FIGURE 3-1. | femperature . Graph of solubility versus Technique 3 CRYSTALLIZATION: PURIFICATION OF SOLIDS Organic compounds that are solid at room temperature are usually puri- fied by crystallization. The general technique involves dissolving the material to be crystallized in a hot solvent (or solvent mixture) and cooling the solution slowly. The dissolved material has a decreased solubility at lower temperatures and will precipitate from the solution as it is cooled. This phenomenon is called crystallization if the crystal growth is relatively slow and selective, and precip- itation if the process is rapid and nonselective. Crystallization is an equilibrium process and produces very pure material. A small seed crystal is formed ini- tially, and it then grows layer by layer in a reversible manner. In a sense, the crystal “selects” the correct moiecules from the solution. In precipitation, the crystal lattice is formed so rapidly that impurities are trapped within the lattice. Therefore, in any attempt at purification, too rapid a process should be avoided, Too slow a process should also be avoided. The time scale for crystal formation should cover tens of minutes or hours, rather than seconds or days. The two principal mistakes that can be made are (1) cooling the solution too rapidly, and (2) suddenly adding an “incompatible” solvent to the solution. Both of these mistakes will be considered in this technique. 3.4 SOLUBILITY The first problem in performing a crystallization is selecting a solvent in which the material to be crystallized shows the desired solubility behavior. Ideally, the material should be sparingly soluble at room temperature and yet quite soluble at the boiling point of the solvent selected. The solubility curve should be steep, as can be seen in line A of Figure 3-1. A curve with a low slope (line B, Figure 3-1) would not cause significant crystallization when the tem- perature of the solution was lowered. A solvent in which the material was very soluble at all temperatures (line C, Figure 3-1) would not be a suitable crystalli- “f 7 4) C. (poor solvent) very soluble at all temperatures ‘A. (good solvent) —very soluble at elevated temperatures —sparingly soluble at room temperature grams soluble. —____— B. (poor solvent) temperature —————> a482 TECHNIQUE 3 zation solvent. The basic problem in performing a crystallization is to select a solvent (or mixed solvent) that will provide a steep solubility-versus-tempera- ture curve for the material to be crystallized; that is, a solvent that allows the behavior shown in line A is an ideal crystallization solvent. The solubility of organic compounds is a function of the polarities of both the solvent and the solute (dissolved material). A general rule states “Like dissolves like.” If the solute is very polar, a very polar solvent will be needed to dissolve it; if it is nonpolar, a nonpolar solvent will be needed. Usually com- pounds having functional groups that can form hydrogen bonds (for example, —OH, —NH, COOH, —CONH) will be more soluble in hydroxylic solvents such as water or methanol than in hydrocarbon solvents such as benzene or hexane. However, if the functional group is not a major part of the molecules, this solubility behavior may be reversed. For instance, dodecyl alcohol, CH,(CH,),oCH,OH, is almost insoluble in water; its twelve-carbon chain causes it to behave more like a hydrocarbon than an alcohol. The list found in Table 3-1 gives an approximate order for decreasing polarity of organic func- tional groups. The stability of the crystal lattice also affects solubility. Often, other things being equal, the higher the melting point (the more stable the crystal), the less soluble the compound, For instance, p-nitrobenzoic acid (mp 242 °C) is, by a factor of ten, less soluble in a fixed amount of ethanol than the ortho (mp 147°C) and meta (mp 141 °C) isomers. 3.2 THEORY OF CRYSTALLIZATION A successful crystallization depends on a large difference in the solubility ofa material in a hot solvent and its solubility in the same solvent cold. Natu- rally, when the impurities in a substance are equally soluble in both the hot and the cold solvent, an effective purification is not easily achieved through crystallization. A material can be purified by crystallization when both the desired substance and the impurity have similar solubilities, but only when the impurity represents a small fraction of the total solid. The desired substance will crystallize on cooling but the impurities will not. For example, consider a case in which the solubilities of substance A and its impurity B are both 1 g/100 mL of solvent at 20 °C and 10 g/100 mL of solvent at 100 °C. In an impure sample of A, the composition is given to be 9 g of A and 2 g of B for this particular example. At 20 °C this total amount of material will not dissolve. However, if the solvent is heated to 100 °C, all 11 g dissolve, since the solvent TABLE 3-1, SOLVENTS, IN DECREASING.ORDER Df OF POLARITY —E H,0 Water = _| RCOOH Organic acids (acetic acid) S@| RCONH, | Amides (¥,0-dimethyltormamide) S| ROH Alcohols (methanol, ethanol) Z| RNH, Amines (triethylamine, pyridine) | ZF] RCOR | Aldehydes, ketones (acetone) BE) RCOOR | Esters (ethyl acetate) Sa] ax Halides (CH,Cl, > CHCl, > CCl,) @<| ROR Ethers (diethyl ether) S ArH Aromatics (benzene, toluene) RH Aikanes (hexane, petroleum ether)CRYSTALLIZATION: PURIFICATION OF SOLIDS 483 4 cRYSTALS MOTHER LiQuoR Impure 9 gA + 2gB) [frst crystallization Purer (8 gA + 1gB) |, | (1 gA + 1 gB) lost | ssvona crystallization | 4g “Pure” (7gA) | ——>[_(1gA + 1gB) lost a FIGURE 3-2. Purtication of a mixture by crystallization has the capacity to dissolve 10 g of A and 10g of B at this temperature. If the solution is then cooled to 20 °C, only 1 g of each solute can remain dissolved, so 8g of A and 1 g of B crystallize, leaving 2 g of material in the solution. This crystallization is shown in Figure 3-2. The solution that remains after a crystal- lization is called the mother liquor. If the process is now repeated by treating the with 100 mL of fesh solvent, 7 g of A will crystallize again, leaving | g of A and 1g of B in the mother liquor. As a result of these operations, 7 g of pure A are obtained, but with the loss of 4 g of material. Again, this second crystallization step is illustrated in Figure 3-2. This result illustrates an impor- tant aspect of crystallization—it is wasteful. Nothing can be done to prevent this waste; some A must be lost along with the impurity B for the method to be successful. Of course, if the impurity B were more soluble than A in the solvent, the losses would be reduced. Losses could also be reduced if the impurity were present in much smaller amounts than the desired material. It should be noticed that for the above case the method operated success- fully because A was present in substantially larger quantity than its impurity B. If there_had_been 2.50/50 mixture of A and B initially, no separation would have been achieved. In general, a crystallization is successful only if there is a small amount of impurity. As the amount of impurity increases, the loss of material must also increase, Two substances with nearly equal solubility behav- ior, present in equal amounts, cannot be separated, If the solubility behavior of two components present in equa! amounts is different, however, a separation or purification is frequently possible. 3.3 SELECTING A SOLVENT A solvent that dissolves little of the material to be crystallized when it is cold but a great deal of the material when it is hot is a good solvent for the crystallization. But the realities of the matter are slightly more complicated than this statement would suggest. Frequently, one selects a solvent for crystallization by experimenting with various solvents and a very small amount of the material to be crystallized. Such experiments are conducted on a small test-tube scale before the entire quantity of material is committed with a particular solvent. Such trial-and-error methods are common when one is trying to purify a solid material that has not been extensively studied. With compounds that are well known, such as the compounds that are either isolated or prepared in this textbook, the correct crystallization solvent is already known through the experiments of earlier workers. In such cases, the484 TECHNIQUE 3 chemical literature can be consulted to determine which solvent should be used. Such sources as handbooks or tables may also provide this information. Quite often, the correct crystallization solvent is indicated in the experimental procedures in this textbook. | One note of caution is pertinent to choosing a crystallization solvent. Care should be taken not to pick one whose boiling point is higher than the melting point of the substance to be crystallized. If the boiling point of the solvent is too high, the solid may melt in the solvent rather than dissolve. In such a case, the solid may “oil out.” Oiling out occurs when the solid substance melts to form a | liquid that is not soluble in the solvent, On cooling, the liquid refuses to crystal- lize; rather, it becomes a supercooled liquid, or oil. Such an oil may be solidi- fied if the temperature is lowered sufficiently, but it will not crystallize. A solidified oil becomes an amorphous solid or a hardened mass—a condition that does not result in the purification of the substance. It is very difficult to deal with oils in the laboratory. One must try to redissolve them and hope that they | will precipitate as crystals with careful cooling. One additional criterion for selecting the correct crystallization solvent is the volatility of that solvent. A solvent with a low boiling point may be removed from the crystals through evaporation without much difficulty. It will be diffi cult to remove a solvent with a high boiling point from the crystals without heating them under vacuum. Table 3-2 lists common crystallization solvents. The solvents used most commonly are listed first in the table. 3.4 TECHNIQUE AND METHOD Dissolving the Solid. To minimize losses of material to the mother liquor. it is desirable to saturate the boiling solvent with solute. This solution, when cooled, will return the maximum possible amount of solute as crystals. To achieve this high return, bring the solvent to its boiling point, and dissolve the i solute in the MINIMUM AMOUNT(!) OF BOILING SOLVENT. For this | procedure it is advisable to maintain a container of boiling solvent. From this container, a small portion (a few milliliters) of the solvent is added to the flask TABLE 3-2. COMMON SOLVENTS FOR CRYSTALLIZATION BOILS | FREEZES | SOLUBLE (ec) cc) IN-H,0 | FLAMMABILITY Water 10 | 0 + - Methanol 65 2 + + 95% Ethanol 78 : +e | + Ligroin 60-90 : - + Benzenet 80 5 - of Chloroform+ 61 e - e Acetic acid 118 7 + + Dioxanet 101 1" + + Acetone 56 = + + Diethyl ether 35 bd Slightly ae Petroleum ether 30-60 2 - a Methylene chloride 4 I - E Carbon tetrachloridet 77 bi - = “Lower than 0 °C (ice temperature), + Suspect carcinogen,SS CRYSTALLIZATION: PURIFICATION OF SOLIDS 485 containing the solid to be crystallized, and this mixture is heated until it re- sumes boiling. If the solid has totally dissolved in this small portion of solvent, too much has been used and the solvent must be partially evaporated. If the solid has not dissolved in this portion of boiling solvent, then another small portion of boiling solvent is added to the flask. The mixture is heated again until it resumes boiling, If the solid has dissolved, no more solvent is added. But if the solid has not dissolved, another portion of boiling solvent is added, as before, and the process is repeated until the solid dissolves. It is important to stress that the portions of solvent added each time are small, so that only the minimum amount of solvent necessary for dissolving the solid is added. It is also important to stress that the procedure requires the addition of solvent to solid. One must never add portions of solid to a fixed quantity of boiling solvent. By this latter method it may be impossible to tell when saturation has been achieved. Occasionally, one encounters an impure solid that contains small particles of insoluble impurities, pieces of dust, or paper fibers that will not dissolve in the hot crystallizing solvent. A common error is to add too much of the hot solvent in an attempt to dissolve these small particles, without realizing that they are not soluble. In such cases, one must be careful not to add too much solvent. It is probably better to add too little solvent and not dissolve all the desired solid than to add too much solvent and lower the yield of solid returned as crystals, Once the solid has dissolved, decolorizing charcoal is added if it is required (see Section 3.5). Filtration, The hot solution is filtered if any insoluble matter remains or if charcoal has been used. A gravity filtration through a fluted filter paper is preferred for this step (see Technique 2, Section 2.1, p. 474). In some cases. especially if the solvent is low-boiling (boiling point lower than 50 °C). it may be advisable to add a small amount of extra solvent to the hot solution. This procedure ensures that crystals will not form in the filter paper during the gravity filtration. It will be necessary to remove this extra solvent by evapora- tion once the filtration is complete (the amount of extra solvent added should have been noted). For the gravity filtration, use a stemless funnel and heat it with boiling solvent before using it, Figure 3-3 illustrates some ways in which a funnel might be preheated. The funnel may be preheated by pouring hot sol- vent through it as it rests within a beaker. After this step. the funnel is fitted with a fluted filter as rapidly as possible and installed at the top of the Erlenmeyer flask to be used for the actual filtration. In this method, the solvent used to preheat the funnel is discarded. Alternatively, or in addition, the funnel and filter paper can be preheated by placing the assembly in the neck of the Erlen- meyer flask and resting the entite apparatus on top of a steam bath or hot plate. The material to be filtered is brought to its boiling point and poured into the filter. The solvent that first passes through the filter into the flask will begin to boil. The hot vapors will rise around the funnel and heat it. These preheating operations prevent the formation of crystals in the filter and also prevent the clogging of the filter that such crystallization would cause. During the filtration, the hot solution is poured through the filter in por- tions. It is necessary to keep the solutions in both flasks at their boiling tempera- tures to prevent premature crystallization. The refluxing action of the filtrate keeps the funnel warm and reduces the chance that the filter will clog with crystals that may have formed during the filtration. With low-boiling solvents,TECHNIQUE 3 S— bent paper clip reflux ring reflux ring FIGURE 3-3. Methods of preheating a funnel one must be aware that some solvent may be lost through evaporation. Conse- quently, extra solvent must be added to make up for this loss. It is advisable to | place a small piece of wire between the funnel and the mouth of the flask to relieve any buildup of pressure caused by the boiling solvent. This filtration procedure is illustrated in Figure 3-4, It should be stressed that if the solution is clear and colorless, if all the solid material has dissolved, or if decolorizing | charcoal was not used, this gravity filtration is not necessary. Finally, if any | extra solvent was added to prevent the formation of crystals in the filter, this, | extra solvent should be removed by evaporation before the crystals are allowed to form. If the crystals begin to crystallize in the filter during gravity filtration, a minimum amount of boiling solvent is added to redissolve the crystals and to allow the solution to pass through the funnel. After the filtration, the filtrate is | boiled until the extra amount of solvent required to redissolve crystals caught in ] the filter has evaporated. Once this extra amount of solvent has evaporated, the solution is set aside to cool until crystals are formed. | Crystallization. It is always a good idea to use an Erlenmeyer flask, not a beaker, for crystallization. The large open top of a beaker makes it an excellent dust catcher. The narrow opening of the Erlenmeyer flask reduces contamina- tion by dust and allows the flask to be stoppered if it is to be set aside for a long period. Mixtures set aside for long periods must be stoppered to prevent evap- oration of solvent. If all the solvent evaporates, no purification is achieved, and the crystals originally formed become coated with the dried contents of the mother liquor. __ If the cooled solution does not crystallize, several techniques may be used | to induce crystallization. First, one should try vigorous scratching of the inside surface of the flask with a glass rod that has not been fire-polished. The motion of the rod should be vertical (in and out of the solution) and should be vigorous enough to produce an audible scratching. Such scratching often induces crystal-CRYSTALLIZATION: PURIFICATION OF SOLIDS 487 Dissolve enstals Sy SL \, toca minima Step 2 Preheat the funnel with hot solvent Filter while still hot Keep the flask hot Set aside to cool FIGURE 3-4. Filtration and crystallizationaoe TECHNIQUE 3 lization, The effect is not well understood, although two explanations have been proposed. The high-frequency vibrations may have something to do with initi- ating crystallization; or perhaps—a more likely possibility—small amounts of solution dry by evaporation on the side of the flask, and the solute is pushed into the solution. These small amounts of material provide “seed crystals,” or nuclei, on which crystallization may begin. A second technique that can be used to induce crystallization is to cool the solution in an ice bath. This decreases the. solubility of the solute. A third technique is useful when small amounts of the original material to be crystal- lized are saved. The saved material can be used to “seed” the cooled solution. A small crystal dropped into the cooled flask often will start the crystallization— this is called seeding. Isolation of Crystals. The crystals are collected by vacuum filtration through a Buchner or a Hirsch funnel (see Technique 2, Section 2.3, p. 476, and Figure 2-4, p. 479). The crystals should be washed with a small amount of cold solvent to remove any mother liquor adhering to their surface. Hot or warm solvent will dissolve some of the crystals. The crystals should then be left for a short time in the funnel, where air as it passes will dry them free of solvent. It is often wise to cover the Biichner (or Hirsch) funnel with an oversize filter paper or towel during this air-drying. This prevents accumulation of dust in the crystals. 3.5 DECOLORIZATION Small amounts of highly colored impurities may make the original crystal- lization solution appear colored; this color can often be removed by decolori- zation, using activated charcoal (called Norit). As soon as the solute is dissolved in the minimum amount of boiling solvent, a small amount of Norit is added to the boiling mixture. The Norit adsorbs the impurities. A reasonable amount of Norit would be what could be held on the end of a small nickel spatula, or about 0.25 g (tsp). If too much Norit is used, it will adsorb product as well as impurities. A small amount of Norit should be used, and its use should be repeated if necessary. Caution should be exercised that the solution does not froth or erupt when the finely divided charcoal is added. The boiling mixture is filtered by gravity, using a fluted filter (see Technique 2, Section 2.1, p. 474 and Technique 3, Section 3.4, p. 484), and the crystallization is carried forward as | described in Section 3.4. The Norit is very finely divided and is removed most | effectively by gravity filtration through fluted filter paper. If a Buchner funnel is used to suction-filter the mixture, a layer of Celite should be used to trap the fine particles of charcoal (see Technique 2, Section 2.4, p. 478). Decolorizing | charcoal usually passes right through filter paper when suction is used. Filtra- | ion by suction through Celite is used only when the solute cannot precipitate or i iff excess solvent has been used. If excess solvent has been used, it is removed by evaporation after the filtration has been completed. The Norit preferentially | adsorbs the colored impurities and removes them from the solution. The tech- nique seems to be most effective with hydroxylic solvents In using Norit, one should be careful not to breathe the dust. Normally, such small quantities are used that little risk of lung irritation exists.CRYSTALLIZATION: PURIFICATION OF SOLIDS 408 3.6 DRYING CRYSTALS The most common method of drying crystals involves placing them in a watch glass or an evaporating dish and allowing them to dry in air. While the advantage of this method is that heat is not required, thus reducing the danger of decomposition or melting, exposure to atmospheric moisture may cause the hydration of strongly hygroscopic materials. A hygroscopic substance is one that absorbs moisture from the air. Another method of drying crystals is to place the crystals on a watch glass or on a piece of absorbent paper in an oven. Although this method is simple, some possible difficulties deserve mention. Crystals that sublime readily should not be dried in an oven, since they might pass into the vapor state and disap- pear. Care should be taken that the temiperature of the oven does not exceed the melting point of the crystals. One must remember that the melting point of crystals is lowered by the presence of solvent, and one must allow for this melting-point depression when selecting a suitable oven temperature. Some materials decompose on exposure to heat, and they should not be dried in an oven. Finally, when many different samples are being dried in the same oven, crystals might be lost due to confusion or reaction with another person's sam- ple. It is important to label the crystals when they are placed in the oven. A third method, which requires neither heat nor exposure to atmospheric moisture, is the use of a vacuum desiccator. In a desiccator, the sample is placed under vacuum in the presence of a drying agent. Two potential problems must be noted. The first deals with samples that sublime readily. Under vacuum, the likelihood of sublimation is increased. The second problem deals with the vacuum desiccator itself. Since the surface area of glass that is under vacuum is large, there is some danger that the desiccator could implode. A vacuum desic- cator should never be used unless it has been placed within a protective metal container (cage). 3.7 MIXED SOLVENTS Often the desired solubility characteristics for a particular compound are not found in a single solvent. In these cases a mixed solvent may be used. One simply selects a first solvent in which the solute is soluble and a second solvent, miscible with the first, in which the solute is relatively insoluble. The compound is dissolved in a minimum amount of the boiling solvent in which'it is soluble. Following this, the second hot solvent is added to the boiling mixture, dropwise, until the mixture barely becomes cloudy. The cloudiness indicates precipita tion. At this point>-more of the first solvent should be added. Just enough is TABLE 3-3. COMMON SOLVENT PAIRS FOR CRYSTALLIZATION se ee ere Methanol-Water Ether-Acetone Ethanol-Water Licdaciaieechitelh ether. ‘Acetic acid-Water Benzene*-Ligroin : ‘Acetone-Water Methylene chioride-Methanol... Ether-Methanol Dioxane*-Water as ne er * Suspect carcinogen.49. TECHNIQUE 3 added to clear the cloudy solution. At that point the solution is saturated, and as it is cooled, crystals should separate. Common solvent mixtures are listed in Table 3-3. Benzene-ligroin and methanol-water are the most common solvent mixtures. It is important not to add an excess of the second solvent or to cool the solution too rapidly. Either of these actions may cause the solute to oil out, or separate as a viscous liquid. If this happens, one should reheat the solution and add more of the first solvent ATEPS IN A CRYSTALLIZATION A. DISSOLVING 1, Find a solvent with a steep solubility-vs-temperature characteristic. (Done by trial and error, using small amounts of material, or by consulting a hand- book.) Heat the desired solvent to its boiling point. Dissolve the solid in a minimum of boiling solvent, ‘Add decolorizing charcoal it necessary. Filter the hot solution through a preheated funnel to remove insoluble im- purities or charcoal. If no decolorizing charcoal has been added or if there are no undissolved particles, this filtration may be omitted. Allow the solution to cool It crystals do not appear, go to part B: if crystals do appear, go to part C. B. INDUCING CRYSTALLIZATION Scratch the flask with a glass rod, or 2. Seed the solution, or 3. Cool the solution in an ice-water bath. ©. COLLECTING 1. Collect crystals by vacuum filtration, using a Buchner (or a Hirsch) funnel. 2. Rinse crystals with a small portion of cold solvent. 3. Continue suction until crystals are dry. D. DRYING ~ 1. Ait-dry the crystals, or 2. Place the crystals in a drying oven, or | 3. Dry the crystals in a vacuum desiccator. 1. Listed below are solubility-vs-temperature data for an organic substance A dissolved in water. TEMPERATURE SOLUBILITY OF A IN \ (Cc) 100 mL OF WATER | 0 1.59 20 3.0 40 65 60 11.0 80 170 (@) Graph the solubiti v i a pot gtr the solubility of Ave Lempersture. Use the dat given above, Connect the da (0) Suppose 0.5 g of A and water were mi eater “ subs SUPROE 05 g of A and S mL of water were mixed and heated to 80 “C. Would all theCRYSTALLIZATION: PURIFICATION OF SOLIDS 491 (6) The solution prepared in (b) is cooled. At what temperature will erystals of A appear? (d) Suppose the cooling described in (c) were continued to 0 °C. How many grams of A would come out of solution? Explain how you obtained your answer. 2, What would be likely to happen if @ hot saturated solution were filtered by vacuum filtration using a Buchner funnel? 3. (a) Draw a graph of a cooling curve (temperature vs time) for a solution of a solid substance that shows no supercooling effects. Assume that the solvent does not freeze. (b) Repeat the above instructions for a solution of a solid substance that shows some supercooling behavior but eventually yields crystals if the solution is cooled sufficiently. 4. A solid substance A is soluble in water to the extent of I g/100 mL of water at 25 °C and 10 g/100 mL of water at 100 °C. You have a sample that contains 10 g of A and an impurity B. (a) Assuming that 0.2 g of the impurity B is present along with 10 g of A, describe how you could purify A if B is completely insoluble in water. (b) Assuming that 0.2 g of the impurity B is present along with 10 g of A, describe how you could purify A if B had the same solubility behavior as A. Would one crystallization produce absolutely pure A? (©) Assume that 3 g of the impurity B is present along with 10 g of A. Describe how you could purify A if B had the same solubility behavior as A. Each time, use the correct amount of ‘water to just dissolve the solid. Would one crystallization produce absolutely pure A? How many crystallizations would be needed to produce pure A? How much A would have been recovered when the crystallizations had been completed?