A process for the preparation of alpha-bromo-2,4-dichloroacetophenone

Abstract

The application discloses a preparation method of alpha-bromo-2,4-dichloroacetophenone, characterized in that: the alpha-bromo-2,4-dichloroacetophenone is prepared from m-dichlorobenzene and acetyl chloride under the catalysis of aluminum oxide, and then the target product alpha-bromo-2,4-dichloroacetophenone is obtained through bromination in a solvent. The method comprises the following steps: taking m-dichlorobenzene as a starting material, and generating 2,4-dichloroacetophenone through a Friedel-Crafts acylation reaction of m-dichlorobenzene and acetyl chloride under the catalysis of aluminum oxide; the obtained 2,4-dichloroacetophenone is subjected to alpha-site monobromination reaction with sodium bromide (NaBr) under the action of a catalyst, and the target product alpha-bromo-2,4-dichloroacetophenone is obtained through heat preservation reaction. The method has the advantages of cheap and easily obtained raw materials, short reaction steps, simple operation, low three wastes, high yield of the target product, high purity, and suitability for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing α-bromo-2,4-dichloroacetophenone. Background Technology

[0002] α-Bromo-2,4-dichloroacetophenone is a core fine chemical intermediate for the preparation of mainstream triazole agricultural fungicides such as difenoconazole and propiconazole, and it is also widely used in pharmaceutical synthesis and organic fine synthesis. With the continuous upgrading of modern agricultural green pest control technologies, the market demand for high-quality, low-impurity triazole fungicides continues to rise, placing more stringent requirements on the purity, synthesis yield, and environmental friendliness of the upstream intermediate α-bromo-2,4-dichloroacetophenone. Developing efficient, low-cost, and green preparation processes has significant industrial application value.

[0003] Currently, the conventional process for preparing α-bromo-2,4-dichloroacetophenone in the industry generally uses commercially available 2,4-dichloroacetophenone as a direct raw material, obtaining the target product through a single bromination reaction. Although this process is concise, it has significant technical shortcomings: the purity of commercially available 2,4-dichloroacetophenone is unstable, and the procurement cost is relatively high. Isomers and process impurities inherent in the raw material can easily enter the subsequent bromination system, inducing side reactions such as polybromination and benzene ring substitution, significantly reducing the selectivity and purity of the target product. Furthermore, the existing mainstream synthetic routes for 2,4-dichloroacetophenone mostly employ Friedel-Crafts acylation processes catalyzed by strong Lewis acids such as anhydrous aluminum trichloride, which have prominent environmental shortcomings: firstly, the large dosage of AlCl3 requires a large amount of acid and alkali quenching after the reaction, generating high-concentration aluminum-containing acidic waste residue and wastewater, resulting in high treatment costs and potential heavy metal pollution; secondly, the strongly acidic system causes severe corrosion to equipment, leading to high maintenance costs and significant safety risks. In subsequent bromination processes, traditional methods heavily rely on highly toxic and corrosive liquid bromine as the bromine source. The storage, transportation, and use of this bromine pose significant safety risks throughout the entire process, and the reaction produces large amounts of hydrogen bromide gas as a byproduct. Direct emission of this gas not only wastes bromine resources but also creates acidic waste gas pollution. While some processes introduce hydrogen peroxide to recover hydrogen bromide, the lack of an efficient catalytic system results in low bromine atom utilization, necessitating excessive addition of liquid bromine. This makes it difficult to effectively control the total amount of waste gas, wastewater, and solid waste, leading to high solvent consumption and energy consumption, which is inconsistent with the green and low-carbon development direction of fine chemicals.

[0004] Therefore, there is an urgent need to develop a solution to the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing α-bromo-2,4-dichloroacetophenone, and to develop a process scheme with short steps and simple operation, thereby obtaining a product with good quality and high production efficiency.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: This invention provides a method for preparing α-bromo-2,4-dichloroacetophenone, comprising the following steps: (1) Friedel-Crafts acylation reaction In a four-necked flask equipped with a thermometer, a constant-pressure dropping funnel, and a reflux condenser with a drying tube, m-dichlorobenzene and alumina were added. The mixture was heated and stirred, and acetyl chloride was slowly added dropwise. After the addition was complete, the reaction mixture was kept at the same temperature until no more hydrogen chloride gas was generated. The generated hydrogen chloride gas was absorbed with sodium hydroxide solution. The reaction mixture was cooled to below 5°C in an ice bath, and hydrochloric acid was added dropwise for acidolysis. Sufficient distilled water was added to precipitate the solid, which was then filtered under reduced pressure and dried to obtain 2,4-dichloroacetophenone.

[0007] (2) Bromination reaction 2,4-Dichloroacetophenone obtained from the Friedel-Crafts acylation reaction was dissolved in a solvent and stirred until the substrate was completely dissolved. Concentrated sulfuric acid and sodium bromide were then added sequentially, and the mixture was stirred until homogeneous and an acidic bromination medium was formed. Hydrogen peroxide solution was slowly added dropwise to the reaction system using a dropping funnel. The addition rate was controlled to maintain the reaction temperature within a suitable range; if necessary, a cold water bath was used for temperature control to prevent violent decomposition of hydrogen peroxide. After the addition was complete, stirring was continued to carry out the α-bromination reaction. After the reaction was completed, the reaction mixture was slowly poured into ice water to quench the reaction, and saturated sodium thiosulfate aqueous solution was added dropwise while stirring until the red color of the reaction solution completely disappeared. The mixture was transferred to a separatory funnel, and cyclohexane was added for multiple extractions. The organic phases were combined, washed sequentially with saturated sodium thiosulfate aqueous solution to remove bromine, and then washed with saturated sodium chloride aqueous solution for salting out and dehydration until the pH of the aqueous phase was neutral. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was further purified by recrystallization to obtain the target α-bromo-2,4-dichloroacetophenone.

[0008] Preferably, in step (1), the alumina is γ-alumina. γ-alumina has the characteristics of large specific surface area, abundant surface acid centers, and high catalytic activity. As a catalyst for Friedel-Crafts acylation reaction, it can efficiently promote the acylation reaction of m-dichlorobenzene and acetyl chloride under mild conditions.

[0009] Preferably, in step (1), the molar ratio of m-dichlorobenzene to acetyl chloride is 1:(1.0-1.2), and the molar ratio of m-dichlorobenzene to alumina is 1:(1.2-1.5).

[0010] Preferably, in step (1), the stirring temperature is 30-40℃ and the stirring time is 0.5-1 hour.

[0011] Preferably, in step (1), the heat preservation reaction temperature is 50-60℃, the time is 2-4 hours, and the generated hydrogen chloride gas is absorbed by a 30% sodium hydroxide solution.

[0012] Preferably, in step (2), the solvent is dichloromethane.

[0013] Preferably, in step (2), the catalyst is tetraethylammonium bromide, and the molar ratio of the catalyst to 2,4-dichloroacetophenone is (0.015-0.025):1.

[0014] Preferably, in step (2), the acid is concentrated sulfuric acid; the molar ratio of the acid to 2,4-dichloroacetophenone is 1:1.

[0015] Preferably, in step (2), the molar ratio of 2,4-dichloroacetophenone and sodium bromide is 1:1, the molar ratio of hydrogen peroxide to 2,4-dichloroacetophenone is 1:1.2, and the mass fraction of hydrogen peroxide is 30%.

[0016] Preferably, in step (2), the α-position bromination reaction temperature is 20-30℃ and the reaction time is 2-3 hours.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Simple and efficient process route: This invention adopts a two-step synthesis route of "Friedrich-Kreutz acylation + α-bromination", with clear procedures and simple operation. It uses readily available and inexpensive sodium bromide as the bromine source, ensuring a stable supply and low procurement cost. The reaction process produces no large amounts of acidic tail gas emissions, eliminating the need for a complex tail gas absorption system. The post-treatment process is simple, and the total amount of waste generated is significantly reduced compared to traditional processes, making it an environmentally friendly green preparation method.

[0018] 2. Catalyst and reaction system innovation enhances selectivity and economy: In the Friedel-Crafts acylation step, alumina is used as a catalyst, replacing the highly corrosive, complex, and costly Lewis acids (such as anhydrous aluminum trichloride) used in traditional methods. This reduces catalyst costs, simplifies the post-processing, and reduces equipment corrosion. The bromination reaction employs a process where sodium bromide and hydrogen peroxide are used to generate active bromine in situ, replacing the traditional direct addition of highly toxic liquid bromine. Combined with a quaternary ammonium salt catalyst, hydrogen peroxide can oxidize and regenerate the byproduct hydrogen bromide into bromine in situ, maximizing the recycling rate of bromine atoms. This significantly reduces the safety and environmental risks of bromine leakage and poisoning, while also substantially reducing actual bromine consumption and hydrogen bromide emissions, thus decreasing the generation of acidic waste gas and aligning with the industry's green catalysis approach.

[0019] 3. Excellent product quality and yield: By optimizing key parameters such as material molar ratio, reaction temperature and time, this invention achieves low-toxicity, low-waste and low-risk operation of the production process while ensuring product yield and HPLC purity. The amount of waste emissions is greatly reduced, demonstrating outstanding environmental friendliness and industrialization promotion value. Attached Figure Description

[0020] Figure 1 The flowchart shows the preparation process of α-bromo-2,4-dichloroacetophenone. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art. The terms "comprising" and similar expressions used herein mean that the element or object preceding the word covers the element or object listed after the word and its equivalents, but does not exclude other elements or objects.

[0022] The present invention will be specifically illustrated below through examples. In this invention, the following examples are provided to better illustrate the invention and are not intended to limit the scope of the invention. Unless otherwise specified, the materials, reagents, etc., used in the following examples are commercially available.

[0023] In the following examples, the product yield is the molar yield, calculated using the following formula: Yield (%) = (Actual yield of target product / Theoretical yield of target product) × 100%; Purity (%) = (Target substance mass / Total sample mass) × 100%; Based on high-performance liquid chromatography (HPLC) analysis: the most commonly used method is the area normalization method, the formula is: Purity (%) = (Target product peak area / Sum of peak areas of all components) × 100% Example 1

[0024] This invention provides a method for preparing α-bromo-2,4-dichloroacetophenone, comprising the following steps: (1) Friedel-Crafts acylation reaction In a four-necked flask equipped with a thermometer, a constant-pressure dropping funnel, a drying tube, and a reflux condenser, add m-dichlorobenzene and alumina (γ-Al₂O₃, specific surface area ≥200 m² / g), and stir at 30-35℃ for 1-2 hours. Slowly add acetyl chloride dropwise, controlling the temperature to not exceed 50℃ during addition. After the addition is complete, raise the temperature to 55-60℃ and maintain the reaction temperature for 3 hours until no hydrogen chloride gas is emitted (moist blue litmus paper does not turn red). The tail gas is absorbed with a 30% NaOH solution. Cool the reaction solution to below 5℃ in an ice bath, slowly add dilute hydrochloric acid for acid hydrolysis, add distilled water to precipitate the solid, filter, wash the filter cake with a small amount of ice water until neutral, and dry under vacuum at 50℃ to obtain white needle-like crystals of 2,4-dichloroacetophenone.

[0025] (2) Bromination reaction Dichloromethane was added to a four-necked flask, followed by the addition of 2,4-dichloroacetophenone and tetraethylammonium bromide while stirring. Concentrated sulfuric acid and sodium bromide were then added, and the mixture was stirred at room temperature for 15 minutes to form an acidic bromination medium. 30% hydrogen peroxide was slowly added dropwise to the reaction system, maintaining the reaction temperature at approximately 25 °C while controlling the dropping rate; a cold water bath was used for temperature control if necessary. After the addition was complete, the mixture was stirred continuously at 30 °C for 2.5 hours. After the reaction was complete, the mixture was slowly poured into ice water to quench the reaction, and saturated sodium thiosulfate solution was added dropwise while stirring until the red color of the reaction solution completely disappeared. The mixture was transferred to a separatory funnel, and cyclohexane was added for extraction. The organic phases were combined and washed successively with saturated sodium thiosulfate solution to remove trace amounts of bromine, and then with saturated sodium chloride solution for salting out and dehydration until the pH of the aqueous phase was neutral. The organic phase was dried over anhydrous sodium sulfate for 30 minutes, filtered, and the filtrate was distilled under reduced pressure below 40 °C to remove the solvent, yielding the crude product. The crude product was recrystallized from an ethanol / water mixture, filtered, and dried to give white crystalline α-bromo-2,4-dichloroacetophenone, with a yield of 92.2% and an HPLC purity of 95.7%.

[0026] a) Friedel-Crafts acylation reaction material ratio: m-dichlorobenzene: 14.7 g, 0.10 mol; alumina (γ-Al2O3): 12.2 g, 0.12 mol; acetyl chloride: 9.4 g, 0.12 mol.

[0027] b) Bromination reaction material ratio: 2,4-Dichloroacetophenone: 18.9 g, 0.10 mol; Dichloromethane: 30 mL; Tetraethylammonium bromide (TEAB, catalyst): 0.32 g, 0.0015 mol; Concentrated sulfuric acid: 9.8 g, 0.10 mol; Sodium bromide: 11.4 g, 0.11 mol; 30% hydrogen peroxide: 13.0 g, 0.12 mol; Cyclohexane (for extraction): 250 mL × 3; Saturated sodium thiosulfate aqueous solution: until the red color completely fades and starch-KI test paper does not turn blue; Saturated sodium chloride aqueous solution: until the aqueous phase is clear and the pH is neutral; Anhydrous sodium sulfate: until the desiccant does not clump and the organic phase is clear and transparent; Ethanol / water mixed solvent (for recrystallization): until a large amount of white crystals precipitate after cooling. Example 2

[0028] (1) Friedel-Crafts acylation reaction The procedure is the same as in Example 1, except that the heat preservation temperature is controlled at 50-55℃ and the heat preservation time is extended to 4 hours to obtain 2,4-dichloroacetophenone.

[0029] (2) Bromination reaction The procedure was the same as in Example 1, except that the amount of tetraethylammonium bromide was halved, the amount of concentrated sulfuric acid remained the same, the reaction time was extended to 3 hours, and the post-treatment was the same as in Example 1. The yield was 90.5%, and the HPLC purity was 93.9%.

[0030] a) Friedel-Crafts acylation reaction material ratio: m-dichlorobenzene: 14.7 g, 0.10 mol; alumina (γ-Al2O3): 15.3 g, 0.15 mol; acetyl chloride: 9.8 g, 0.125 mol.

[0031] b) Bromination reaction material ratio: 2,4-Dichloroacetophenone: 19.1 g, 0.101 mol; Dichloromethane: 30 mL; Tetraethylammonium bromide (TEAB, catalyst): 0.16 g, 0.00075 mol; Concentrated sulfuric acid: 9.8 g, 0.10 mol; Sodium bromide: 11.5 g, 0.111 mol; 30% hydrogen peroxide: 11.9 g, 0.11 mol; Cyclohexane (for extraction): 250 mL × 3; Saturated sodium thiosulfate aqueous solution: until the red color completely fades and starch-KI test paper does not turn blue; Saturated sodium chloride aqueous solution: until the aqueous phase is clear and the pH is neutral; Anhydrous sodium sulfate: until the desiccant does not clump and the organic phase is clear and transparent; Ethanol / water mixed solvent (for recrystallization): until a large amount of white crystals precipitate after cooling. Example 3

[0032] (1) Friedel-Crafts acylation reaction The procedure is the same as in Example 1, except that the stirring temperature is controlled at 30 ℃, the holding temperature is 50 ℃, and the reaction time is 2 hours to obtain 2,4-dichloroacetophenone.

[0033] (2) Bromination reaction The procedure was the same as in Example 1, except that dichloromethane was added as a solvent to a four-necked flask, and the above-mentioned 2,4-dichloroacetophenone and tetraethylammonium bromide were added with stirring. Then, concentrated sulfuric acid (acid to substrate molar ratio approximately 2:1) and sodium bromide were added, and the mixture was stirred at room temperature for 10 minutes. 30% hydrogen peroxide was slowly added dropwise, controlling the temperature at 20–25 °C. After the addition was complete, the reaction was stirred at 25 °C for 2 hours, and the post-treatment was the same as in Example 1. α-Bromo-2,4-dichloroacetophenone was obtained with a yield of 89.1% and an HPLC purity of 91.2%.

[0034] a) Friedel-Crafts acylation reaction material ratio: m-dichlorobenzene: 14.7 g, 0.10 mol; alumina (γ-Al2O3): 10.2 g, 0.10 mol; acetyl chloride: 7.8 g, 0.10 mol.

[0035] b) Bromination reaction material ratio: 2,4-Dichloroacetophenone: 18.3 g, 0.97 mol; Dichloromethane: 30 mL; Tetraethylammonium bromide (TEAB, catalyst): 0.41 g, 0.019 mol; Concentrated sulfuric acid: 19.6 g, 0.20 mol; Sodium bromide: 11.0 g, 0.107 mol; 30% hydrogen peroxide: 12.6 g, 0.117 mol; Cyclohexane (for extraction): 250 mL × 3; Saturated sodium thiosulfate aqueous solution: until the red color completely fades and starch-KI test paper does not turn blue; Saturated sodium chloride aqueous solution: until the aqueous phase is clear and the pH is neutral; Anhydrous sodium sulfate: until the desiccant does not clump and the organic phase is clear and transparent; Ethanol / water mixed solvent (for recrystallization): until a large amount of white crystals precipitate after cooling.

[0036] Comparative Example 1 The difference between this comparative example and Example 1 is that in the Friedel-Crafts acylation reaction, an equimolar amount of anhydrous aluminum trichloride (13.3 g, 0.10 mol) was used instead of alumina as the catalyst; the bromination reaction steps and conditions were the same as in Example 1. α-Bromo-2,4-dichloroacetophenone was obtained in 89.3% yield with an HPLC purity of 93.0%.

[0037] Comparative Example 2 The difference between this comparative example and Example 1 is that liquid bromine (16.0 g, 0.10 mol) was directly added dropwise in the bromination reaction to replace the sodium bromide and 30% hydrogen peroxide system. The Friedel-Crafts acylation reaction steps and conditions were the same as in Example 1. α-Bromo-2,4-dichloroacetophenone was obtained with a yield of 88.1% and an HPLC purity of 92.4%.

[0038] Comparative Example 3 The difference between this comparative example and Example 1 is that: in the Friedel-Crafts acylation reaction, an equimolar amount of anhydrous aluminum trichloride (13.3 g, 0.10 mol) was used instead of alumina as a catalyst; and in the bromination reaction, liquid bromine (16.0 g, 0.10 mol) was directly added dropwise instead of the sodium bromide and 30% hydrogen peroxide system. α-Bromo-2,4-dichloroacetophenone was obtained with a yield of 85.6% and an HPLC purity of 89.2%.

[0039] Table 1: Comparison of yield and purity between the examples and comparative examples

[0040] As shown in Table 1, the yield and purity of Example 1 were significantly better than those of the comparative examples. Comparative Example 1 used traditional aluminum trichloride-catalyzed Friedel-Crafts acylation, which not only resulted in significantly lower product yield and purity than Example 1, but also generated a large amount of difficult-to-dispose-of aluminum-containing acidic wastewater during the post-processing stage. Comparative Example 2 used direct bromination with liquid bromine, which also resulted in lower yield and purity than Example 1. The reaction process continuously emitted a large amount of highly corrosive hydrogen bromide gas, posing both safety hazards and a serious environmental burden. Comparative Example 3 used both traditional aluminum trichloride catalysis and liquid bromine bromination, resulting in the lowest yield and purity among all samples. This is because aluminum trichloride-catalyzed acylation is vigorous and has poor selectivity, easily generating positional isomer impurities; liquid bromine bromination has high activity but poor selectivity, easily causing benzene ring bromination and polybromination side reactions, significantly increasing the difficulty of separation and purification, ultimately resulting in the lowest yield and purity. In contrast, the parameter combination of Example 1 among Examples 1-3 represents the optimal solution for this process, achieving a total target product yield of 92.2% and an HPLC purity of 95.7%. This invention achieves efficient and high-quality synthesis of α-bromo-2,4-dichloroacetophenone through the selection of raw materials and optimization of processes. It features simple operation, low waste volume, and easy scale-up, making it suitable for industrial application.

[0041] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention using the methods and techniques disclosed above, or modify them into equivalent embodiments with equivalent changes, without departing from the spirit and technical essence of the present invention. Therefore, any simple modifications, equivalent substitutions, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solutions of the present invention shall still fall within the protection scope of the technical solutions of the present invention.

Claims

1. A method for preparing α-bromo-2,4-dichloroacetophenone, characterized in that, Includes the following steps: Step 1, Friedel-Crafts acylation reaction: Add m-dichlorobenzene and alumina sequentially to a reaction flask, heat and stir, slowly add acetyl chloride dropwise, and raise the temperature after the addition is complete, and keep the reaction at this temperature until no hydrogen chloride gas is generated; extract 2,4-dichloroacetophenone with dichloromethane, and dichloromethane is removed under reduced pressure to obtain 2,4-dichloroacetophenone. Step 2, bromination reaction: The 2,4-dichloroacetophenone obtained by Friedel-Crafts acylation reaction is dissolved in a solvent, and a catalyst, sodium bromide, acid, and hydrogen peroxide are added to carry out the α-position bromination reaction; after the reaction is completed, the reaction mixture is quenched in ice water, sodium thiosulfate is added to reduce the residual bromine, and after extraction, washing, drying, and solvent removal, α-bromo-2,4-dichloroacetophenone is obtained.

2. The preparation method according to claim 1, characterized in that, In step 1, the alumina is γ-alumina (γ-Al2O3), the molar ratio of m-dichlorobenzene to acetyl chloride is 1:(1.0-2.0), and the molar ratio of m-dichlorobenzene to alumina is 1:(1.0-1.5).

3. The preparation method according to claim 1, characterized in that, In step 1, the stirring temperature is 30-50℃ and the stirring time is 0.5-2 hours.

4. The preparation method according to claim 1, characterized in that, In step 1, the heat preservation reaction temperature is 50-80℃, the time is 2-5 hours, and the generated hydrogen chloride gas is absorbed by sodium hydroxide solution.

5. The preparation method according to claim 1, characterized in that, In step 2, the solvent is at least one of dichloromethane, trichloromethane, carbon tetrachloride, cyclohexane, and alkane solvent oil.

6. The preparation method according to claim 1, characterized in that, In step 2, the catalyst is one of the quaternary ammonium salts, and the molar ratio of the catalyst to 2,4-dichloroacetophenone is (0.01-0.05):

1.

7. The preparation method according to claim 1, characterized in that, In step 2, the acid is one of concentrated sulfuric acid, p-toluenesulfonic acid, hydrochloric acid, and glacial acetic acid; the molar ratio of the acid to 2,4-dichloroacetophenone is (1.0-3.0):

1.

8. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of 2,4-dichloroacetophenone to sodium bromide is 1:(0.5-1.5), and the molar ratio of hydrogen peroxide to 2,4-dichloroacetophenone is (0.6-0.9):1, wherein the mass fraction of hydrogen peroxide is 27.5-30%.

9. The preparation method according to claim 1, characterized in that, In step 2, the α-position bromination reaction temperature is 10-30℃ and the reaction time is 1-4 hours.

10. The preparation method according to claim 1, characterized in that, In step 2, the quenching step includes: pouring the reaction mixture into ice water and adding saturated sodium thiosulfate aqueous solution dropwise until the red color of the reaction solution fades; the extraction is performed using cyclohexane, and the extraction volume each time is 1.5-2 times the volume of the organic solvent.

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