Recrystallization

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Recrystallization is the process of dissolving a crystal in a solvent or melting it, and then allowing it to crystallize again from the solution or melt. Recrystallization can purify impure substances or separate salts that are mixed together. It is the result of physicochemical processes. Principle: The solubility of solid organic substances in a solvent is closely related to temperature. Generally, as temperature increases, solubility increases. If a solid is dissolved in a hot solvent until saturation is reached, upon cooling the solution becomes supersaturated due to the decreased solubility, and crystals precipitate out. By taking advantage of the different solubilities of the substance to be purified and impurities in the solvent, the substance to be purified can be precipitated from the supersaturated solution. This allows all or most of the impurities to remain in the solution (if their solubility in the solvent is very low, they are removed by filtration after forming a saturated solution), thereby achieving the purpose of purification. Conditions for selecting a solvent: 1. It should not react chemically with the substance to be purified; for example, aliphatic halogenated hydrocarbons are not suitable as solvents for the crystallization and recrystallization of basic compounds ； Alcohol compounds are not suitable as solvents for the crystallization and recrystallization of ester compounds, nor as solvents for the crystallization and recrystallization of amino acid hydrochlorides. 2. The solvent chosen should have a high solvating capacity for the chemical reagent to be purified at high temperatures, whereas its solvating capacity for that reagent decreases at lower temperatures. 3. The solubility of impurities is either very high or very low (in the former case, the impurities remain in the mother liquor and do not precipitate along with the crystals of the substance being purified) ； The latter case involves removing impurities during thermal filtration.) 4. The boiling point of the selected solvent should not be too high, so as to prevent it from adhering to the crystal surface during crystallization and recrystallization and remaining there difficult to remove. Common solvents used for crystallization and recrystallization include: water, methanol, ethanol, isopropanol, acetone, ethyl acetate, chloroform, glacial acetic acid, dioxane, carbon tetrachloride, benzene, petroleum ether, etc. In addition, toluene, nitromethane, ether, dimethylformamide, dimethyl sulfoxide, etc. are also commonly used. Dimethylformamide and dimethyl sulfoxide have high solvating power, and can be tried when no other suitable solvents are available. However, its disadvantages include the difficulty in precipitating crystals from the solvent, a relatively high boiling point, and the difficulty in removing the solvent adsorbed on the crystals. Although ether is a commonly used solvent, it is best to avoid using it when other suitable solvents are available, as it is highly flammable and explosive, posing significant risks during use; therefore, special caution is required ； On the other hand, since diethyl ether tends to evaporate by creeping along the walls, the chemical reagent to be purified deposits on the bottle walls, thereby affecting the purity of the crystals. For stronger solvents such as methanol and water, solvents with lower polarity should be tried first, such as propane, dioxane, benzene, and petroleum ether. The final selection of the suitable solvent can only be determined through testing. If it is not possible to select a single solvent for the crystallization and recrystallization of the chemical reagent to be purified, mixed solvents can be used. A mixed solvent is generally composed of two solvents that are miscible with each other in any proportion, one of which readily dissolves the chemical reagent to be purified, while the other has difficulty dissolving it. Commonly used mixed solvents include: ethanol and water, ethanol and ether, ethanol and propanol, ethanol and chloroform, dioxane and water, ether and petroleum ether, chloroform and petroleum ether, etc. The selection of the optimal composite solvent must be determined through preliminary tests. 5. It can produce high-quality crystals. 6. It is non-toxic or has very low toxicity, making it easy to use. Additionally, it is advisable to use a single solvent whenever possible; this also helps to address the issue of reusing mother liquor on a large scale, thereby reducing costs. In research, mixed solvents generally yield better results. Also, safety and low cost are factors to consider. After selecting the appropriate solvent, proceed with dissolution: Determine the amount of solvent required for the extract by using experimental results or solubility data. Place the extract crystals in a conical flask, add an amount of solvent that is slightly less than the required quantity, and heat the mixture until it just begins to boil. If the crystals do not dissolve completely, more solvent can be added; after each addition, the mixture must be heated again until the crystals are fully dissolved. It should be noted, however, that if no reduction in the amount of undissolved solid occurs after adding more solvent, this indicates the presence of insoluble impurities, and no further solvent should be added to avoid an excess of solvent. Precautions: 1. The amount of solvent depends on considering two factors simultaneously. A very low tolerance results in a high yield, but it may cause problems with thermal filtration and could lead to greater losses ； There is a great deal of tolerance, which obviously affects the recovery rate. Therefore, both should be considered comprehensively. Generally, about 20% more solvent is required than the standard amount needed (some believe that 20–100% more solvent is necessary). 2. The solid can be dissolved at the boiling point of the solvent, but it is necessary to pay attention to the actual operating temperature; otherwise, a large amount of crystals of the substance to be purified will precipitate during the actual operation. However, for purified substances that are not sensitive to the precipitation of certain crystals, it is possible to dissolve them in a saturated solution at the boiling point of the solvent; therefore, the decision depends on the specific circumstances and cannot be generalized. For example, in this experiment a saturated solution was prepared at 100°C, but the temperature for the hot filtration operation cannot be 100°C; it might be 80°C? Could it also be 90°C? Therefore, when considering how much solvent to add, the actual operating temperature for thermal filtration must also be taken into account. 3. To prevent solvent evaporation, fires caused by flammable solvents, or poisoning from toxic solvents, a reflux condenser should be installed on the conical flask, and solvents can be added through the upper end of the condenser. 4. If the solution contains colored impurities, activated carbon should be added for decolorization; special attention must be paid to the use of activated carbon. Filter while hot. 1. If it is a flammable solvent, prevent ignition or solvent evaporation. 2. Attention should be paid to the method of folding the filter paper and the key operating steps (including preheating the funnel, wetting the filter paper with hot water, etc.) ； The Büchner funnel should be washed thoroughly. Pay attention to details such as the size of the filter paper and its wetting. Initially, do not apply excessive vacuum, so as to prevent the filter paper from tearing (in hot solvents, the strength of the filter paper **decreases**). Crystallization: 1. Allow the filtrate to stand at room temperature or with heat retention to cool down slowly (if crystals have already formed in the filtrate, heat it to dissolve them), then let crystals precipitate and cool them thoroughly with cold water. If necessary, further cooling can be carried out using ice water or ice saline, etc. (depending on the specific circumstances; if the solvent used will form crystals in ice water or ice saline, this step cannot be employed). 2. Sometimes, the presence of tar-like substances or gelatinous materials in the filtrate makes it difficult for crystals to form; or sometimes, no crystals form due to the creation of a supersaturated solution. In such cases, rubbing the wall of the container with a glass rod can create a rough surface, which allows the solute molecules to arrange themselves in an orderly manner, thereby facilitating crystal formation more quickly and easily than on a smooth surface ； Alternatively, seed crystals can be added (crystals of the same substance; if no such crystals are available, a glass rod dipped in the solution and allowed to dry slightly will result in crystal formation), providing nuclei that facilitate the rapid growth of crystals. Timing of seed addition: If seeds are added too early, the seeds dissolve or the crystal form formed is generally finer ； If added too late, crystal nuclei may have already formed in the solution, causing the crystals to potentially encapsulate impurities. 3. Sometimes, the purified compound precipitates as an oil; although this oil can solidify after being left to stand for a long time or after sufficient cooling, such solids often contain more impurities (impurities generally have a higher solubility in oil than in solvents) ； Secondly, the precipitated solid also contains some mother liquor; thus, its purity is not high. Diluting with a large amount of solvent can prevent the formation of an oily substance, but it will result in significant loss of the product. At this point, the solution in which the oily substance has precipitated can be reheated to dissolve it, and then slowly cooled. Once the oily substance precipitates, the mixture is stirred vigorously to ensure that the oily substance solidifies in a uniformly dispersed state; however, it is better to choose a different solvent in order to obtain a crystalline product. Procedure for suction filtration/depressurization filtration: Cut a filter paper that meets the specifications and place it in the funnel → Moisten the filter paper with a small amount of solvent → Turn on the water pump and close the stopcock on the safety flask to secure the filter paper in place → Open the stopcock on the safety flask, then turn off the water pump → Using a glass rod, add the substance to be separated into the funnel in batches; also use a little of the filtrate to wash any crystals adhering to the container into the funnel → Once again, turn on the water pump and close the stopcock on the safety flask to carry out depressurization filtration until no droplets remain at the neck of the funnel → Open the stopcock on the safety flask, then turn off the water pump → Moisten the crystals with a small amount of solvent → Finally, turn on the water pump once more and close the stopcock on the safety flask to perform depressurization filtration until no droplets are seen at the funnel’s neck (if necessary, a glass stopper can be used to compress the crystals; this step is usually performed 1–2 times). If the recrystallization solvent has a relatively high boiling point, after washing at least once with the original solvent, it can be washed with a solvent having a lower boiling point, thereby facilitating the drying of the final crystalline product (it should be noted that this solvent must be miscible with the first solvent, while being immiscible or only slightly soluble with respect to the crystals). If the mother liquor obtained by suction filtration is useful, it can be transferred to another container for the recovery of solvents and products of lower purity. Drying and purity determination of crystals: Before determining the melting point, the crystals must be thoroughly dried; otherwise, the measured melting point will be lower than it actually is. There are many methods for drying solids; the choice depends on the solvent used for recrystallization and the properties of the crystals. 1. Air drying (drying low-melting substances that do not absorb moisture in air is the simplest method of drying). 2. Drying (Substances that are stable to air and temperature can be dried in an oven; the oven temperature should be 20–50°C lower than the melting point of the substance being dried.) 3. Absorb the excess liquid with filter paper (this method can easily contaminate the solid material with filter paper fibers). 4. Place it in a desiccator to dry. The purity of the crystals is determined using standard conventional methods. However, for certain products, experience can be used when a large number of samples have been processed; for example, after multiple recrystallizations of a sample, if the expected crystal form is observed, and based on previous test results, the purity can be determined with high accuracy. In cases of uncertainty, HPLC can be used for measurement. Method for determining crystalline purity: uniform physicochemical properties ； Melting distance of solid compounds ≤ 2℃ ； A single spot is observed on TLC or PC development ； HPLC or GC analysis shows a single peak. Summary of recrystallization experience: The crystallization process involves the orderly placement of ions, atoms, or molecules in a solid state, from gas, liquid, or solution phases. The initial stage is the formation of nuclei, followed by deposition on the crystal surfaces; this latter process can be considered as a dynamic equilibrium between the fluid and the crystal. Growth occurs when the forward velocity becomes dominant. Factors that affect this equilibrium include the chemical properties of the crystal surface, the concentration of the substance being crystallized, and the properties of the medium inside and around the crystal. Crystal formation occurs after the appearance of a nucleus of critical size, at which point the free energy changes from positive to negative. The nucleation rate increases significantly with supersaturation; to limit the number of nuclei, the supersaturation level should be kept as low as possible. The supersaturation should be increased gradually, and once such a low level of supersaturation is reached, careful control is necessary to allow a few nuclei to grow slowly in a quasi-equilibrium state. During the nucleation process, external particles such as dust particles make the process more thermodynamically favorable; therefore, these particles must be removed in advance through centrifugation or filtration. The seed addition method is also often a way to control the number of nuclei. The selection of solvent (single or mixed), crystallization temperature, stirring speed, stirring method, selection of supersaturation, crystal growth time, method and rate of adding the solvent, and so on. Additionally, during the processes of dissolution, crystallization, and crystal growth, the aforementioned temperature, stirring speed, time duration, and addition method and rate vary as well. So with all these factors coming together, it seems even more difficult. Generally speaking, the main conditions should be selected first to enable the crystallization process to proceed and produce crystals, after which those conditions can be optimized. Pilot testing and production can only proceed once the conditions are met. . Crystallization and recrystallization involve the following main steps: 1. Dissolve the chemical reagent to be purified in a suitable solvent that is boiling or about to boil ； 2. Filter the hot solution while it is still hot to remove insoluble impurities ； 3. Cool the filtrate to allow crystals to precipitate ； 4. Filter out the crystals, and wash them with an appropriate solvent if necessary. When performing the operation, pay attention to the following points: 1. When dissolving pre-purified chemical reagents, it is necessary to strictly follow the laboratory safety procedures. When heating flammable and explosive solvents, the operation should be carried out in an environment free from open flames, and direct heating should be avoided. Since, under normal circumstances, the solubility curve rises steeply near the boiling point of the solvent, the solvent should be heated to its boiling point during crystallization and recrystallization. To achieve high yields in crystallization and recrystallization while using as little solvent as possible, the initial amount of solvent added is not sufficient to dissolve all of the chemical reagent to be purified; during heating, solvent can be added gradually until all of the solid material is dissolved at boiling point. When adding a solvent, it is important to note that if the solution is cooled below its boiling point, the anti-boiling zeolite loses its effectiveness, and new zeolite needs to be added. 2. To quantitatively evaluate the crystallization and recrystallization processes and to facilitate repetition, both the solid and the solvent should be weighed and measured. 3. When using mixed solvents for crystallization and recrystallization, it is best to dissolve the chemical reagent to be purified in a small amount of a solvent with higher solubility, and then slowly add, while the mixture is still hot, small amounts of a second solvent with lower solubility, until precipitation forms where it comes into contact with the solution, only to dissolve again shortly thereafter. If the total volume of the solution is too small, more solvent with high solubility can be added, and then the above steps can be repeated. Sometimes the reverse procedure can also be used: suspend the chemical reagent to be purified in a solvent with low solubility, gradually add a solvent with high solubility until it dissolves, and then add a small amount of the solvent with low solubility to cool it down. 4. If necessary, after the chemical reagent to be purified is dissolved, activated carbon can be added for decolorization (the amount used is approximately 1/50 to 1/20 of the weight of the substance to be purified), or filter paper pulp, diatomaceous earth, etc. can be added to clarify the solution. The solvent should be cooled slightly before adding the decolorizing agent, as the added decolorizing agent may trigger boiling that was previously suppressed, resulting in intense and explosive boiling. Activated carbon contains a large amount of air, which allows it to produce foam. After adding activated carbon, it can be boiled for 5–10 minutes, and then the activated carbon is removed by vacuum filtration while it is still hot. In non-polar solvents such as benzene and petroleum ether, activated carbon does not provide an effective decolorization effect; other methods can be tried, such as adsorption decolorization using alumina. 5. When the chemical reagent to be purified is an organic reagent, there is a strong tendency to form a supersaturated solution; to avoid this phenomenon, seeds of the same reagent or of a polymorph can be added. Frictioning the wall with a glass rod can also create nuclei, after which the crystals grow along these nuclei. 6. The crystallization rate can sometimes be very slow; it may take several hours for the crystallization of a cold solution to be complete. In some cases, crystals continue to precipitate weeks or months later, so the mother liquor should not be discarded too early. 7. To reduce the solubility of the reagent to be purified in the solution, thereby promoting more crystallization and increasing the yield, the solution is often frozen. It can be placed in the refrigerator or cooled with ice or a mixed refrigerant. 8. The prepared hot solution must be filtered to remove insoluble impurities, and it is necessary to prevent crystallization on the filter during suction filtration. If all procedures are followed properly and crystallization of the reagent occurs too easily, thereby hindering filtration by vacuum, the solution can be prepared to be slightly more dilute, or filtration can be carried out using a temperature-controlled or heating filtration device (such as a thermosiphon funnel). 9. To effectively separate the precipitated crystals from the mother liquor, suction filtration using a Büchner funnel is generally used. To better separate the crystals from the mother liquor, it is best to use a clean glass stopper to compress the crystals in a Büchner funnel and remove as much of the mother liquor as possible by suction. The mother liquor on the crystal surface can be washed using as little solvent as possible. It is necessary to temporarily stop suction, use a glass rod or stainless steel knife to loosen the compressed crystals, add a small amount of solvent to moisten them, wait for a moment so that the crystals are evenly saturated, and then remove the solvent. This process should be repeated one or two times until all the mother liquor adhering to the saturated surface has been removed. 10. If the crystal does not decompose when heated, it can be dried by heating it in an oven. If the crystal decomposes easily when heated, care should be taken to keep the temperature of the oven from being too high, or it can be dried at room temperature in a vacuum dryer. When recrystallizing with a solvent of high boiling point, it is necessary to wash with a solvent of low boiling point and very low solubility for the crystals in order to facilitate drying. For hygroscopic crystals, the oven should first be heated to a certain temperature, and then the crystals should be placed inside it ； However, crystals that are highly deliquescent often cannot be dried in an oven; they must be quickly placed in a vacuum dryer for drying. Crystals recrystallized from flammable organic solvents should be dried in air beforehand before being placed in an oven; otherwise, it may cause the solvent to burn or explode. 11. Recrystallization of small and trace amounts of substances: The basic requirements for the crystallization or recrystallization of small amounts of substances are the same as those mentioned earlier, but small containers suitable for the amount of that substance are used. The crystallization and recrystallization of trace substances can be carried out in small centrifuge tubes. Immediately after preparation with a hot solution, centrifugation is carried out to allow the insoluble impurities to settle at the bottom of the tube. The upper clear liquid is then transferred using a pipette to another small centrifuge tube, where it is allowed to crystallize. After crystallization, the crystals are separated from the mother liquor by centrifugation. The crystals can also be washed in a centrifuge tube using a small amount of solvent, and the solvent can be separated from the crystals through centrifugation. 12. The mother liquor often contains a certain amount of the desired substance, so it is important to recover it. If part of the solvent is removed and then the mixture is cooled to allow crystallization to occur, the purity of the crystals obtained is usually lower than that of the crystals formed in the first instance. If the purity check does not meet the requirements, crystallization using fresh solvent can be carried out until the purity requirements are satisfied. Recrystallization issues and cases 1. What are the general steps involved in the recrystallization method? What is the main purpose of each step? Answer: Generally, it includes: (1) selecting an appropriate solvent to prepare a hot saturated solution. (2) Thermal filtration to remove insoluble impurities (including decolorization). (3) Filter by suction, cool for crystallization, and remove the mother liquor. (4) Wash and dry to remove the attached mother liquor and solvent. 2. Why cannot the amount of solvent used during recrystallization be too large or too small? What should be the correct approach? Answer: The amount is too excessive, preventing the formation of a thermally saturated solution; as it cools, no crystals are formed or only very few crystals form. Too little; some of the substance that is supposed to crystallize does not dissolve when heated, and remains on the filter paper along with the insoluble impurities during hot filtration, resulting in losses. Considering that during thermal filtration some solvent is evaporated and lost, causing some crystals to remain on the filter paper or in the funnel neck and resulting in crystal loss, it is appropriate to add about 20% more after preparing a hot saturated solution. 3. Why is it necessary to wait until the solid substances are completely dissolved before adding activated carbon for decolorization? Why can’t it be added while the solution is boiling? Answer: Activated carbon can adsorb colored impurities, resinous substances, and evenly dispersed materials. Although colored impurities can dissolve in a boiling solvent, when the solution is cooled and crystals precipitate, some of the impurities are adsorbed by the crystals, resulting in a colored product. Therefore, when using activated carbon for decolorization, it should be added only after the solid substances have completely dissolved, and then boiled for 5–10 minutes. Note that activated carbon must not be added to a boiling solution, to prevent the solution from boiling over and spilling out of the container. 4. When recrystallizing using organic solvents, which operations are prone to catching fire? How can it be avoided? Answer: Organic solvents are often either flammable or toxic, or both. When handling them, all open flames in the vicinity must be extinguished, and it is best to work in a fume hood. Erlenmeyer flasks or round-bottom flasks are commonly used as containers, as they have narrow mouths, which prevent the solvent from evaporating easily, and they also facilitate shaking to help dissolve solid substances. If the solvent used is flammable with a low boiling point, it is strictly prohibited to heat it directly on an asbestos mesh; a reflux condenser must be installed. A heat bath should be chosen depending on the boiling point of the solvent. If the solid substance dissolves in the solvent slowly and requires a long time, a reflux condenser is also necessary to prevent loss of the solvent. 5. Recrystallize acetanilide using water; does any oily substance appear during the dissolution process? What is this? Answer: Oil-like substances may appear during the dissolution process; these are not impurities. The melting point of acetanilide is 114°C, but when it is recrystallized from water, it usually melts into a liquid at 83°C. At this point, acetanilide is dissolved in the water layer, while the melted acetanilide layer contains water; therefore, the oily substance represents acetanilide that has melted but remains insoluble in water. Thus, more solvent should be added until complete dissolution is achieved. 6. What are the disadvantages when using a Büchner funnel for filtration if the filter paper is larger than the surface of the funnel’s porcelain pores? Answer: If the filter paper is larger than the surface of the funnel’s porcelain pores, the edges of the filter paper will fold. As a result, during vacuum filtration, the filtrate will be drawn into the bottle along the edges of the filter paper, leading to a loss of crystals. So it can’t be large; it just needs to cover the porcelain hole. 7. Before stopping the vacuum filtration, what problems may occur if the water valve (pump) is closed without first removing the rubber tube? Answer: If the water pump is turned off without first removing the rubber tube, water will flow back into the suction filter flask; if what is needed is the filtrate, that will cause serious problems. 8. When recrystallizing a certain organic compound, what properties should the most suitable solvent possess? Answer: (1) It does not undergo a chemical reaction with the organic compound being purified. (2) The organic substance to be purified should be thermally soluble but insoluble in cold. (3) The impurities and the substance to be purified should be one that is thermally soluble and the other that is thermally insoluble. (4) The organic compound to be purified should be able to form relatively well-ordered crystals within it. (5) The boiling point of the solvent should not be too low (as it is prone to damage), nor too high (as it is difficult to remove). (6) Low cost, readily available, and non-toxic. 9. Why is it necessary to minimize the evaporation of the solvent as much as possible when thermally filtering the solution? How to reduce its volatilization? Answer: If too much solvent evaporates, some of the crystals will precipitate during hot filtration and remain on the filter paper and in the funnel neck, resulting in losses. When organic solvents are used, excessive evaporation leads to waste and also environmental pollution. To this end, a watch glass (with the concave side facing down) should be placed over the funnel during filtration to reduce solvent evaporation. The container for holding the solution is usually a conical flask (except for aqueous solutions), which can also reduce the evaporation of the solvent. 10. What should be noted when washing solids with a solvent in a Büchner funnel? Answer: Wash with the same solvent used for recrystallization, using as little amount as possible to minimize dissolution losses. If the melting point of the recrystallization solvent is high, after washing at least once with the original solvent. It can be washed with a low-boiling-point solvent to make the final crystalline product easy to dry; note that this solvent must be miscible with the first solvent but insoluble or slightly soluble in the crystals. I have been working on a reaction recently in which the solvent contains a certain amount of pyridine. For the post-treatment step, the solvent is evaporated and then a low-polarity solvent is added for recrystallization, but pyridine is difficult to evaporate, which affects the formation of the crystals. Is there anyone who can come up with a good method? Answer: If the solvent is immiscible with water, you can consider washing it first with water to remove most of the pyridine, and then evaporating the solvent ； If your solvent is miscible with water but the product is not soluble in water, you can consider evaporating the solvent to a certain extent and then adding it to water; this will cause the product to precipitate as a solid, thereby removing most of the pyridine. My product is yellow and viscous; after vacuum distillation, it remains stuck to the flask, and I’m not sure whether it has dissolved or not during each recrystallization process, so the crystals don’t form! Does anyone have any good suggestions? (The product is a quaternary ammonium salt.) Answer: I don’t know what the structure is like I have synthesized some heterocyclic quaternary ammonium compound; I think you can dissolve them in acetonitrile, and then add solvents with lower polarity such as ethyl acetate or propylene to precipitate the product. The method worked very well for me, and I hope it will be helpful to you as well. 13. The product of my initial reaction was a viscous solid; after discarding the reaction mixture, recrystallization with propane yielded excellent crystals. So I carried out another reaction with a structurally similar compound but a different substituent; the product was an oily substance. Again, after discarding the reaction mixture, recrystallization from propane was attempted, but no solid formed ； Recrystallization with ethanol yields only an oily substance ； So a mixture of propanol and ethanol was tried, with the result being either sticky solids precipitating or no solids at all. I wonder if anyone has any good tips for the recrystallization of oily substances? The compound I want has very low polarity; generally, petroleum ether/ethyl acetate (10:1) is sufficient for separating it. Answer: Dissolve the oily substance in an appropriate amount of solvent, and cool it using liquid nitrogen and ethanol (a temperature of 50 to 60 degrees is sufficient). When it becomes cloudy, check whether there are any fine particles present. If there aren’t any, continue cooling slowly without rushing, as this will prevent the substance from turning back into oil all at once. If fine particles are present, let the mixture stand at room temperature; over time these particles will gather together and gradually crystallize. It’s better to have seeds; if there are fine particles present, adding seeds will result in crystallization occurring quite quickly at room temperature! The method of hot extraction with petroleum ether should work. Dissolve it in ether; once it has been concentrated to about the right degree, leave it to evaporate naturally until it dries out, and good crystals will be obtained. There are many methods that can work; trying this approach can make crystallization easier, but the problem is that the crystal form is not good and the crystals tend to contain impurities. Your compound has low polarity, so ethanol, methanol, and propanol are all excellent crystallization solvents. If the product itself is a solid (as stated in the literature), and you find that the product remains relatively pure when measured using slab or solution methods, then ethanol crystallization should work. When crystallization cooling occurs and the crystal solution becomes cloudy, seed crystals can be added (obtainable by column filtration), which allows for rapid crystal precipitation ； Alternatively, let the oily substance and ethanol be stirred in an ice bath overnight; there might be a surprising discovery the next day. The crystallization of oils is complex, and there is no universal method. (1) Usually, the formation of oily substances is caused by poor control of the reaction; therefore, it is necessary to first check whether the reaction conditions are suitable. (2) Oily substances typically require rough purification and recrystallization steps, such as decolorization using activated carbon, extraction of most high-boiling-point substances with insoluble organic solvents, and complete removal of water. (3) Selecting an appropriate adsorption resin for adsorption and purification, followed by elution and crystallization, is the most effective method for crystallizing oily substances. (4) The choice of solvent is largely arbitrary; however, for products with very low polarity, crystallization using n-hexane and moderately polar solvents often yields unexpected results. 14. My product is a carboxylic acid. It has poor solubility in common solvents such as methanol, ethanol, and acetone; however, it dissolves well in DMF. Only a small amount of it dissolves in water, and it deteriorates in water (possibly polymerizes). The impurities are highly polar substances (when subjected to TLC using a CHCl3/CH3OH mixture at a ratio of 2:1, the impurities remain at the origin). How can these impurities be removed without using column chromatography? ? Answer: The carboxylic acid is salted, impurities are removed using an organic solvent, and then the pH is adjusted to acidic. (The classic \"acid-base inversion\" method.) 15. My product has a relatively low melting point; the bromine in the triazolobenzene ring gives it low polarity, and it is almost insoluble in water. I have tried various recrystallization methods, such as using a single solvent or multiple solvents, but what results are obtained are oils only. Could anyone with expertise help me? Answer: After dissolving the smallest amount of petroleum ether at room temperature, freeze it in the refrigerator or using dry ice. Ethanol dissolves minimally at room temperature; add a little water to ensure no oil-like substance precipitates (if it does, add a bit more ethanol to redissolve it). Then freeze it in a refrigerator or in dry ice. One of my previous samples had a melting point of 25 degrees, was soluble in petroleum ether, and it was in this way that the crystals formed. Image 16. Experts, have you ever done the recrystallization of potassium salts? For example, what solvent is better to use? I would like to carry out the recrystallization of LOSANTAN potassium salts. I have tried many solvents, but without success. Organic potassium salts generally have good water solubility, yet they have very poor solubility in most organic solvents Crystallization using a single solvent is very difficult; a small amount of potassium salt products can be recrystallized using methanol. Mixed solvents are a good choice for potassium salts – water is commonly used as one phase, while methanol, ethanol, isopropanol, or propanol make reasonable choices for the other phase. Acetonitrile can sometimes be used, but it tends to cause separation, so it can only be employed for crystallization on a large scale. 17. In organic experiments, it is often necessary to purify the products or reagents. But going through the column is too troublesome, so I often slack off and use recrystallization instead? Answer: (1) Just avoid what goes against the principle of \"like dissolves like\"; for highly polar substances, use moderately polar solvents for crystallization ； For low-polarity substances, use high-polarity solvents. In this way, more than half of the cases are suitable. (2) Try first: petroleum ether (n-hexane), diethyl ether, ethyl acetate, ethanol, water; then try: propane, methanol, acetonitrile, benzene, chloroform, acetic acid, pyridine, etc. If that still doesn’t work, then mixing is the only option. Diethyl ether can be utilized due to its volatility ； The property of the extended glass to climb upward and cause solid precipitation. If Bingtongru is not mixed with water, it should be dried. (3) Mixed solvent method: Dissolve with an excess of a good solvent at high temperature, filter, heat, slowly add the poor solvent until turbidity appears, and then heat again to achieve clarity. Wait quietly. . . (4) Using fractional crystallization.