Crystallisation process control and product property regulation
In organic synthesis, the problem of post-processing is often ignored by most people, that as long as you find the right synthesis method, the task of synthesis can be twice as easy, this is not bad, the correct synthesis method is important, but the task of organic synthesis is to get a fairly pure product, any reaction does not have a 100 per cent yield, there are always accompanied by a greater or lesser number of side reactions, resulting in a greater or lesser number of impurities, the completion of the reaction, the huge problem is to separate the pure product from the reaction mixing system, and the reaction is completed. After the reaction is completed, the big problem is to separate the pure product from the reaction mixture. The purpose of reprocessing is to accomplish this task in the best possible way.

Why is the problem of reprocessing so easily overlooked? The literature we usually read, especially the academic research papers, tends to pay insufficient attention to this problem or treat it lightly, and they often pay attention to new synthetic methods, synthetic reagents, etc. The patents also pay little attention to this problem. This issue is also downplayed in patents because it involves commercial profits. Organic textbooks do not even talk about this issue. Only participated in the industrial machine synthesis project people can recognise the importance of this issue, sometimes the reaction is done in a good, post-processing problems do not get pure products, business losses are often huge. It is then realised that organic synthesis is not only a matter of synthesis method, but also involves many aspects of the problem, that aspect of the problem is not well thought out, may be a lost cause.
Where can I learn about reprocessing? In addition to consulting with experienced researchers, we should also pay attention to the literature, although it is less involved in the literature, but there are still many papers are involved, which requires us to think more, more organised, and to learn by example. In addition, in the scientific research work, should pay attention to take experience, more honed. The basic knowledge to complete the reprocessing problem is still the physical and chemical properties of organic compounds, and reprocessing is the specific application of these properties. Of course, the first thing to do is to make the reaction well and minimise the occurrence of side reactions, which can reduce the pressure of reprocessing. Thus, reprocessing is still a matter of testing one’s basic skills, and only if one is good at chemistry is it possible to excel at reprocessing tasks. Post-processing according to the purpose of the reaction has different solutions, if in the laboratory, just for the publication of the paper, to get pure compounds for the purpose of making a variety of spectra, then the problem is simple, to get pure compounds is no more than the method of walking columns, TLC, preparative chromatography, etc., do not have to consider too many problems, and the compounds obtained is relatively pure; if for the purpose of industrial production, then the problem is complex, try to use a simple method, and try to use a simple method, so as to minimize the occurrence of side effects, which can help to complete the task. If it is for the purpose of industrial production, the problem is complicated, try to use simple, low-cost methods, the set in the laboratory will not work, if you still use the laboratory methods, the enterprise will lose money.
The following is only a brief description of some of the methods used in industry.
The test of the merit of the post-treatment process is:
(1) whether the product is recovered to the maximum extent possible and the quality is guaranteed; (2) whether the raw materials, intermediates, solvents and valuable by-products are recycled to the maximum extent possible; (3) whether the steps of the post-processing procedure, whether it be process or equipment, are sufficiently simplified; and (4) whether the amount of the three types of wastes is at a minimum.
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Several common and practical methods of reprocessing:
The most complete recrystallisation experience and methods ever made
(1) Separation and purification of organic acid-base compounds
Organic compounds with acid-base groups can gain or lose protons to form ionic compounds, which have different physicochemical properties from the original parent compound. Alkaline compounds are treated with organic or inorganic acids to obtain amine salts, and acidic compounds are treated with organic or inorganic bases to obtain sodium salts or organic salts. According to the strength of the acidity and alkalinity of organic compounds, organic and inorganic acids and bases are generally formic acid, acetic acid, hydrochloric acid, sulphuric acid and phosphoric acid. The bases are triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and so on. In general, ionic compounds in water with considerable solubility, while in the organic solvent solubility is very small, while the activated carbon is only able to adsorb non-ionic impurities and pigments. These properties can be used to purify acid-base organic compounds. The above properties are not common to all acid-base compounds. In general, the greater the proportion of molecular weight of acid-base groups in a molecule to the molecular weight of the whole molecule, the greater the water solubility of ionic compounds, and the more water-soluble groups such as hydroxyl groups in a molecule, the more water-soluble it will be, so the above properties are applicable to acid-base compounds of small molecules. Therefore, the above properties apply to acid-base compounds of small molecules. For compounds of large molecules, the water solubility is significantly reduced. Acid-base groups include amino groups. Acidic groups include: acylamino groups, carboxyl groups, phenolic hydroxyl groups, sulfonylamino groups, thiophenol groups, 1,3-dicarbonyl compounds, and so on. It is worth noting that amino compounds are generally alkaline groups, but become acidic compounds when accompanied by strong electron-withdrawing groups, such as acylamino and sulfonylamino compounds, which are prone to lose protons under the action of bases such as sodium hydroxide and potassium hydroxide to form sodium salts.
Neutralisation adsorption method:
Acid-base compounds into ionic compounds, so that it is dissolved in water, with activated carbon adsorption of impurities after filtration, the removal of impurities and mechanical impurities that do not contain acid-base groups, and then add acid and alkali neutralisation back to the parent molecular state, which is the method of recycling and purification of acid-base products. As the activated carbon does not adsorb ions, so there is activated carbon adsorption caused by the loss of product neglect.
Neutralisation and extraction method:
Is a common method of industrial processes and laboratories, it uses acid and alkaline machine compounds generate ions dissolved in water and the parent molecular state dissolved in the characteristics of the machine solvent, by adding acid and alkali so that the parent compound generates ions dissolved in water to achieve the transfer of the phase and the use of non-water-soluble organic solvents extract non-acidic and alkaline impurities, so that they are dissolved in the machine solvent so as to achieve the separation of impurities and products method.
Salt formation method:
For non-water-soluble macromolecular organic ionic compounds, the organic acid-base compounds can be salted in organic solvents to precipitate crystals, while non-salted impurities remain in organic solvents to achieve the separation of organic acid-base compounds and non-acid-base impurities, acid-base organic impurities can be separated by the precipitation of crystals and then recrystallised, so that the acid-base machine impurities are separated. For large molecules of organic acid-base compounds of salt at this time can also be used to remove small molecules of acid-base compounds have become salt and water-soluble impurities by water washing. For water-soluble organic ionic compounds, can be salted in water, the water with azeotropic distillation or direct distillation to remove the residue with organic solvents to fully wash several times, so that the impurities and products are separated. The above three methods are not isolated, according to the nature of the compounds and product quality standards, the use of a combination of methods, as far as possible to obtain a fairly pure product.
(2) Several special machine extraction solvents
n-Butanol: Most small molecular alcohols are water-soluble, such as methanol, ethanol, isopropanol, n-propanol and so on. Most high molecular weight alcohols are non-water soluble, but lipophilic to be able to dissolve in the machine solvent. However, intermediate alcohol solvents such as n-butanol are an excellent solvent for organic extraction. N-butanol itself is insoluble in water and shares the characteristics of both small and large molecule alcohols. It is able to dissolve some polar compounds that can be dissolved with small molecular alcohols, while at the same time insoluble in water. Using this property, n-butanol can be used to extract polar reaction products from aqueous solutions. Butanone: Its properties are intermediate between those of small and large ketones. Unlike acetone, which is soluble in water, butanone is insoluble in water and can be used to extract products from water.
Butyl acetate: nature between small molecules and macromolecular esters, the solubility in water is very small, unlike ethyl acetate in water has a certain solubility, can be extracted from water compounds, especially amino acid compounds, so in the antibiotic industry is commonly used to extract cephalosporin, penicillin and other large molecules containing amino acid compounds.
Isopropyl ether and tert-butyl tert-butyl ether: nature between small molecules and large molecules of ether, the polarity of the two is relatively small, similar to hexane and petroleum ether, the solubility of the two in water is small. It can be used as crystallisation solvent and extraction solvent for molecules with very small polarity. It can also be used as a crystallisation and extraction solvent for compounds with large polarity.
(3) After doing the reaction, extraction should be used first to remove some of the impurities first, this is to take advantage of the nature of the impurities and products in different solvents with different solubility.
(4) An aqueous solution of dilute acid washes away some of the basic impurities. For example, the reactants are basic and the products are neutral, the basic reactants can be washed away with dilute acid. For example, the acylation of amine compounds.
(5) An aqueous solution of dilute alkali removes part of the acidic impurities. If the reactants are acidic and the products are neutral, the acidic reactants can be washed away with dilute alkali. For example, esterification of carboxyl compounds.
(6) Wash away some of the water-soluble impurities with water. For example, for esterification of lower alcohols, the water-soluble reactant alcohols can be washed away with water.
(7) If the product is to be crystallised out of water and its solubility in aqueous solution is large, try adding inorganic salts such as sodium chloride and ammonium chloride to reduce the solubility of the product in aqueous solution – the method of salting out.
(8) Sometimes two insoluble organic solvents can be used as an extractant, for example, the reaction is carried out in chloroform, petroleum ether or n-hexane can be used as an extractant to remove some of the small polar impurities, and in turn can be used in chloroform extraction to remove the impurities of the polarity of the large.
(9) two mutually soluble solvents are sometimes added to another substance variable incompatibility, for example, in the case of water as a solvent, after the reaction is complete, can be added to the system of inorganic salts sodium chloride, potassium chloride so that water saturation, then add acetone, ethanol, acetonitrile and other solvents can be extracted from the water product.
(10) Methods of Crystallisation and Recrystallisation
The basic principle is to use the principle of similarity and compatibility. That is, polar compounds with polar solvent recrystallisation, polar compounds with non-polar solvent recrystallisation. For compounds that are more difficult to crystallise, such as oils, gels, etc., the method of mixed solvents is sometimes used, but the mixing of solvents is very knowledgeable, and sometimes can only be based on experience. General use of polar solvents and non-polar solvents with the principle of collocation is generally based on the polarity of the product and the size of the impurities to choose the ratio of polar solvents and non-polar solvents. If the polarity of the product is large, the impurity polarity is small, the proportion of polar solvents in the solvent is greater than the proportion of non-polar solvents; if the polarity of the product is small, the impurity polarity is large, the proportion of non-polar solvents in the solvent is greater than the proportion of polar solvents. The more commonly used combinations are: alcohol – petroleum ether, acetone – petroleum ether, alcohol – n-hexane, acetone – n-hexane and so on. However, if the product is very impure or impurities and the nature of the product and its similarity, to get the price of pure compounds is a number of recrystallisation, sometimes after a number of times can not be pure. In this case, the impurities that are generally more difficult to remove must be similar to the nature and polarity of the product. Removing impurities can only be considered from the reaction up.
Industrial crystallisation process development and equipment design points of analysis
(11) Water vapour distillation, reduced pressure distillation and distillation methods
This is a common method for purifying low melting point compounds. In general, the recovery rate of decompression distillation is correspondingly low, this is because with the continuous evaporation of the product, the concentration of the product is gradually reduced to ensure that the saturation vapour pressure of the product is equal to the external pressure, it is necessary to continuously raise the temperature to increase the saturation vapour pressure of the product, it is clear that the temperature can not be raised indefinitely, i.e. the saturation vapour pressure of the product can not be zero, that is to say, the product is not possible to steam the net, must be a certain amount of product left in the distillation Equipment within the equipment is difficult to volatile components dissolved, a large number of axe residue is proof.
Water vapour distillation for volatile low melting point machine compounds, there is close to quantitative recovery. This is because in the water distillation, axe all components plus water saturation vapour pressure and equal to the external pressure, due to the presence of a large number of water, its saturation vapour pressure at 100 ℃ has reached the external pressure, so in the 100 ℃ the following, the product can be with the water vapour all the vapour, the recovery rate is close to complete. Water vapour distillation is particularly suitable for systems with tar. Because the tar on the product recovery has two negative effects: one is affected by the equilibrium relationship, the tar can dissolve part of the product so that it can not be steamed out; the second is due to the high boiling point of tar so that the distillation of the axe temperature is too high so that the product continues to decompose. Water vapour distillation can be close to the quantitative recovery of products from tar, but also in the distillation process to avoid the overheating of the product polymerisation, the yield compared with the decompression distillation increased by about 3-4%. Although water distillation can improve the recovery of volatile components, however, water distillation is difficult to solve the problem of product purification, because the volatile impurities along with the product was steamed out, this time with the distillation method, not only to ensure the recovery of the product, but also to ensure the quality of the product. It should be noted that water vapour distillation is only a special case of azeotropic distillation, when other solvents can also be used. Azeotropic distillation is not only applicable to the product separation process, but also to the dehydration of the reaction system, the dehydration of the solvent, the dehydration of the product and so on. It has the advantages of simple equipment, easy operation and no consumption of other raw materials than molecular sieve and inorganic salt dehydration process. For example: in the production of aminohydroxamic acid, due to the presence of several polar groups in the molecule of amino, carboxyl, etc., they can form hydrogen bonds with water, alcohol and other molecules, so that aminohydroxamic acid in the presence of a large number of free and hydrogen-bonded water, such as the use of general drying methods, such as vacuum drying, not only time-consuming, but also prone to cause the decomposition of the product, which can be used in azeotropic distillation to remove the water molecules, the specific operation is to aminohydroxamic acid and methanol at the reflux stirring for a few hours, the product can be dehydrated. This is done by stirring aminohydroxamic acid with methanol under reflux for a few hours, which removes the water molecules and gives anhydrous aminohydroxamic acid. For example, when free or hydrogen-bonded methanol is present in the molecule, it can be removed by refluxing it with another solvent, such as hexane, petroleum ether, etc. It can be seen that azeotropic distillation occupies an important place in the separation process of organic synthesis.
(12) Supramolecular methods, the use of molecular recognition to purify the product.
(13) The method of decolourisation
Activated carbon, silica gel and alumina are generally used. Activated carbon adsorbs non-polar compounds and small molecules, silica gel and alumina adsorb polar and large molecules, such as tar. For polar impurities and non-polar impurities exist at the same time, the two should be combined at the same time. It is difficult to decolourise the material system, generally with silica gel and aluminium oxide can be removed. For the decolorization of acid and alkaline compounds, sometimes more difficult, when the acidic compounds with alkali neutralization to form ionic compounds and dissolved in water for decolorization, in addition to the weak alkaline conditions in the decolorization of a removal of alkaline impurities, but also should be gradual neutralization of the material system to the weakly acidic, and then decolorization of a removal of acidic impurities, so that the pigment can be completely removed. Similarly, when alkaline compounds are neutralised with acid to a weak base and dissolved in water for decolourisation, in addition to decolourising once under weakly acidic conditions to remove acidic impurities, the system should also be gradually neutralised to weakly alkaline, and then decolourised once to remove alkaline impurities.