Experience in organic synthesis – post-processing issues

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In organic synthesis, the issue of post-processing is often ignored by most people. They think that as long as the right synthesis method is found, the synthesis task can be done with twice the result with half the effort. This is true. The correct synthesis method is certainly important, but the task of organic synthesis is to obtain a fairly pure product. Any reaction without 100% yield will always be accompanied by more or less side reactions and produce more or less impurities. After the reaction is completed, the huge problem is to separate the pure product from the reaction mixture system. The purpose of post-processing is to use as many methods as possible to complete this task. Why are post-processing issues so easily overlooked? The various literatures we usually see, especially academic research papers, often do not pay enough attention to this issue or underestimate it. What they pay attention to is often new synthesis methods, synthetic reagents, etc. The patent also downplays this issue because it involves commercial profit issues. This issue is even less discussed in organic textbooks. Only those who have participated in industrial organic synthesis projects can realize the importance of this issue. Sometimes the reaction is done well, but problems arise in post-processing and the pure product cannot be obtained, and the company often suffers huge losses. Only then did I realize that organic synthesis is not only a matter of synthesis methods, but also involves many aspects of problems. If any aspect of the problem is not considered carefully, all previous efforts may be wasted. Where can I learn about post-processing issues? In addition to asking experienced scientific researchers for advice, you should also pay attention to everything. Although it is less involved in various literatures, there are still many papers that are involved. This requires you to think more, organize more, and draw inferences from one example to other cases. In addition, in scientific research work, attention should be paid to learning from experience and practicing more. The basic knowledge to complete the post-processing problem is still the physical and chemical properties of organic compounds, and post-processing is the specific application of these properties. Of course, first of all, the reaction must be done well and the occurrence of side reactions should be minimized, which can reduce the pressure of post-processing. Therefore, post-processing is still a test of a person's basic skills. Only by mastering chemistry can it be possible to complete post-processing tasks excellently. There are different solutions for post-processing according to the purpose of the reaction. If the purpose of obtaining pure compounds in the laboratory is to publish a paper and do various spectra, then the problem is simple. The only way to obtain pure compounds is to use columns, TLC, preparative chromatography and other methods. You don’t need to consider too many problems, and the compounds obtained are relatively pure. ； If it is for the purpose of industrial production, the problem becomes complicated. Try to use simple and low-cost methods. The ones in the laboratory will not work. If you still use the methods in the laboratory, the company will lose money. Below we only briefly introduce some methods in industry. The inspection standard for the quality of the post-processing process is: (1) Whether the product is recycled to the maximum extent and quality is guaranteed ； (2) Whether raw materials, intermediates, solvents and valuable by-products have been recycled and utilized to the maximum extent ； (3) Whether the post-processing steps, whether process or equipment, are simplified enough? ； (4) Whether the amount of three wastes is minimized. Xiaomu Chong Academic Blog'B Several common and practical methods of post-processing (1) Separation and purification of organic acid-base compounds Organic compounds with acid-base groups can gain and lose protons to form ionic compounds, and ionic compounds have different physical and chemical properties from the original parent compound. Basic compounds are treated with organic acids or inorganic acids to obtain amine salts, and acidic compounds are treated with organic bases or inorganic bases to obtain sodium salts or organic salts. According to the acidity and alkalinity of organic compounds, organic and non-calculated acids and bases are generally formic acid, acetic acid, hydrochloric acid, sulfuric acid, and phosphoric acid. The base is triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc. In general, ionic compounds have considerable solubility in water but very little solubility in organic solvents. At the same time, activated carbon can only adsorb non-ionic impurities and pigments. The above properties can be used to purify acidic and alkaline organic compounds. The above properties are not universal for all acid-base compounds. Generally speaking, the greater the proportion of the molecular weight of the acid-base group in the molecule to the molecular weight of the entire molecule, the greater the water solubility of the ionic compound. The more water-soluble groups such as hydroxyl groups contained in the molecule, the greater the water solubility. Therefore, the above properties are applicable to small-molecule acid-base compounds. For macromolecular compounds, the water solubility is significantly reduced. Acidic and basic groups include amino groups. Acidic groups include: Amidido, carboxyl, phenolic hydroxyl, sulfonylamino, thiophenol, 1,3-dicarbonyl compounds, etc. It is worth noting that amino compounds are generally basic groups, but when connected with strong electron-withdrawing groups, they become acidic compounds, such as amido and sulfonylamino compounds. These compounds easily lose their protons under the action of bases such as sodium hydroxide and potassium hydroxide to form sodium salts. Convert acidic and alkaline compounds into ionic compounds, make them soluble in water, use activated carbon to absorb impurities and then filter them to remove impurities and mechanical impurities that do not contain acidic and alkaline groups, and then combine them with acids and alkalis to return to the parent molecular state. This is a method for recycling and purifying acidic and alkaline products. Since activated carbon does not adsorb ions, the product loss caused by activated carbon adsorption is negligible. neutralization extraction method: It is a common method in industrial processes and laboratories. It takes advantage of the characteristics that acidic and alkaline organic compounds dissolve in water when generating ions and the parent molecular state is soluble in organic solvents. By adding acid and alkali, the parent compound generates ions and dissolve in water to achieve phase transfer, and uses non-water-soluble organic solvents to extract non-acidic and alkaline impurities, making them soluble in organic solvents to achieve separation of impurities and products. Salt formation method: 0 For non-water-soluble macromolecular organic ionic compounds, the organic acidic and alkaline compounds can be salted out and crystallized in the organic solvent, while the non-salt-forming impurities remain in the organic solvent, thereby achieving the separation of the organic acidic and alkaline compounds from the non-acidic and alkaline impurities. The acidic and alkaline organic impurities can be separated by recrystallizing the precipitated crystals, thereby separating the acidic and alkaline organic impurities. For the salts of macromolecular organic acid-base compounds, water washing can also be used to remove the water-soluble impurities of small-molecule acid-base compounds that have become salts. For water-soluble organic ionic compounds, after salt formation in water, the water can be removed by azeotropic distillation or direct distillation, and the residue can be fully washed several times with an organic solvent to separate impurities from the product. The above three methods are not isolated. They can be combined according to the properties of the compounds and the requirements of the product quality standards to obtain products of considerable purity. Xiaomu Chong Academic Blog 4Q1|N^0y Several special organic extraction solvents n-butanol: Most small molecular alcohols are water-soluble, such as methanol, ethanol, isopropanol, n-propanol, etc. Most high molecular weight alcohols are not water-soluble, but are lipophilic and soluble in organic solvents. But the intermediate alcohol solvent such as n-butanol is a good organic extraction solvent. n-butanol itself is insoluble in water, and it has the common characteristics of small molecular alcohols and large molecular alcohols. It can dissolve some polar compounds that can be dissolved in small alcohols, while being insoluble in water. This property can be used to extract polar reaction products from aqueous solutions using n-butanol. Ding Tong: The properties are between those of small molecules and those of large molecules. Unlike acetonitrile, which is soluble in water, acetonitrile is insoluble in water and can be used to extract products from water. Butyl acetate: Its properties are between small molecules and macromolecule esters, and its solubility in water is extremely small. Unlike ethyl acetate, which has a certain solubility in water, it can extract organic compounds, especially amino acid compounds, from water. Therefore, it is often used in the antibiotic industry to extract macromolecular amino acid-containing compounds such as cephalosporins and penicillins. Isopropyl ether and tert-butyl tert-butyl ether: The properties are between small molecule and macromolecular ethers. The polarity of the two is relatively small, similar to n-hexane and petroleum ether, and the solubility of the two in water is small. It can be used as a crystallization solvent and extraction solvent for very small polar molecules. It can also be used as a crystallization and extraction solvent for more polar compounds. (3) After completing the reaction, the extraction method should be used first to remove part of the impurities. This is to take advantage of the different solubility properties of impurities and products in different solvents. (4) The aqueous solution of dilute acid washes away some alkaline impurities. For example, if the reactants are alkaline and the product is neutral, the alkaline reactants can be washed away with dilute acid. For example, the acylation reaction of amine compounds. (5) A dilute alkali aqueous solution washes away part of the acidic impurities. The reactants are acidic and the product is neutral. The acidic reactants can be washed away with dilute alkali. For example, the esterification reaction of carboxyl compounds. (6) Wash away some water-soluble impurities with water. For example, in the esterification reaction of lower alcohol, water-soluble reactant alcohol can be washed away with water. (7) If the product wants to crystallize out of water and its solubility in the aqueous solution is large, you can try to add inorganic salts such as sodium chloride and ammonium chloride to reduce the solubility of the product in the aqueous solution - the method of salting out. (8) Sometimes two immiscible organic solvents can be used as extraction agents. For example, if the reaction is carried out in chloroform, petroleum ether or n-hexane can be used as the extraction agent to remove some small polar impurities. In turn, chloroform extraction can be used to remove highly polar impurities. (9) Two mutually miscible solvents sometimes become mutually incompatible by adding another substance. For example, when water is used as the solvent, after the reaction is completed, the inorganic salt sodium chloride and potassium chloride can be added to the system to saturate the water. At this time, the product can be extracted from the water by adding solvents such as propylene glycol, ethanol, and acetonitrile. (10) The basic principle of crystallization and recrystallization methods is to use the principle of similarity and compatibility. That is, highly polar compounds are recrystallized from polar solvents, and weakly polar compounds are recrystallized from non-polar solvents. For compounds that are difficult to crystallize, such as oils, colloids, etc., sometimes mixed solvents are used. However, the combination of mixed solvents is very knowledgeable and sometimes can only be based on experience. Generally, polar solvents and non-polar solvents are matched. The principle of matching is generally to select the ratio of polar solvents to non-polar solvents based on the polarity of the product and impurities. If the product is more polar and the impurity is less polar, the proportion of polar solvents in the solvent will be greater than the proportion of non-polar solvents. ； If the product is less polar and the impurities are more polar, the proportion of non-polar solvents in the solvent will be greater than the proportion of polar solvents. The more commonly used combinations are: Alcohol - petroleum ether, propylene - petroleum ether, alcohol - n-hexane, propylene - n-hexane, etc. However, if the product is very impure or the properties of the impurities are very similar to the product, the cost of obtaining a pure compound is multiple recrystallizations, and sometimes it cannot be purified even after multiple times. At this time, the impurities that are generally difficult to remove must be very similar to the properties and polarity of the product. Removing impurities can only be considered from the perspective of reaction. (11) Steam distillation, vacuum distillation and rectification methods are common methods for purifying low melting point compounds. Under normal circumstances, the recovery rate of vacuum distillation is relatively low. This is because as the product continues to evaporate, the concentration of the product gradually decreases. To ensure that the saturated vapor pressure of the product is equal to the external pressure, the temperature must be continuously raised to increase the saturated vapor pressure of the product. Obviously, the temperature cannot be increased infinitely, that is, the saturated vapor pressure of the product cannot be zero, that is, the product cannot be evaporated clean. There must be a certain amount of product left in the distillation equipment to be dissolved by the less volatile components in the equipment, as evidenced by the large amount of ax residue. Steam distillation has near-quantitative recoveries for volatile low-melting organic compounds. This is because during steam distillation, the sum of the saturated vapor pressure of all components in the ax plus water is equal to the external pressure. Due to the presence of a large amount of water, the saturated vapor pressure has reached the external pressure at 100°C. Therefore, below 100°C, all the products can be evaporated with the water vapor, and the recovery rate is close to complete. For systems with tar, steam distillation is particularly suitable. Because tar has two negative effects on product recycling: First, affected by the balance relationship, tar can dissolve part of the product so that it cannot be steamed out. ； Second, due to the high boiling point of tar, the temperature during distillation is too high, causing the product to continue to decompose. , Steam distillation can nearly quantitatively recover products from tar, and avoids overheating polymerization of products during the distillation process. The yield is about 3-4% higher than that of vacuum distillation. Although steam distillation can improve the recovery rate of volatile components, steam distillation is difficult to solve the problem of product purification because volatile impurities are evaporated together with the product. At this time, coupled with the rectification method, not only the recovery rate of the product is guaranteed, but also the product quality is guaranteed. It should be noted that steam distillation is only a special case of azeotropic distillation, and other solvents can also be used. Azeotropic distillation is not only suitable for product separation processes, but also for dehydration of reactant systems, dehydration of solvents, dehydration of products, etc. Compared with molecular sieve and inorganic salt dehydration processes, it has the advantages of simple equipment, easy operation, and does not consume other raw materials. For example: When producing aminothixamic acid, due to the presence of several polar amino groups, carboxyl groups, etc. in the molecule, they can form hydrogen bonds with molecules such as water and alcohol, so that there is a large amount of free and hydrogen-bonded water in the aminothixamic acid. For example, general vacuum drying and other drying methods are used. This method is not only time-consuming, but also easily causes the decomposition of the product. In this case, azeotropic distillation can be used to remove water molecules. The specific operation is to stir aminothixamic acid and methanol under reflux for several hours, and the water molecules can be removed to obtain anhydrous aminothixamic acid. For another example, when there is free or hydrogen-bonded methanol in the molecule, another solvent, such as n-hexane, petroleum ether, etc., can be used for reflux to remove the methanol. It can be seen that azeotropic distillation plays an important role in the separation process of organic synthesis. (12) Supramolecular methods use molecular recognition to purify products. (13) Decolorization methods generally use activated carbon, silica gel, alumina, etc. Activated carbon adsorbs non-polar compounds and small molecular compounds, while silica gel and alumina adsorb highly polar and macromolecular compounds, such as tar. For systems where polar impurities and non-polar impurities exist at the same time, both should be combined at the same time. Materials that are difficult to decolor can generally be removed with silica gel and alumina. It is sometimes difficult to decolorize acidic and alkaline compounds. When acidic compounds are neutralized with alkali to form ionic compounds and dissolved in water for decolorization, in addition to decolorizing once under weakly alkaline conditions to remove alkaline impurities, the system should be gradually neutralized to weak acidity and decolorized again to remove acidic impurities, so that the pigment can be completely removed. Similarly, when an alkaline compound is neutralized with an acid until it is weakly alkaline and dissolved in water for decolorization, in addition to decolorizing once under weakly acidic conditions to remove acidic impurities, the system should also be gradually neutralized to weakly alkaline and decolorized again to remove alkaline impurities. This post was last edited by hwqckr on 2009-2-12 01:38 ]