How to choose a solvent efficiently for recrystallization

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I. Principles and experience in selecting solvents 1. Commonly used solvents: DMF, chlorobenzene, xylene, toluene, acetonitrile, ethanol, THF, chloroform, ethyl acetate, cyclohexane, butane, propane, petroleum ether. 2. Commonly used solvents: DMSO, hexamethylphosphamide, N-methylpyrrolidone, benzene, **, butane, **, dichlorobenzene, pyridine, acetic acid, dioxane, ethylene glycol monomethyl ether, 1,2-dichloroethane, diethyl ether, n-octane. 3. A good solvent has a high solubility for the substance to be crystallized near its boiling point, but very low solubility at lower temperatures. DMF, benzene, dioxane, and cyclohexane have very poor solvating capacity at low temperatures near their freezing points, making them ideal solvents. Acetonitrile, chlorobenzene, xylene, toluene, butane, and ethanol are also ideal solvents. 4. The boiling point of the solvent should ideally be 50°C lower than the melting point of the substance to be crystallized. Otherwise, solute liquefaction and stratification may occur. The higher the boiling point of a solvent, the stronger its solvating power at the time of boiling; for substances with high melting points, it is best to use solvents with high boiling points. 5. For substances containing hydroxyl and amino groups with a relatively low melting point, oxygen-containing solvents should be avoided as much as possible. Because it is difficult for the solute to precipitate after intermolecular hydrogen bonds are formed with the solvent. 6. For substances containing oxygen and nitrogen, alcohols should be avoided as solvents for the same reason as above. 7. The polarity of the solute and solvent should not differ too greatly. Water > Formic acid > Methanol > Acetic acid > Ethanol > Isopropanol > Acetonitrile > DMSO > DMF > Propanone > HMPA > CH2Cl2 > Pyridine > Chloroform > Chlorobenzene > THF > Dioxane > Diethyl ether > Benzene > Toluene > CCl4 > n-Octane > Cyclohexane > Petroleum ether. II. Recrystallization Procedure 1. Selecting the solvent: Add a small amount (the size of a wheat grain) of the substance to be crystallized into a test tube, then add 0.5 mL of the solvent selected according to the rules mentioned above. Heat it until it boils for a few minutes to check whether the solute has dissolved. If it dissolves, rinse the outside of the test tube with tap water to check if any crystals precipitate. Beginners often mistake insoluble impurities for the substance to be crystallized! If insoluble residues remain after prolonged heating, let the test tube stand for a while and cool it with cold water (do not shake it). If a substance precipitates in the upper clear solution, it indicates that more dissolution can still occur. If it is slightly turbid, it indicates that the solubility of the solvent is too low ； If there are no changes, it indicates that the insoluble solid is one type of substance, while the dissolved substances are highly soluble and do not easily precipitate. 2. Standard procedure: Add the solute and an appropriate amount of solvent to a conical flask or round-bottom flask, install a ball cooler, and heat for 10 minutes. If there are still insoluble residues, continue to add solvent through the top of the condenser until complete dissolution is achieved, then add an additional 30% excess of solvent. Filter while it is still hot into a conical flask using folded filter paper (the folded filter paper and the Erlenmeyer flask should be preheated first). After the filtrate has cooled naturally, it is filtered using a Büchner funnel (rinsing the conical flask with the filtrate in reverse!) ). If the solubility of the substance at room temperature is very low, the filter cake can be washed with a small amount of cold solvent (first remove the reduced pressure, add a small amount of solvent to wet the filter cake, and then remove the pressure to drain it). Note: Pressing the filter cake with a glass plug helps remove more solvent! ). If the solvent used is not volatile, a small amount of a volatile solvent can be added under normal pressure to wash the filter cake; for example, DMF can be washed with ethanol, while dichlorobenzene, chlorobenzene, xylene, and **can be washed with toluene. Beginners often encounter the problem of a large amount of crystals precipitating on the filter paper, due to poor preheating of the funnel and filter paper, insufficient solvent, or too long filtration time. If the product is valuable, a triangular funnel and filter paper can be placed on an Erlenmeyer flask and preheated with steam; while filtering, the filtrate that has already been filtered can be used to maintain heat. However, this method is relatively dangerous, and flammable solvents such as toluene, ethers, petroleum ether, and cyclohexane should be used with caution when employing this approach. Note: Washing the filter paper and all equipment with solute-adherent mother liquor using hot solution followed by cooling can reduce crystal loss. 3. Unconventional hot filtration: The suction filter flask cannot be preheated; the Büchner funnel and filter paper are placed on the conical flask containing the solute, and moistened by the rising vapor, after which hot filtration is carried out immediately on the suction filter flask. Be careful not to use too high a pumping pressure to prevent the mother liquor in the suction filter flask from boiling over! Common mistakes made by beginners: the filter paper is not pressed tightly enough (a double layer can be used), slow movements cause crystals to precipitate in the Büchner funnel, too high a suction pressure draws the filtrate into the pump, and failing to release pressure immediately after filtration results in a large amount of solvent being drawn into the pump. In short, it’s best to go against the principle of \"like dissolves like\"; highly polar substances should be crystallized using moderately polar solvents ； For low-polarity substances, use high-polarity solvents. In this way, more than half of the cases are suitable. 1. 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 (1) volatility ； (2) The property of the extended glass climbing upward to cause solid precipitation. If Bingtongru is not mixed with water, it should be dried. 2. Mixed solvent method: Dissolve with an excess of a good solvent at high temperature, filter, heat, then slowly add the poor solvent until turbidity occurs, and heat again until clarity is achieved. Wait quietly. . . 3. Use fractional crystallization. The accumulated mother liquor is passed through the column. 1) Pre-purification by column chromatography, followed by recrystallization after rough separation ； 2) Petroleum ether hot extraction-cold precipitation method ； 3) Choose a solvent with a low boiling point such as ether ； 4) Obtaining seeds: Use a glass rod to pick up a drop of the solution and let it evaporate. 5) Do not freeze easily; use a method that allows the solvent to evaporate naturally. Regarding crystallization with ether. A condenser should be added when refluxing diethyl ether. Keep adding ether from the top until the turbidity disappears; sometimes it is due to slow dissolution rather than an inability to dissolve, so patience is required. If a large amount of diethyl ether is added and a small amount of precipitate remains insoluble, it is filtered off. The filtrate is then concentrated until solids precipitate out, and heating is applied again with the addition of a small amount of diethyl ether to clarify the solution. Cooling naturally yields crystals with a better crystal form. Filter. Wash the crystals with a small amount of ether. The washing solution is combined with the mother liquor; a layer of filter paper is placed over the mouth of the bottle containing the mother liquor, or a wad of toilet paper is inserted there, so that ether can evaporate naturally without any dust getting in. Take a look every morning until a satisfactory number of crystals have formed; don’t be too greedy, as if they evaporate away you’ll have to start over :) I once used this method to successfully separate levorotatory and dextrorotatory alkaloids. . “The \"petroleum ether heating extraction-cooling method\" is also the approach I use to deal with oily substances: petroleum ether is added, the mixture is heated to boiling, and the upper layer is poured off; the oil remaining at the bottom is then subjected to further heating extraction with petroleum ether until the petroleum ether layer becomes colorless, indicating that the extraction is essentially complete. Crystals generally precipitate after cooling. Another reason for oil formation is too rapid cooling.