Method for synthesizing 5-bromoindole-2-carboxylic acid based on Cu-Ni bimetallic catalytic system and electrochemical CO2 activation
Through the Cu-Ni bimetallic catalytic system and electrochemical CO2 activation method, the problems of toxic reagents and solvents in the traditional 5-bromoindole-2-carboxylic acid synthesis method, environmental pollution and high production costs are solved, and efficient, environmentally friendly and economical synthesis effects are achieved.
Patent Information
- Application Number
- CN202510376354.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-27
- Publication Date
- 2025-05-13
AI Technical Summary
The traditional synthesis method of 5-bromoindole-2-carboxylic acid has problems such as the use of toxic reagents and solvents, environmental pollution, safety hazards and high production costs.
Using a synthesis method based on Cu-Ni bimetallic catalytic system and electrochemical CO2 activation, CO2 is converted into CO2- through electrochemical reduction under low potential conditions and coupled with C-H activation intermediates to form the target product 5-bromoindole-2-carboxylic acid.
It realizes the synthesis of 5-bromoindole-2-carboxylic acid, which is green, environmentally friendly, cost-effective, synthesis of 5-bromoindole-2-carboxylic acid, reduces the generation of by-products, improves the purity and yield of the product, and is suitable for industrial production.
Smart Images
Figure BDA0005332899860000211 
Figure BDA0005332899860000221
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate preparation, and in particular to a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalytic system and electrochemical CO2 activation. Background Art
[0002] 5-Bromoindole-2-carboxylic acid, as an important drug intermediate, is widely used in the synthesis of various drugs such as anti-tumor, antibacterial, and antiviral drugs, and has significant medical application value. The synthesis of this compound is not only of great significance to the pharmaceutical industry, but also plays a key role in the research and development of new drugs. However, traditional synthesis methods, such as the Vilsmeier-Haack method and the Pd catalytic method, have many problems in practical applications. These methods usually rely on highly toxic reagents and solvents, leading to environmental pollution and potential safety hazards. For example, the Vilsmeier-Haack method often uses toxic and corrosive chemicals such as POCl3 (phosphite chloride), which not only increases the danger of operation, but also produces a large number of harmful by-products, which burdens the environment. Similarly, although the Pd catalytic method has high selectivity, the production cost is high due to the high price of palladium (metal catalyst) and the easy deactivation of the catalyst.
[0003] In addition, traditional synthesis methods usually need to be carried out under relatively harsh reaction conditions, such as high temperature, high pressure or strong acid and strong base environment, which not only increases energy consumption, but also leads to the formation of by-products, reduces the yield of the target product, and requires further separation and purification steps, further increasing the production time and cost. Summary of the invention
[0004] The purpose of the present invention is to provide a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation. The present invention provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation. The method combines electrochemically catalyzed CO2 reduction, a continuous flow microreactor and an ionic liquid solvent system, and has the advantages of being green, environmentally friendly, economical and efficient, and suitable for industrial production.
[0005] The above technical objectives of the present invention are achieved through the following technical solutions:
[0006] The present invention provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation, comprising the following steps:
[0007] 5-bromoindole is combined with a Cu-Ni bimetallic catalyst and a nitrogen-phosphine-containing bifunctional ligand is used to activate the CH bond at the 2-position of 5-bromoindole under reaction conditions to form a metallated intermediate.
[0008] Convert CO2 to CO2 by electrochemical reduction under low potential conditions - ,CO2 - Couple with CH activated intermediate to form carboxylic acid intermediate;
[0009] After the carboxylic acid intermediate undergoes a proton transfer reaction, the target product 5-bromoindole-2-carboxylic acid is released, and the catalyst is restored to enter the next reaction cycle.
[0010] Furthermore, the metal sources of the Cu-Ni bimetallic catalyst are Cu(OAc)2 and NiCl2.
[0011] Furthermore, the ligand is a PNN ligand.
[0012] Furthermore, the solvent is [BMIM]PF6 or [EMIM]BF4.
[0013] Furthermore, the potential of the electrochemical reduction under the low potential condition is -0.5 to -0.1 V vs Ag / AgCl.
[0014] Furthermore, the CO2 supplied is high-pressure CO2 or supercritical CO2.
[0015] Furthermore, in the reaction conditions, the reaction temperature is 80-100° C. and the reaction time is 30-60 minutes.
[0016] Furthermore, the catalyst is a supported catalyst, supported on MOF material or SiO2.
[0017] Furthermore, a continuous flow reaction is achieved through a microreactor, CO2 is continuously introduced and a carboxylation reaction is carried out.
[0018] Furthermore, in the Cu-Ni bimetallic catalyst, the mass ratio of Cu to Ni is calculated based on the potential of electrochemical reduction.
[0019] In summary, the present invention has the following beneficial effects:
[0020] The present invention combines low-potential catalysis with bimetallic catalysts to further enhance the selectivity of the reaction. Low-potential catalysis can accurately control the degree of copper reduction, so that it can more effectively activate the CH bond and provide a highly active intermediate for subsequent reactions. Through the electronic effect of copper, the breakage of the CH bond becomes more gentle, avoiding excessive breakage or the generation of by-products. At low potential, nickel can more effectively reduce CO2 to generate CO2- , and under the synergistic effect of copper and nickel, CO2 - It is easier to combine with CH activated intermediates for efficient insertion. This synergistic effect can ensure the efficient utilization of CO2 and improve the yield of the target product. Due to the synergistic effect of low potential catalysis and bimetallic catalysis, the formation of by-products during the reaction is suppressed. Especially at low potential, the formation of side reactions such as methane or ethylene is limited, and the reaction generates the target product more selectively, further improving the purity and yield of the product. DETAILED DESCRIPTION
[0021] In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined purpose of the invention, a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation proposed in the present invention, its specific implementation method, characteristics and effects are described in detail as follows.
[0022] The present specific embodiment provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation, comprising the following steps:
[0023] 5-bromoindole is combined with a Cu-Ni bimetallic catalyst and a nitrogen-phosphine-containing bifunctional ligand is used to activate the CH bond at the 2-position of 5-bromoindole under reaction conditions to form a metallated intermediate.
[0024] Convert CO2 to CO2 by electrochemical reduction under low potential conditions - ,CO2 - Couple with CH activated intermediate to form carboxylic acid intermediate;
[0025] After the carboxylic acid intermediate undergoes a proton transfer reaction, the target product 5-bromoindole-2-carboxylic acid is released, and the catalyst is restored to enter the next reaction cycle.
[0026] It can be understood that -bromoindole is combined with a Cu-Ni bimetallic catalyst to achieve C-H bond activation using a nitrogen-containing phosphine bifunctional ligand:
[0027] In this stage, 5-bromoindole is combined with the Cu-Ni bimetallic catalyst as a substrate. The bimetallic catalyst plays a synergistic role in the reaction process, and copper (Cu) and nickel (Ni) are involved in different reaction steps:
[0028] Copper: Responsible for CH activation, that is, through the electron attraction of copper, the CH bond in the indole molecule becomes more activated and easier to break, forming a highly reactive metal intermediate.
[0029] Nickel: Assists in the activation of copper and participates in the reduction and activation of CO2 in the subsequent process.
[0030] The role of nitrogen-phosphine-containing bifunctional ligands (such as PNN ligands) is to provide a stable coordination environment, help metal sites (Cu and Ni) bind to substrates more effectively, and ensure that the metal surface is in the correct geometric configuration for efficient activation of CH bonds.
[0031] Electrochemical reduction of CO2 to CO2 under low potential conditions - And coupled with CH activated intermediates: CO2 is reduced to CO2 by electrochemical reduction under low potential conditions - (carbonate ion), which is a key step in the electrochemical reaction. Low potential can control the reaction rate, make it more selective, and reduce the formation of by-products.
[0032] CO2 - As a highly reactive intermediate, it undergoes a coupling reaction with the CH activated intermediate previously generated by copper-nickel catalysis to form a carboxylic acid intermediate. This process efficiently converts CO2 into a component of the reaction product.
[0033] The carboxylic acid intermediate releases the target product 5-bromoindole-2-carboxylic acid after proton transfer, and the catalyst recovers: After the carboxylic acid intermediate undergoes a proton transfer reaction, the target product 5-bromoindole-2-carboxylic acid is finally released. Proton transfer is a necessary step to ensure the formation of the final product, and in this reaction, the metal catalyst (Cu-Ni) is restored to its initial state and can participate in the next reaction cycle again.
[0034] In some preferred embodiments, the metal sources of the Cu-Ni bimetallic catalyst are Cu(OAc)2 and NiCl2.
[0035] In some preferred embodiments, the ligand is a PNN ligand.
[0036] It is understood that the PNN ligand provides electron pairs through its phosphine group (P) and pyridine ring (N), which can regulate the electron density of the metal through electronic effects. This regulation can enhance the affinity of the metal for the reactant and thus improve the catalytic activity. This electronic regulation can help copper and nickel better play their respective catalytic roles in the bimetallic catalytic system, with copper mainly responsible for the activation of the CH bond, while nickel promotes CO2 reduction and insertion reactions.
[0037] Due to the structural characteristics of the PNN ligand, it can provide a good spatial coordination environment, so that the metal center exhibits good stereoselectivity in the reaction. This structure enables the catalyst to preferentially generate the target product and reduce the generation of by-products in a complex reaction system. The bifunctionality of the PNN ligand (phosphine and nitrogen) makes it very effective in regulating the active sites of the metal, thereby improving the selectivity of the reaction in complex reactions. The PNN ligand can accelerate the rate of metal-catalyzed reactions by promoting electron transfer. Especially in low-potential catalytic reactions, the PNN ligand can enhance the reactivity between the metal and the substrate by stabilizing the metal-ligand coordination, thereby improving the efficiency of the reaction.
[0038] In the bimetallic catalytic system, the presence of PNN ligands can optimize the interaction between copper and nickel and further increase the rate of the catalytic reaction through synergistic effects.
[0039] In some preferred embodiments, the solvent is [BMIM]PF6 or [EMIM]BF4.
[0040] It is understandable that [BMIM]PF6 and [EMIM]BF4 are ionic liquids with very high polarity and low vapor pressure, which enable them to effectively dissolve a variety of organic and inorganic substances, including CO2. This is particularly important for the electrochemical reduction of CO2, which can significantly improve the solubility and reaction efficiency of CO2. Among them, the high solubility of CO2 in these ionic liquids can promote the transfer of CO2 to the catalyst surface, improve CO2 activation and CO2 - The production rate of the reaction is increased, thereby enhancing the overall efficiency of the reaction.
[0041] In some preferred embodiments, the potential of the electrochemical reduction under low potential conditions is -0.5 to -0.1 V vs Ag / AgCl.
[0042] In some preferred embodiments, the CO2 supply is high pressure CO2 or supercritical CO2.
[0043] It is understandable that under high-pressure CO2 or supercritical CO2 conditions, CO2 can adjust the surface electron density of the catalyst and optimize the electronic structure of copper and nickel, making them more conducive to CH activation and CO2 reduction reactions. High-pressure CO2 or supercritical CO2 can also serve as a solubilizer for ionic liquid solvents to improve CO2 - (carbonate ions), reducing the resistance to charge transfer and making the reaction more efficient.
[0044] In some preferred embodiments, the reaction conditions include a reaction temperature of 80 to 100° C. and a reaction time of 30 to 60 minutes.
[0045] In some preferred embodiments, the catalyst is a supported catalyst, supported on a MOF material or SiO2.
[0046] It is understandable that both MOF (metal organic framework) and SiO2 (silica gel) have high specific surface areas and can provide a large number of active sites, making the Cu-Ni bimetallic catalyst more stably dispersed on the carrier and avoiding the agglomeration and deactivation of metal particles. At the same time, in traditional homogeneous catalytic systems, metal catalysts may dissolve or deactivate during the reaction, while catalysts loaded on MOF or SiO2 can reduce metal loss and improve catalytic life.
[0047] In some preferred embodiments, a continuous flow reaction is achieved by a microreactor, CO2 is continuously introduced and the carboxylation reaction is carried out.
[0048] It is understandable that the microreactor has a small reactor volume and a very high surface area to volume ratio, which allows for more complete contact between the reactants and the catalyst. The small reactor volume can quickly and evenly distribute the reactants, thereby increasing the reaction rate. In a continuous flow reaction, the contact time between the reactants and the catalyst is short, and the reaction conditions can be optimized by precisely controlling the flow rate, temperature, and pressure. This can effectively avoid side reactions during the reaction and maximize the yield and selectivity of the target product.
[0049] In some preferred embodiments, in the Cu-Ni bimetallic catalyst, the mass ratio of Cu to Ni is calculated based on the potential of electrochemical reduction.
[0050] It is understandable that when low-potential catalysis is combined with a bimetallic catalyst, the selectivity of the reaction is further enhanced, as shown in the following aspects:
[0051] Enhanced CH activation: Low potential catalysis can precisely control the degree of copper reduction, making it more effective in activating the CH bond and providing a highly active intermediate for subsequent reactions. Through the electronic effect of copper, the breaking of the CH bond becomes more gentle, avoiding excessive breaking or the formation of by-products.
[0052] Improve CO2 reduction efficiency: At low potential, nickel can more effectively reduce CO2 to generate CO2 - , and under the synergistic effect of copper and nickel, CO2 - It is easier to combine with CH activated intermediates for efficient insertion. This synergistic effect can ensure the efficient utilization of CO2 and increase the yield of the target product.
[0053] Reduce the generation of by-products: Due to the synergistic effect of low-potential catalysis and bimetallic catalysis, the generation of by-products during the reaction is suppressed. In particular, at low potential, the generation of side reactions such as methane or ethylene is limited, and the reaction generates the target product more selectively, further improving the purity and yield of the product.
[0054] In this embodiment, the potential can determine the ratio of copper and nickel in the Cu-Ni bimetallic catalyst because it directly affects the reduction rate of the two metals, the catalytic performance, and the interaction of the metals. By accurately adjusting the potential, the loading ratio of copper and nickel can be optimized under specific reaction conditions to maximize the efficiency and selectivity of the catalytic reaction. Therefore, the potential is not only an important factor in controlling the reaction efficiency, but also can affect the overall performance of the catalyst by adjusting the composition and properties of the catalyst.
[0055] In some preferred embodiments, the molar ratio of copper to nickel in the Cu-Ni bimetallic catalyst is given by the formula:
[0056] calculate;
[0057] Wherein, C is the molar ratio of copper to nickel in the Cu-Ni bimetallic catalyst, and the unit is 1;
[0058] E is the potential of electrochemical reduction under low potential conditions, in V;
[0059] α is the correction factor, the unit is 1, and in this embodiment, the value is e +3 ;
[0060] Standard electrode electric potential of copper Cu = +0.34V;
[0061] The standard electrode potential of nickel is E Ni =-0.23V.
[0062] The correction factor α is obtained by comparing experimental data with theoretical calculations. It is calculated based on the adsorption characteristics of the metal surface, reaction temperature, electron transfer rate, and ion diffusion rate. In this specific implementation, the value is e +18 ; The surface properties of metals have an important influence on their catalytic performance, especially in bimetallic catalysis, where surface adsorption and interaction will significantly affect the reduction and catalytic activity of metals. The distribution of copper and nickel on the catalyst surface, surface energy, and the interaction between them are one of the factors affecting the correction factor; temperature will affect the temperature coefficient in the Nernst equation, and thus affect the reduction ability of metal ions. When the temperature rises, the activation energy of the metal decreases, the reaction rate increases, and then changes the ratio of copper and nickel in the catalytic reaction. The kinetic factors in the actual reaction, such as the electron transfer rate, ion diffusion rate, electrolyte concentration, etc., will affect the correction factor.
[0063] In this embodiment, the reduction reaction of copper is more likely to occur, so at a higher potential, copper will be reduced first. Nickel needs to be reduced at a lower potential. When the potential increases, the reduction rate of copper increases, and it is easier to be reduced to metal, while nickel is more difficult to reduce. Therefore, the proportion of copper will be higher. The lower potential means that more nickel is reduced in the reaction, rather than copper. Since nickel has a lower standard electrode potential, it is more easily reduced under low potential conditions. Under low potential conditions, the proportion of nickel will increase because the reduction reaction rate of nickel is higher at low potentials.
[0064] It is understandable that the principle of calculating the ratio of copper and nickel by potential is based on the difference in standard electrode potential in electrochemical reactions, reflecting the reduction rate of the two metals under different potential conditions. When the potential increases, the standard electrode potential of copper is higher, making it easier to be reduced in the reaction, so that the proportion of copper increases; when the potential decreases, the standard electrode potential of nickel is lower, and it is easier to reduce at low potential, so the proportion of nickel increases. Using this principle, the relative proportion of copper and nickel can be accurately controlled under different potential environments, thereby optimizing the selectivity and efficiency of the reaction. The advantage of this method is that it provides a means to achieve precise control of reactants and efficient utilization of catalysts by adjusting the potential, thereby improving the yield of the target product and the green environmental protection of the reaction. In addition, it can help optimize the reaction conditions, reduce the generation of by-products, reduce energy consumption and costs, and make the catalytic reaction more controllable and suitable for industrial production.
[0065] The present invention will be further described below in conjunction with specific embodiments.
[0066] Example 1
[0067] This Example 1 provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation, and describes an efficient method for synthesizing 5-bromoindole-2-carboxylic acid using a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation. This method converts CO2 into CO2 by electrochemical reduction under low potential conditions. - , coupled with the activated C-H bond intermediate to form the target product 5-bromoindole-2-carboxylic acid, while maintaining the high activity and recovery ability of the catalyst.
[0068] Here are the steps:
[0069] (1) Preparation of reactants and catalysts: 5-bromoindole (10 mmol) was mixed with Cu(OAc)2 (1.8 mmol) and NiCl2 (1 mmol), and the mixture was added to a solution containing a PNN ligand (0.28 mmol). The ligand provided a stable coordination environment and regulated the electronic effect of the metal in this step, ensuring that Cu and Ni formed a stable metal complex and exerted a synergistic effect in the reaction. The mixture was dissolved in an ionic liquid [BMIM]PF6 (1 mL) as a solvent. The solvent had high polarity, low volatility and high CO2 solubility, which helped to improve the CO2 conversion efficiency.
[0070] (2) CO2 reduction under low potential conditions: Under set low potential conditions (-0.5Vvs Ag / AgCl), CO2 is reduced to CO2 by electrochemical reduction. - (carbonate ion), this process uses the synergistic effect of Cu-Ni bimetallic catalyst, copper is responsible for the activation of CH bond, nickel is responsible for the reduction of CO2, CO2 - As a highly active intermediate, it undergoes a coupling reaction with the CH activated intermediate produced by the copper-nickel catalyst. The process is carried out at a temperature of 90°C to promote the reaction rate and increase the conversion rate of CO2.
[0071] (3) Generation of carboxylic acid intermediates: CO2 - The carboxylic acid intermediate is coupled with the CH activated intermediate, and the intermediate is stably coordinated with the metal surface during the reaction to reduce the generation of by-products. As the reaction proceeds, the generated carboxylic acid intermediate undergoes a proton transfer reaction and finally releases the target product 5-bromoindole-2-carboxylic acid. In this process, the copper and nickel catalysts are restored and enter the next reaction cycle.
[0072] Since the catalyst is a solid-supported catalyst, it is loaded on SiO2 (silica gel), which improves the stability of the catalyst. The metal catalyst will not be lost during the reaction, avoiding the agglomeration and deactivation of metal particles, thereby extending the service life of the catalyst.
[0073] Reaction conditions: electrochemical potential: -0.5V vs Ag / AgCl; reaction temperature: 90℃; reaction time: 40 minutes; CO2 supply: high pressure CO2; solvent: [BMIM]PF6 ionic liquid; catalyst: Cu-Ni bimetallic catalyst supported on SiO2; ligand: PNN ligand.
[0074] Among them, the molar ratio of copper and nickel in the Cu-Ni bimetallic catalyst is given by the formula:
[0075] calculate;
[0076] Wherein, C is the molar ratio of copper to nickel in the Cu-Ni bimetallic catalyst, and the unit is 1;
[0077] E is the potential of electrochemical reduction under low potential conditions, the unit is V, and the value is -0.5V;
[0078] α is the correction factor, the unit is 1, and in this embodiment, the value is e +3 ;
[0079] Standard electrode electric potential of copper Cu = +0.34V;
[0080] The standard electrode potential of nickel is E Ni =-0.23V, then the calculated result is C=1.8.
[0081] Example 2
[0082] This Example 2 provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation, and describes an efficient method for synthesizing 5-bromoindole-2-carboxylic acid using a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation. This method converts CO2 into CO2 by electrochemical reduction under low potential conditions. - , coupled with the activated C-H bond intermediate to form the target product 5-bromoindole-2-carboxylic acid, while maintaining the high activity and recovery ability of the catalyst.
[0083] Here are the steps:
[0084] (1) Preparation of reactants and catalysts: 5-bromoindole (15 mmol) was mixed with Cu(OAc)2 (2.35 mmol) and NiCl2 (0.5 mmol), and the mixture was added to a solution containing a PNN ligand (0.3 mmol). The ligand provided a stable coordination environment and regulated the electronic effect of the metal in this step, ensuring that Cu and Ni formed a stable metal complex and exerted a synergistic effect in the reaction. The mixture was dissolved in an ionic liquid [BMIM]PF6 (2 mL) as a solvent. The solvent had high polarity, low volatility and high CO2 solubility, which helped to improve the CO2 conversion efficiency.
[0085] (2) CO2 reduction under low potential conditions: Under set low potential conditions (-0.3Vvs Ag / AgCl), CO2 is reduced to CO2 by electrochemical reduction. - (carbonate ion), this process uses the synergistic effect of Cu-Ni bimetallic catalyst, copper is responsible for the activation of CH bond, nickel is responsible for the reduction of CO2, CO2 -As a highly active intermediate, it undergoes a coupling reaction with the CH activated intermediate produced by the copper-nickel catalyst. The process is carried out at a temperature of 85°C to promote the reaction rate and increase the conversion rate of CO2.
[0086] (3) Generation of carboxylic acid intermediates: CO2 - The carboxylic acid intermediate is coupled with the CH activated intermediate, and the intermediate is stably coordinated with the metal surface during the reaction to reduce the generation of by-products. As the reaction proceeds, the generated carboxylic acid intermediate undergoes a proton transfer reaction and finally releases the target product 5-bromoindole-2-carboxylic acid. In this process, the copper and nickel catalysts are restored and enter the next reaction cycle.
[0087] Since the catalyst is a solid-supported catalyst, it is loaded on SiO2 (silica gel), which improves the stability of the catalyst. The metal catalyst will not be lost during the reaction, avoiding the agglomeration and deactivation of metal particles, thereby extending the service life of the catalyst.
[0088] Reaction conditions: electrochemical potential: -0.5V vs Ag / AgCl; reaction temperature: 85°C; reaction time: 40 minutes; CO2 supply: high pressure CO2; solvent: [EMIM] BF4 ionic liquid; catalyst: Cu-Ni bimetallic catalyst supported on SiO2; ligand: PNN ligand.
[0089] Among them, the molar ratio of copper and nickel in the Cu-Ni bimetallic catalyst is given by the formula:
[0090] calculate;
[0091] Wherein, C is the molar ratio of copper to nickel in the Cu-Ni bimetallic catalyst, and the unit is 1;
[0092] E is the potential of electrochemical reduction under low potential conditions, the unit is V, and the value is -0.3V;
[0093] α is the correction factor, the unit is 1, and in this embodiment, the value is e +3 ;
[0094] Standard electrode electric potential of copper Cu = +0.34V;
[0095] The standard electrode potential of nickel is E Ni =-0.23V, then the calculated result is C=4.7.
[0096] Example 3
[0097] This Example 3 provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalytic system and electrochemical CO2 activation. This method describes an efficient method for synthesizing 5-bromoindole-2-carboxylic acid using a Cu-Ni bimetallic catalytic system and electrochemical CO2 activation. This method converts CO2 into CO2 by electrochemical reduction under low potential conditions. - , coupled with the activated C-H bond intermediate to form the target product 5-bromoindole-2-carboxylic acid, while maintaining the high activity and recovery ability of the catalyst.
[0098] Here are the steps:
[0099] (1) Preparation of reactants and catalysts: 5-bromoindole (12 mmol) was mixed with Cu(OAc)2 (1.45 mmol) and NiCl2 (0.5 mmol), and the mixture was added to a solution containing a PNN ligand (0.2 mmol). The ligand provided a stable coordination environment and regulated the electronic effect of the metal in this step, ensuring that Cu and Ni formed a stable metal complex and exerted a synergistic effect in the reaction. The mixture was dissolved in an ionic liquid [BMIM]PF6 (1.5 mL) as a solvent. The solvent had high polarity, low volatility and high CO2 solubility, which helped to improve the CO2 conversion efficiency.
[0100] (2) CO2 reduction under low potential conditions: Under set low potential conditions (-0.4Vvs Ag / AgCl), CO2 is reduced to CO2 by electrochemical reduction. - (carbonate ion), this process uses the synergistic effect of Cu-Ni bimetallic catalyst, copper is responsible for the activation of CH bond, nickel is responsible for the reduction of CO2, CO2 - As a highly active intermediate, it undergoes a coupling reaction with the CH activated intermediate produced by the copper-nickel catalyst. The process is carried out at a temperature of 80°C to promote the reaction rate and increase the conversion rate of CO2.
[0101] (3) Generation of carboxylic acid intermediates: CO2 - The carboxylic acid intermediate is coupled with the CH activated intermediate, and the intermediate is stably coordinated with the metal surface during the reaction to reduce the generation of by-products. As the reaction proceeds, the generated carboxylic acid intermediate undergoes a proton transfer reaction and finally releases the target product 5-bromoindole-2-carboxylic acid. In this process, the copper and nickel catalysts are restored and enter the next reaction cycle.
[0102] Since the catalyst is a solid-supported catalyst, it is loaded on SiO2 (silica gel), which improves the stability of the catalyst. The metal catalyst will not be lost during the reaction, avoiding the agglomeration and deactivation of metal particles, thereby extending the service life of the catalyst.
[0103] Reaction conditions: electrochemical potential: -0.5V vs Ag / AgCl; reaction temperature: 80℃; reaction time: 50 minutes; CO2 supply: high pressure CO2; solvent: [EMIM]BF2 ionic liquid; catalyst: Cu-Ni bimetallic catalyst supported on SiO2; ligand: PNN ligand.
[0104] Among them, the molar ratio of copper and nickel in the Cu-Ni bimetallic catalyst is given by the formula:
[0105] calculate;
[0106] Wherein, C is the molar ratio of copper to nickel in the Cu-Ni bimetallic catalyst, and the unit is 1;
[0107] E is the potential of electrochemical reduction under low potential conditions, the unit is V, and the value is -0.4V;
[0108] α is the correction factor, the unit is 1, and in this embodiment, the value is e +3 ;
[0109] Standard electrode electric potential of copper Cu = +0.34V;
[0110] The standard electrode potential of nickel is E Ni =-0.23V, then the calculated result is C=2.9.
[0111] Comparative Example 1
[0112] This comparative example 1 provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu catalytic system and electrochemical CO2 activation, and describes a method for synthesizing 5-bromoindole-2-carboxylic acid using a Cu catalytic system and electrochemical CO2 activation. This method converts CO2 into CO2 by electrochemical reduction under low potential conditions. - , coupled with the activated C-H bond intermediate to form the target product 5-bromoindole-2-carboxylic acid, while maintaining the high activity and recovery ability of the catalyst.
[0113] Here are the steps:
[0114] (1) Preparation of reactants and catalysts: 5-bromoindole (10 mmol) and Cu(OAc)2 (2.8 mmol) were added to a solution containing a PNN ligand (0.28 mmol). The ligand provided a stable coordination environment and regulated the electronic effect of the metal in this step, ensuring that Cu and Ni formed a stable metal complex and exerted a synergistic effect in the reaction. The mixture was dissolved in an ionic liquid [BMIM]PF6 (1 mL) as a solvent. The solvent has high polarity, low volatility and high CO2 solubility, which helps to improve the CO2 conversion efficiency.
[0115] (2) CO2 reduction under low potential conditions: Under set low potential conditions (-0.5Vvs Ag / AgCl), CO2 is reduced to CO2 by electrochemical reduction. - (carbonate ion);
[0116] (3) Generation of carboxylic acid intermediates: CO2 - The carboxylic acid intermediate is coupled with the CH activated intermediate, and the intermediate is stably coordinated with the metal surface during the reaction to reduce the generation of by-products. As the reaction proceeds, the generated carboxylic acid intermediate undergoes a proton transfer reaction and finally releases the target product 5-bromoindole-2-carboxylic acid. In this process, the copper catalyst is restored and enters the next reaction cycle.
[0117] Since the catalyst is a solid-supported catalyst, it is loaded on SiO2 (silica gel), which improves the stability of the catalyst. The metal catalyst will not be lost during the reaction, avoiding the agglomeration and deactivation of metal particles, thereby extending the service life of the catalyst.
[0118] Reaction conditions: electrochemical potential: -0.5 V vs Ag / AgCl; reaction temperature: 90°C; reaction time: 40 minutes; CO2 supply: high pressure CO2; solvent: [BMIM]PF6 ionic liquid; catalyst: Cu catalyst supported on SiO2; ligand: PNN ligand.
[0119] Comparative Example 2
[0120] This comparative example 2 provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Ni catalytic system and electrochemical CO2 activation, and describes an efficient method for synthesizing 5-bromoindole-2-carboxylic acid using a Ni bimetallic catalytic system and electrochemical CO2 activation. This method converts CO2 into CO2 by electrochemical reduction under low potential conditions. - , coupled with the activated C-H bond intermediate to form the target product 5-bromoindole-2-carboxylic acid, while maintaining the high activity and recovery ability of the catalyst.
[0121] Here are the steps:
[0122] (1) Preparation of reactants and catalysts: 5-bromoindole (10 mmol) was mixed with NiCl2 (2.8 mmol), and then added to a solution containing a PNN ligand (0.28 mmol). The ligand provided a stable coordination environment and regulated the electronic effect of the metal in this step, ensuring that Cu and Ni formed a stable metal complex and exerted a synergistic effect in the reaction. The mixture was dissolved in an ionic liquid [BMIM]PF6 (1 mL) as a solvent. The solvent had high polarity, low volatility, and high CO2 solubility, which helped to improve the CO2 conversion efficiency.
[0123] (2) CO2 reduction under low potential conditions: Under set low potential conditions (-0.5Vvs Ag / AgCl), CO2 is reduced to CO2 by electrochemical reduction. - (Carbonate ion).
[0124] (3) Generation of carboxylic acid intermediates: CO2 - The carboxylic acid intermediate is coupled with the CH activated intermediate, and the intermediate is stably coordinated with the metal surface during the reaction to reduce the generation of by-products. As the reaction proceeds, the generated carboxylic acid intermediate undergoes a proton transfer reaction and finally releases the target product 5-bromoindole-2-carboxylic acid. In this process, the nickel catalyst is restored and enters the next reaction cycle.
[0125] Since the catalyst is a solid-supported catalyst, it is loaded on SiO2 (silica gel), which improves the stability of the catalyst. The metal catalyst will not be lost during the reaction, avoiding the agglomeration and deactivation of metal particles, thereby extending the service life of the catalyst.
[0126] Reaction conditions: electrochemical potential: -0.5V vs Ag / AgCl; reaction temperature: 90℃; reaction time: 40 minutes; CO2 supply: high pressure CO2; solvent: [BMIM]PF6 ionic liquid; catalyst: Cu-Ni bimetallic catalyst supported on SiO2; ligand: PNN ligand.
[0127] Comparative Example 3
[0128] This comparative example 3 provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation, and describes an efficient method for synthesizing 5-bromoindole-2-carboxylic acid using a Cu-Ni bimetallic catalyst system. This method converts CO2 into CO2 - , coupled with the activated C-H bond intermediate to form the target product 5-bromoindole-2-carboxylic acid, while maintaining the high activity and recovery ability of the catalyst.
[0129] Here are the steps:
[0130] (1) Preparation of reactants and catalysts: 5-bromoindole (10 mmol) was mixed with Cu(OAc)2 (1.8 mmol) and NiCl2 (1 mmol), and the mixture was added to a solution containing a PNN ligand (0.28 mmol). The ligand provided a stable coordination environment and regulated the electronic effect of the metal in this step, ensuring that Cu and Ni formed a stable metal complex and exerted a synergistic effect in the reaction. The mixture was dissolved in an ionic liquid [BMIM]PF6 (1 mL) as a solvent. The solvent had high polarity, low volatility and high CO2 solubility, which helped to improve the CO2 conversion efficiency.
[0131] (2) Utilizing the synergistic effect of Cu-Ni bimetallic catalysts, copper is responsible for the activation of CH bonds, and nickel is responsible for the reduction of CO2. - As a highly active intermediate, it undergoes a coupling reaction with the CH activated intermediate produced by the copper-nickel catalyst. The process is carried out at a temperature of 90°C to promote the reaction rate and increase the conversion rate of CO2.
[0132] (3) Generation of carboxylic acid intermediates: CO2 - The carboxylic acid intermediate is coupled with the CH activated intermediate, and the intermediate is stably coordinated with the metal surface during the reaction to reduce the generation of by-products. As the reaction proceeds, the generated carboxylic acid intermediate undergoes a proton transfer reaction and finally releases the target product 5-bromoindole-2-carboxylic acid. In this process, the copper and nickel catalysts are restored and enter the next reaction cycle.
[0133] Since the catalyst is a solid-supported catalyst, it is loaded on SiO2 (silica gel), which improves the stability of the catalyst. The metal catalyst will not be lost during the reaction, avoiding the agglomeration and deactivation of metal particles, thereby extending the service life of the catalyst.
[0134] Reaction conditions: reaction temperature: 90°C; reaction time: 40 minutes; CO2 supply: high-pressure CO2; solvent: [BMIM]PF6 ionic liquid; catalyst: Cu-Ni bimetallic catalyst supported on SiO2; ligand: PNN ligand.
[0135] Comparative Example 4
[0136] This comparative example 4 provides a method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation, and describes an efficient method for synthesizing 5-bromoindole-2-carboxylic acid using a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation. This method converts CO2 into CO2 by electrochemical reduction under low potential conditions. - , coupled with the activated C-H bond intermediate to form the target product 5-bromoindole-2-carboxylic acid, while maintaining the high activity and recovery ability of the catalyst.
[0137] Here are the steps:
[0138] (1) Preparation of reactants and catalysts: 5-bromoindole (10 mmol) was mixed with Cu(OAc)2 (1.4 mmol) and NiCl2 (1.4 mmol), and the mixture was added to a solution containing a PNN ligand (0.28 mmol). The ligand provided a stable coordination environment and regulated the electronic effect of the metal in this step, ensuring that Cu and Ni formed a stable metal complex and exerted a synergistic effect in the reaction. The mixture was dissolved in an ionic liquid [BMIM]PF6 (1 mL) as a solvent. The solvent had high polarity, low volatility and high CO2 solubility, which helped to improve the CO2 conversion efficiency.
[0139] (2) CO2 reduction under low potential conditions: Under set low potential conditions (-0.5Vvs Ag / AgCl), CO2 is reduced to CO2 by electrochemical reduction. - (carbonate ion), this process uses the synergistic effect of Cu-Ni bimetallic catalyst, copper is responsible for the activation of CH bond, nickel is responsible for the reduction of CO2, CO2 - As a highly active intermediate, it undergoes a coupling reaction with the CH activated intermediate produced by the copper-nickel catalyst. The process is carried out at a temperature of 90°C to promote the reaction rate and increase the conversion rate of CO2.
[0140] (3) Generation of carboxylic acid intermediates: CO2 - The carboxylic acid intermediate is coupled with the CH activated intermediate, and the intermediate is stably coordinated with the metal surface during the reaction to reduce the generation of by-products. As the reaction proceeds, the generated carboxylic acid intermediate undergoes a proton transfer reaction and finally releases the target product 5-bromoindole-2-carboxylic acid. In this process, the copper and nickel catalysts are restored and enter the next reaction cycle.
[0141] Since the catalyst is a solid-supported catalyst, it is loaded on SiO2 (silica gel), which improves the stability of the catalyst. The metal catalyst will not be lost during the reaction, avoiding the agglomeration and deactivation of metal particles, thereby extending the service life of the catalyst.
[0142] Reaction conditions: electrochemical potential: -0.5V vs Ag / AgCl; reaction temperature: 90℃; reaction time: 40 minutes; CO2 supply: high pressure CO2; solvent: [BMIM]PF6 ionic liquid; catalyst: Cu-Ni bimetallic catalyst supported on SiO2; ligand: PNN ligand.
[0143] Performance Testing
[0144] The following is a comparison table of the reaction yields and product purities of Examples 1 to 3 and Comparative Examples 1 to 4: See Table 1 for specific experimental data.
[0145] Table 1 Experimental data
[0146]
[0147]
[0148] Summarize:
[0149] (1) Examples 1 to 3: Using a Cu-Ni bimetallic catalyst in combination with electrochemical CO2 activation, the reaction yields all reached 88% to 90%, and the product purity was as high as 97.8% to 98.5%, indicating that the synergistic effect of electrochemical CO2 activation and Cu-Ni significantly improved the reaction efficiency and product purity.
[0150] (2) Comparative Examples 1-2: Due to the lack of synergistic effect, the reaction yield of single Cu or Ni catalyst is significantly reduced (45%-50%), and the product purity is low (82.5%-85.0%).
[0151] (3) Comparative Example 3: Without electrochemical CO2 activation, the reaction yield was extremely low (20%) and the product purity was only 75.0%, indicating that electrochemical CO2 activation was crucial to the reaction.
[0152] (4) Comparative Example 4: When the molar ratio of Cu and Ni is unbalanced, the reaction yield is reduced to 70% and the product purity is 90.5%, indicating that the optimization of the Cu-Ni molar ratio has an important influence on the reaction efficiency and product purity.
[0153] By comparison, the key role of the synergistic effect of electrochemical CO2 activation and Cu-Ni bimetallic catalytic system in the synthesis of 5-bromoindole-2-carboxylic acid was further verified.
[0154] The above description is only a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been presented as a preferred embodiment as above, it is not intended to limit the present invention. Any technician familiar with the profession can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the scope of the technical solution of the present invention.
Claims
1. A method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation, characterized in that: The steps include: 5-bromoindole is combined with a Cu-Ni bimetallic catalyst and a nitrogen-phosphine-containing bifunctional ligand is used to activate the CH bond at the 2-position of 5-bromoindole under reaction conditions to form a metallated intermediate. Convert CO2 to CO2 by electrochemical reduction under low potential conditions - ,CO2 - Couple with CH activated intermediate to form carboxylic acid intermediate; After the carboxylic acid intermediate undergoes a proton transfer reaction, the target product 5-bromoindole-2-carboxylic acid is released, and the catalyst is restored to enter the next reaction cycle.
2. A method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 1, characterized in that: The metal sources of the Cu-Ni bimetallic catalyst are Cu(OAc)2 and NiCl2.
3. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 1, characterized in that: The ligand is a PNN ligand.
4. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 1, characterized in that: The solvent is [BMIM]PF6 or [EMIM]BF4.
5. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 1, characterized in that: The potential of the electrochemical reduction under the low potential condition is -0.5 to -0.1 V vsAg / AgCl.
6. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 1, characterized in that: The CO2 supply is high pressure CO2 or supercritical CO2.
7. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 1, characterized in that: The reaction conditions include a reaction temperature of 80 to 100° C. and a reaction time of 30 to 60 minutes.
8. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 7, characterized in that: The catalyst is a supported catalyst, supported on MOF material or SiO2.
9. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 1, characterized in that: Continuous flow reaction is achieved through a microreactor, CO2 is continuously introduced and carboxylation reaction is carried out.
10. The method for synthesizing 5-bromoindole-2-carboxylic acid based on a Cu-Ni bimetallic catalyst system and electrochemical CO2 activation according to claim 5, characterized in that: In the Cu-Ni bimetallic catalyst, the mass ratio of Cu to Ni is calculated based on the potential of electrochemical reduction.