“Questions related to “hydroxyacetic acid”

In the early 1940s, the American company DuPont successfully produced glycolic acid through chemical synthesis; this substance could be used in industries such as printing and dyeing, cosmetics, electroplating, and the petroleum industry, offering a broad market potential. Initially, this production technology was held in monopoly by DuPont. Later, countries such as Japan and Germany **also developed corresponding production technologies. Over several decades of development, many synthetic methods for hydroxyacetic acid have been developed, including the glycine oxidation method, the cyanide method, the aldehyde carboxylation method, the formaldehyde and methyl formate coupling method, the oxalic acid electrolysis method, and the chloroacetic acid hydrolysis method. 3.1 Hydrolysis of monochloroacetic acid: There are two methods for the hydrolysis of chloroacetic acid. In one method, chloroacetic acid is hydrolyzed in a solution of calcium carbonate or barium carbonate; the basic reaction process is as follows. Hydroxyacetic acid is more acidic than carbonic acid, but less acidic than oxalic acid and sulfuric acid. This reaction utilizes the principle of strong acids displacing weak acids to produce hydroxyacetic acid. Due to the excessively long reaction time of this process, as well as the large amount of oxalic acid and sulfuric acid required, the costs are too high to enable large-scale production. One method is hydrolysis in an aqueous sodium hydroxide solution. Under alkaline conditions, the chlorine atom in monochloroacetic acid is easily attacked by hydroxide ions and replaced. The basic procedure is as follows: for example, chloroacetic acid is prepared as a 30% solution, and then a measured amount of 30% NaOH solution is added to neutralize the pH to 7–11. The mixture is heated to boiling point and allowed to react under reflux for several hours. At this point, the acidity of the solution increases; the reflux reaction is then changed to slow evaporation, with sodium chloride crystals being continuously filtered out. The concentrated liquid can be subjected to crystallization and recrystallization, or to crystallization using organic solvents such as propanol, in order to obtain glycolic acid crystals. Alternatively, after filtering out the sodium chloride crystals, the mixture can be acidified with hydrochloric acid and then distilled to purify glycolic acid. Xu Jiyu and others studied the kinetics of the basic hydrolysis reaction of monochloroacetic acid. The experimental results showed that this basic hydrolysis reaction is a second-order reaction that follows an SN2 mechanism. Temperature has a significant impact on this reaction; within the range of 40°C to 96°C, for every 20°C increase in temperature, the reaction rate increases by 4 to 9 times. The optimal temperature for this reaction is maintained between 80°C and 96°C. This method is currently the main approach for the small-scale production of glycolic acid in China. Advantages of this method: (1) The process for synthesizing glycolic acid using chloroacetic acid and sodium hydroxide as raw materials is relatively simple ； (2) The manufacturing process is relatively simple, allowing for small-scale production ； Disadvantages of this method: (1) The product is difficult to separate. Since the reaction mixture contains sodium chloride, it is difficult to separate and purify it using conventional crystallization methods ； (2) Separation by ion exchange resin method: this process consumes a large amount of acid and base, has a slow production speed, and results in high costs ； (3) It is difficult to obtain high-quality products ； (4) The process is lengthy and the yield is low, making it suitable only for small-scale production; (5) It generates a large amount of wastewater containing acids, alkalis, and organic substances, causing significant environmental pollution ； (6) Chloroacetic acid is a highly toxic substance that can be absorbed through the respiratory tract, digestive tract, and skin; it causes environmental pollution, increases equipment costs, and requires high safety standards. The process of producing glycolic acid through the hydrolysis of chloroacetic acid and sodium hydroxide is quite common in China. This is the most traditional production method in the country; due to inadequate separation processes, the yield is very low, making it suitable only for small-scale production. Using this process for crystallization or recrystallization, at most 96% glycolic acid can be obtained; the product also contains 1–3% sodium chloride, which makes it unsuitable for use in pharmaceuticals and cosmetics. Research is still ongoing to improve this process in order to obtain hydroxyacetic acid products with high concentration and high purity. For example, the Japanese company Otsuka Chemical Corporation hydrolyzes chloroacetic acid with an aqueous NaOH solution for 2 hours, then treats it with 35% concentrated hydrochloric acid. Solid impurities such as NaCl are removed by filtration, and the filtrate is subjected to methyl isobutyl ketone extraction. The resulting organic phase is back-extracted with water to yield an aqueous solution of glycolic acid. After concentration, an 88% aqueous solution of glycolic acid can be obtained, with a purity of glycolic acid of not less than 99.6%. 3.2 Carbonylation method using formaldehyde and carbon monoxide: Formaldehyde, water, and carbon monoxide can be used to directly synthesize glycolic acid under the action of a catalyst, at high pressure, and at appropriate temperatures; DuPont was the first company to use this method for the industrial production of glycolic acid in 1940. This reaction requires the presence of catalysts such as H2SO4 or HCl, H3PO4, etc., with the temperature controlled between 130°C and 200°C and the pressure between 30 MPa and 90 MPa. In this reaction, the higher the pressure of CO, the higher the conversion rate of formaldehyde, and the higher the yield of glycolic acid as well. The yield of glycolic acid at 90 MPa is nearly 90%. This method has low raw material costs, but it requires high pressure and liquid acid catalysis, which imposes high demands on the equipment; the initial investment is large, the equipment suffers severe corrosion, the separation and purification of the final product are complex, and the catalyst cannot be reused. DuPont stopped producing this technology in 1968. DuPont has been working to improve this process, and it is said that the problem of equipment corrosion has now been resolved; this method is currently the most widely used industrial approach abroad. To reduce the reaction temperature and pressure, strong acid catalysts such as concentrated H2SO4 and HF are used, and even group VII transition elements are added for catalysis]. This allows the reaction to proceed at a temperature of 20°C to 60°C, with the reaction pressure also dropping to 0.1 OMPa to 2.0 OMPa. Salvatore et al.] introduced copper and silver compounds as catalysts (the best copper catalyst is copper monoxide, while the best silver catalysts are silver sulfide, silver acetate, and silver carbonate). The reaction was also carried out in an acidic solution (usually sulfuric acid with a mass fraction of 50–100%), with the reaction temperature reduced to 0°C–90°C and the reaction pressure reduced to 0.01–3.0 MPa. Shigeto et al. used hydrofluoric acid as a catalyst; with the reaction temperature ranging from 0°C to 100°C and the pressure ranging from 0.069 to 27.56 MPa, the yield of glycolic acid increased significantly. The yield of the by-product dihydroxyacetic acid decreased as the molar ratio of formaldehyde to water decreased. However, hydrogen fluoride present in the crude product had to be removed through high-temperature distillation. Kiran] and others found that when acetic acid is present in the reaction mixture, the amount of the by-product dihydroxyacetic acid **decreases**, and the optimal amount of acetic acid to add per 1 mol of formaldehyde is 0.3–0.5 mol. Advantages of this process: (1) Low raw material cost ； (2) Low pollution. Disadvantages: (1) High technical requirements. 3.3 Coupling reaction of formaldehyde and methyl formate: Under acid catalysis, the coupling of formaldehyde and methyl formate can yield glycolic acid, methyl glycolate, and methyl methoxyacetate. Methyl glycolate is hydrolyzed to glycolic acid. Methyl glycolate was synthesized using methyl formate and formaldehyde or trioxane as raw materials, with solid Lewis acids, phosphomolybdic acid, montmorillonite, and cation-exchange resins as catalysts, at 6 M Pa and 110°C ； Using Diaion (cation exchange resin) as a catalyst, the yield of methyl glycolate was 56% under reaction conditions of 110°C and 6 M Pa. The reaction products include methyl methoxyacetate, methoxyacetic acid, methyl glycolate, methyl acetate, etc. The corrosion problem with this method is easy to solve, but it requires a high reaction pressure. [Huang Weiguo] Using solid heteropoly acids, their acid salts, and their metal salts as catalysts, and methyl formate and formaldehyde as raw materials, the effects of four types of heteropoly acids (phosphotungstic acid, silicotungstic acid, phosphomolybdic acid, and silicomolybdic acid), along with their acid salts and metal salts, on the coupling reaction were investigated in a pilot-scale reactor; methane sulfonic acid and sulfuric acid were used as catalysts for comparison. The research results show that silicotungstic acid and phosphotungstic acid exhibit high catalytic activity for coupling reactions, while molybdenum-based heteropolyacids with strong oxidizing properties have lower activity. The catalytic activity of heteropoly acids is higher than that of sulfuric acid and methanesulfonic acid. This method features mild reaction conditions; the catalyst does not corrode the reaction equipment, and it enables the efficient simultaneous synthesis of methyl glycolate and methyl methoxyacetate from methyl formate and formaldehyde. The catalyst is also easy to recover. From the perspective of separating products, raw materials, and catalysts, as well as considering equipment corrosion and environmental protection, replacing liquid acid catalysts with solid acids is one of the development directions in research and development. From the perspective of synthesizing glycolic acid through the coupling of formaldehyde and methyl formate, this reaction does not require high pressure, and methyl formate serves both as a reactant and as a solvent in this reaction. If liquid acid catalysis is chosen, the reaction takes place in a homogeneous phase; whereas the use of solid acid as a catalyst results in a liquid-solid phase reaction. This approach is superior, both in terms of process and operation, to the gas-liquid phase reaction used in the formaldehyde carbonyl method for the synthesis of glycolic acid. For this reaction, current research efforts are still focused on the catalyst, as well as the separation and reuse of the catalyst and the product, as well as the purification and separation of the product. 3.4 Hydrolysis of hydroxyacetonitrile: The reaction process for converting hydroxyacetonitrile into hydroxyacetic acid is as follows. The hydrolysis of hydroxyacetonitrile is carried out using aqueous solutions of sulfuric acid or phosphorous acid, and the amount of sulfuric acid used exceeds the theoretical amount; therefore, the hydrolysis solution contains a certain amount of sulfuric acid and sulfates. Oil-based extraction agents also have a certain capacity to dissolve salts. The presence of sulfuric acid leads to competitive extraction, thereby reducing the extractant’s ability to extract glycolic acid. Since the organic phase contains sulfuric acid, the aqueous solution of glycolic acid obtained after back-extraction will inevitably contain the impurity sulfuric acid as well as a small amount of the extractant. To reduce the sulfuric acid content in glycolic acid products, it is necessary to pre-treat the hydrolyzed material to remove sulfuric acid. In practice, lime milk is used to neutralize the excess sulfuric acid, and the resulting calcium sulfate precipitate is filtered out. After re-extraction and back-extraction of the treated hydroxyacetonitrile hydrolyzate, a hydroxyacetic acid product containing sulfuric acid and the extractant is obtained. The product quality is poor, and the production process causes significant environmental pollution. The purity of the product does not meet the requirements for pharmaceuticals and cosmetics.] Since hydroxyacetonitrile is produced by the reaction of formaldehyde with hydrogen cyanide or potassium cyanide, this synthetic route is highly toxic, unsafe, and costly. However, this method has a relatively simple process, which is why it is currently the main method we use for producing glycolic acid. 3.5 Oxalic acid electrolysis method: Oxalic acid first forms glyoxalic acid, which is then further reduced to glycolic acid. If the amount of electricity used is low, the main product is glycolic acid; only by increasing the amount of electricity and extending the electrolysis time to over 7 hours can the final product, glycolic acid, be produced ； The solution flow rate must be appropriate to ensure that the electrolyte has enough time to react on the electrodes. For the above reasons, the electrolysis level should be kept high; otherwise, it is difficult to produce glycolic acid. The electrolytic reduction of oxalic acid to synthesize glycolic acid was once used for industrial production in Germany, but high energy consumption, complex by-products, and poor product purity led to high production costs, preventing its sustained use. 3.5 Microbial method: The microbial method for producing glycolic acid is a new technique developed in recent years, and industrial pilot production has already begun in the West. Its process steps are: (1) Culturing Corynebacterium propionicium to produce nitrile hydratase ； (2) Using nitrile hydratase as a catalyst, an ammonium hydroxyacetic acid solution of low concentration is produced via the hydration reaction of hydroxyacetonitrile ； (3) A low-concentration ammonium hydroxyacetate solution is subjected to scraper evaporation, and then passed through an ion exchange column for ammonium removal to produce a higher-concentration hydroxyacetate solution ； (4) High-purity glycolic acid is prepared by low-temperature crystallization and drying of solutions with high concentrations of glycolic acid. The advantages include: a short production process, low energy consumption, high utilization rate of raw materials, minimal environmental pollution, high product quality, and low production costs. The Shanghai Biochemical Engineering Research Center took on the 973 key project during the **10th Five-Year Plan period, titled “Enzymatic Studies on the Microbial Catalytic Transformation of Nitriles and the Development of Industrialization Technologies,” and developed industrialization technologies for the production of glycolic acid via microbial catalysis. This process technology produces microorganisms containing specific nitrilase through microbial fermentation; under normal temperature and pressure, this specific nitrilase is used to catalyze the conversion of hydroxyacetonitrile into hydroxyacetic acid. It boasts advantages over chemical methods, such as specific substrate selectivity, high product purity, mild reaction conditions, simple product purification, and low requirements for equipment. However, no reports of industrialization have been seen.

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