bromide THF solution.
[0016] In some embodiments of the present invention, in step I, the molar ratio of bromoethane and o-chlorotrifluorotoluene is (0.005-0.05):1; preferably (0.01-0.03):1; for example, 0.02:1.
[0017] In some embodiments of the present invention, in step I, the magnesium is magnesium strips and / or magnesium powder.
[0018] In some embodiments of the present invention, in step I, the molar ratio of magnesium to o-chlorotrifluorotoluene is (1-1.2):1; preferably (1-1.1):1.
[0019] In some embodiments of the present invention, in step I, the reaction temperature is 35-50°C; preferably 40-45°C.
[0020] In some embodiments of the present invention, in step I, the reaction ends when the raw material disappears or the product no longer increases; the reaction time is preferably 12-20 hours; for example, 16 hours.
[0021] In some embodiments of the present invention, step I includes the following steps: in a solvent, the magnesium, lithium chloride, ethyl magnesium bromide and bromoethane are stirred for 15-45 minutes, o-chlorotrifluorotoluene is added dropwise, the temperature is controlled at 35-50°C, toluene is added, and the temperature is maintained.
[0022] In some embodiments of the present invention, step I includes the following steps: in tetrahydrofuran, the elemental magnesium, lithium chloride, ethyl magnesium bromide and bromoethane are stirred at 15-25°C for 20-30 min, o-chlorotrifluorotoluene is added dropwise, the temperature is controlled at 40-45°C, toluene is added, and the mixture is kept at 45°C for 16 h.
[0023] In some embodiments of the present invention, in step I, the mass ratio of toluene to o-chlorotrifluorotoluene is (0.1-0.5):1; preferably (0.2-0.3):1; for example, 0.23:1 or 0.29:1.
[0024] In this invention, the Grignard reaction solution containing the Grignard reagent obtained in step I is directly used in step II.
[0025] In some embodiments of the present invention, in step II, the molar ratio of ferric chloride and o-chlorotrifluorotoluene is (0.005-0.015):1; preferably (0.008-0.013):1; for example, 0.01:1 or 0.013:1.
[0026] In some embodiments of the present invention, in step II, the volume percentage of oxygen in the mixed gas of oxygen and nitrogen is 8%-40%, preferably 10%-35%; more preferably 20%-25%.
[0027] In some embodiments of the present invention, in step II, the mixture of oxygen and nitrogen does not contain CO2 and water vapor.
[0028] In some embodiments of the present invention, in step II, the mixed gas of oxygen and nitrogen is introduced into the reaction liquid at a certain rate, which is a conventional rate for such reactions in the art, and is usually related to the reaction scale and the volume percentage of oxygen; the mixed gas of oxygen and nitrogen is preferably introduced into the reaction liquid at a rate of 0.5-1.5 L / min.
[0029] In some embodiments of this aspect, in step II, the temperature of the self-coupling reaction is 40-55°C; for example, 50°C.
[0030] In some embodiments of this aspect, in step II, the self-coupling reaction ends when the starting material disappears or the product no longer increases. The duration of the self-coupling reaction is preferably 3-6 hours; for example, 4 hours, 4.5 hours, or 5.5 hours.
[0031] In some embodiments of this aspect, the post-processing of the preparation method of 2,2'-bis(trifluoromethyl)biphenyl includes the following steps: quenching with hydrochloric acid and distillation to obtain 2,2'-bis(trifluoromethyl)biphenyl; preferably, quenching with 15% hydrochloric acid and distillation at -0.099 MPa to obtain 2,2'-bis(trifluoromethyl)biphenyl.
[0032] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.
[0033] The reagents and raw materials used in this invention are all commercially available.
[0034] The positive and progressive effects of this invention are as follows:
[0035] The synthetic route of this invention uses inexpensive and readily available raw materials, especially a green, inexpensive and readily available mixture of oxygen and nitrogen as an oxidant. In addition, the yield of this invention is as high as 85%, which is significantly higher than that of existing technologies. Detailed Implementation
[0036] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.
[0037] Example 1
[0038] Add 3000 g THF, 114 g (1 eq.) magnesium powder (strip), 30 g (0.15 eq.) lithium chloride, 36 mL (0.03 eq.) ethyl magnesium bromide THF solution (4 M), and 10 g (0.02 eq.) bromoethane to a 5 L reaction flask. Under nitrogen protection, stir for 30 min at room temperature (20 °C). Slowly add 860 g (4.76 mol) of o-chlorotrifluorotoluene, maintaining the temperature at 40-45 °C. After the addition is complete, add 200 g of toluene and incubate at 45 °C for 16 h to prepare the Grignard reaction solution.
[0039] 10 g of ferric chloride was added to the prepared Grignard reaction solution, and oxidizing gas (25% oxygen volume fraction and 75% nitrogen volume fraction) was introduced into the Grignard reaction solution at a rate of 1 L / min for 4 h at 50 °C. The reaction was confirmed to be complete by GC. The reaction was quenched with 15% hydrochloric acid and distilled at -0.099 MPa to obtain 589.5 g of 2,2'-bis(trifluoromethyl)biphenyl. The GC purity was 99.5% and the yield was 85%. 1 H NMR(CDCl3): 7.75 (dd, J1 = 1.2 Hz, J2 = 7.6 Hz, 2 H), 7.56-7.48 (m, 4 H), 7.29 (d, J =7.6 Hz, 2 H, ).
[0040] Example 2
[0041] In a 5L reaction flask, add 3000 g THF, 125.4 g (1.1 eq.) magnesium powder (strips), 20 g (0.1 eq.) lithium chloride, 36 mL (0.03 eq.) ethyl magnesium bromide THF solution (4M), and 10 g (0.02 eq.) bromoethane. Under nitrogen protection, stir for 20 min at room temperature (20°C). Slowly add 860 g (4.76 mol) of o-chlorotrifluorotoluene, maintaining the temperature at 40-45°C. After the addition is complete, add 250 g of toluene and incubate at 45°C for 16 h to prepare the Grignard reaction solution.
[0042] 8 g of ferric chloride was added to the prepared Grignard reaction solution, and oxidizing gas (35% oxygen and 65% nitrogen) was introduced into the Grignard reaction solution at a rate of 0.5 L / min for 6 h at 50 °C. The reaction was confirmed to be complete by GC. The reaction was quenched with 15% hydrochloric acid and distilled at -0.099 MPa to obtain 586.4 g of 2,2'-bis(trifluoromethyl)biphenyl. The GC purity was 99.5% and the yield was 84.6%.
[0043] Example 3
[0044] In a 5L reaction flask, add 2700 g THF, 125.4 g (1.1 eq.) magnesium powder (strips), 30 g (0.15 eq.) lithium chloride, 36 mL (0.03 eq.) ethyl magnesium bromide THF solution (4M), and 10 g (0.02 eq.) bromoethane. Under nitrogen protection, stir for 30 min at room temperature (20°C). Slowly add 860 g (4.76 mol) of o-chlorotrifluorotoluene, maintaining the temperature at 40-45°C. After the addition is complete, add 200 g of toluene and incubate at 45°C for 16 h to prepare the Grignard reaction solution.
[0045] 10 g of ferric chloride was added to the prepared Grignard reaction solution. Oxidizing gas (10% oxygen volume fraction and 90% nitrogen volume fraction) was introduced into the Grignard reaction solution at a rate of 1.5 L / min for 5.5 h at 50 °C. The reaction was confirmed to be complete by GC. The reaction was quenched with 15% hydrochloric acid and distilled at -0.099 MPa to obtain 583.6 g of 2,2'-bis(trifluoromethyl)biphenyl. The GC purity was 99.5% and the yield was 84.2%.
[0046] Example 4
[0047] In a 5L reaction flask, add 2800 g THF, 124 g (1.1 eq.) magnesium powder (strips), 25 g (0.12 eq.) lithium chloride, 36 mL (0.03 eq.) ethyl magnesium bromide THF solution (4M), and 10 g (0.02 eq.) bromoethane. Under nitrogen protection, stir for 30 min at room temperature (20°C). Slowly add 860 g (4.76 mol) of o-chlorotrifluorotoluene, maintaining the temperature at 40-45°C. After the addition is complete, add 200 g of toluene and incubate at 45°C for 16 h to prepare the Grignard reaction solution.
[0048] 10 g of ferric chloride was added to the prepared Grignard reaction solution, and oxidizing gas (20% oxygen volume fraction and 80% nitrogen volume fraction) was introduced into the Grignard reaction solution at a rate of 1 L / min for 4.5 h at 50 °C. The reaction was confirmed to be complete by GC. The reaction was quenched with 15% hydrochloric acid and distilled at -0.099 MPa to obtain 589.5 g of 2,2'-bis(trifluoromethyl)biphenyl. The GC purity was 99.5% and the yield was 85%.
[0049] Comparative Example 1
[0050] Add 3000 g THF, 114 g (1 eq.) magnesium powder, 30 g (0.15 eq.) lithium chloride, and 36 mL (0.03 eq.) ethyl magnesium bromide THF solution (4 M) to a 5 L reaction flask. Add 10 g (0.02 eq.) bromoethane. Under nitrogen protection, stir at room temperature (20 °C) for 30 min. Slowly add 860 g (1 eq.) o-chlorotrifluorotoluene, controlling the temperature at 40-45 °C. After the addition is complete, add 200 g toluene and keep at 45 °C for 16 h to prepare the Grignard reaction solution.
[0051] 10 g of ferric chloride was added to the prepared Grignard reaction solution, and industrial oxygen (99.5%) was introduced into the Grignard reaction solution at a rate of 0.5 L / min for 3 h at 50 °C. The reaction was confirmed to be complete by GC. The reaction was quenched with 15% hydrochloric acid and distilled at -0.099 MPa to obtain 388 g of 2,2'-bis(trifluoromethyl)biphenyl. The GC purity was 98.8% and the yield was 56%.
[0052] Comparative Example 2
[0053] Add 3000 g THF, 114 g (1 eq.) magnesium powder, 30 g (0.15 eq.) lithium chloride, and 36 mL (0.03 eq.) ethyl magnesium bromide THF solution (4 M) to a 5 L reaction flask. Add 10 g (0.02 eq.) bromoethane. Under nitrogen protection, stir at room temperature (20 °C) for 30 min. Slowly add 860 g (1 eq.) o-chlorotrifluorotoluene, controlling the temperature at 40-45 °C. After the addition is complete, add 200 g toluene and keep at 45 °C for 16 h to prepare the Grignard reaction solution.
[0054] 10 g of manganese chloride was added to the prepared Grignard reaction solution, and industrial oxygen (99.5%) was introduced into the Grignard reaction solution at a rate of 0.5 L / min for 3 h at 50 °C. The reaction was confirmed to be complete by GC. The reaction was quenched with 15% hydrochloric acid and distilled at -0.099 MPa to obtain 166.5 g of 2,2'-bis(trifluoromethyl)biphenyl. The GC purity was 97% and the yield was 24%.
[0055] GC analysis methods:
[0056]
Claims
1. A method for preparing 2,2'-bis(trifluoromethyl)biphenyl, characterized in that, It includes the following steps: ， Step I: In a solvent, in the presence of lithium chloride, ethyl magnesium bromide, and bromoethane, o-chlorotrifluorotoluene reacts with magnesium to obtain a Grignard reagent; Step II: In a mixed atmosphere of oxygen and nitrogen, in the presence of ferric chloride, the Grignard reagent obtained in Step I undergoes a self-coupling reaction to obtain 2,2'-bis(trifluoromethyl)biphenyl.
2. The preparation method according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In step I, the mass ratio of the solvent to o-chlorotrifluorotoluene is (2-5):1; (2) In step I, the molar ratio of lithium chloride to o-chlorotrifluorotoluene is (0.05-0.25):1; (3) In step II, the volume percentage of oxygen in the mixed gas of oxygen and nitrogen is 8%-40%.
3. The preparation method according to claim 2, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In step I, the mass ratio of the solvent to o-chlorotrifluorotoluene is (3-4):1; (2) In step I, the molar ratio of lithium chloride to o-chlorotrifluorotoluene is (0.1-0.2):1; (3) In step II, the volume percentage of oxygen in the mixed gas of oxygen and nitrogen is 10%-35%.
4. The preparation method according to claim 3, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In step I, the mass ratio of the solvent to o-chlorotrifluorotoluene is 3.1:1, 3.3:1 or 3.5:1; (2) In step I, the molar ratio of lithium chloride to o-chlorotrifluorotoluene is 0.1:1, 0.125:1 or 0.15:1; (3) In step II, the volume percentage of oxygen in the mixture of oxygen and nitrogen is 20%-25%.
5. The preparation method according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In step I, the reaction is carried out in an inert gas atmosphere; (2) In step I, the solvent is an ether solvent; (3) In step I, the magnesium is magnesium strips and / or magnesium powder; (4) In step I, the ethyl magnesium bromide is preferably added in the form of ethyl magnesium bromide THF solution; (5) In step I, the molar ratio of ethyl magnesium bromide to o-chlorotrifluorotoluene is (0.01-0.05):1; (6) In step I, the molar ratio of bromoethane to o-chlorotrifluorotoluene is (0.005-0.05):1; (7) In step I, the molar ratio of magnesium to o-chlorotrifluorotoluene is (1-1.2):1; (8) In step I, the reaction temperature is 35-50℃; (9) In step I, the reaction time is 12-20h.
6. The preparation method according to claim 5, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In step I, the reaction is carried out in a nitrogen atmosphere; (2) In step I, the solvent is tetrahydrofuran; (3) In step I, the molar ratio of ethyl magnesium bromide to o-chlorotrifluorotoluene is (0.02-0.04):1; for example, 0.03:1; (4) In step I, the molar ratio of bromoethane to o-chlorotrifluorotoluene is (0.01-0.03):1; for example, 0.02:1; (5) In step I, the molar ratio of magnesium to o-chlorotrifluorotoluene is (1-1.1):1; (6) In step I, the reaction temperature is 40-45℃; (7) In step I, the reaction time is 16h.
7. The preparation method according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In step II, the molar ratio of ferric chloride and o-chlorotrifluorotoluene is (0.005-0.015):1; (2) In step II, the temperature of the self-coupling reaction is 40-55℃; (3) In step II, the time of the self-coupling reaction is 3-6h; (4) In step II, the mixed gas of oxygen and nitrogen is introduced into the reaction solution at a rate of 0.5-1.5L / min; (5) The post-processing of the preparation method of 2,2'-bis(trifluoromethyl)biphenyl includes the following steps: quenching with hydrochloric acid and distillation to obtain 2,2'-bis(trifluoromethyl)biphenyl.
8. The preparation method according to claim 7, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In step II, the molar ratio of ferric chloride and o-chlorotrifluorotoluene is (0.008-0.013):1; for example, 0.01:1; (2) In step II, the temperature of the self-coupling reaction is 50°C; (3) In step II, the time of the self-coupling reaction is 4h, 4.5h or 5.5h; (4) The post-processing of the preparation method of 2,2'-bis(trifluoromethyl)biphenyl includes the following steps: quenching with 15% hydrochloric acid and distilling at -0.099MPa to obtain 2,2'-bis(trifluoromethyl)biphenyl.
9. The preparation method according to any one of claims 1-8, characterized in that, Step I includes the following steps: In the solvent, the magnesium, the lithium chloride, the ethyl magnesium bromide and the bromoethane are stirred for 15-45 minutes, the o-chlorotrifluorotoluene is added dropwise, the temperature is controlled at 35-50℃, then toluene is added and kept warm; the mass ratio of toluene to o-chlorotrifluorotoluene is (0.1-0.5):
1.
10. The preparation method according to claim 9, characterized in that, The preparation method satisfies one or two of the following conditions: (1) Step I includes the following steps: in tetrahydrofuran, the magnesium, the lithium chloride, the ethyl magnesium bromide and the bromoethane are stirred at 15-25°C for 20-30 min, o-chlorotrifluorotoluene is added dropwise, the temperature is controlled at 40-45°C, toluene is added, and the temperature is kept at 45°C for 16 h; (2) the mass ratio of toluene to o-chlorotrifluorotoluene is (0.2-0.3):1; for example, 0.23:1 or 0.29:1.