Recrystallization,

Recrystallization involves allowing a hot solution of the required compound to cool. Crystallization implies allowing the solvent to evaporate from a solution of the compound. Crystallization will not remove solvent-soluble impurities since they will be deposited as the solvent evaporates. 

Limits of purification - crude solids containing only up to 10-15% impurities can be purified by recrystallization. Otherwise chemical purification or chromatography (p, 217) will be required to produce a compound, which can then be further purified by recrystallization. 

Practice in the technique of recrystallization is important, since the aim of the procedure is to produce the maximum quantity of the highest quality product. Poor technique often results in low recovery of high-quality product or high recovery of low-quality product. 

The products from many synthetic preparations are seldom pure and the technique of recrystallization, which involves dissolving the impure material in a hot solvent and then cooling the solution to produce crystals, is routinely used to purify covalent organic and inorganic solids. 

In general there are three types of impurities, which are removed by the recrystallization process  

Recrystallization is a purification step involving the dissolution and crystallization of a solid from a solvent or solvent mixture. 

After synthesis and chromatographic separation of a solid compound, recrystallization is usually used as the final purification step. Suppose you wish to separate a compound A from minor impurities. First, it is necessary to find a solvent in which A is insoluble at low temperatures, but is very soluble at higher temperatures. Typically, polar or ionic compounds are soluble in polar solvents (e.g. water, acetonitrile, dichloromethane, methanol), while non-polar compounds are soluble in non-polar solvents (e.g. hexanes, toluene). The impurities may also be soluble in the same solvent or solvent mixture but, ideally, a solvent is found in which the impurities are insoluble. For the latter case, after preliminary tests to find a suitable solvent, the solvent is added to crude A and the mixture is heated. The insoluble impurities are removed by filtering the hot solution, and the filtrate is allowed to cool either at or below room temperature. As the solution cools, the solubility of A decreases and, once the solution has become saturated, A begins to crystallize from the solution. If crystallization is relatively rapid, microcrystals form. If both A and the impurities are soluble in the same solvent, the crude sample is dissolved in boiling solvent and the solution is allowed to cool slowly. Crystal growth involves the assembly of an ordered crystal lattice (Fig. 4.5 and see Chapter 6) and the aim is to exclude impurities from the lattice. 

The essence of a recrystallization is a purification. Messy, dirty, compounds are cleaned up, purified, and can then hold their heads up in public again. The sequence of events you use will depend a lot on how messy your crude product is, and just how soluble it will be in various solvents. 

Find a solvent that will dissolve the solid while hot. 

The same solvent should not dissolve it while cold. 

The cold solvent must keep impurities dissolved in it forever or longer. 

This is the major problem. And it requires some experimentation. That s right Once again, art over science. Usually, you ll know what you should have prepared, so the task is easier. It requires a trip to your notebook, and possible, a handbook (see Chapter 2, Keeping a Notebook and Chapter 3, Interpreting a Handbook ). You have the data on the solubility of the compound in your notebook. What s that you say You don t have the data in your notebook Congratulations, you get the highest F in the course. 

The most widespread purification techniques are recrystallization and sublimation for solids, filtration and distillation for liquids, and the separation of the impurities hy ahsorhing them by various chemical reagents for gases. 

Purification of Potassium Dichromate . Using the table of solubilities (see Appendix 1, Table 1), calculate the amount of potassium dichromate that has to be taken to obtain a saturated solution in 50 ml of water at 60 °C. 

Weigh the calculated amount of potassium dichromate on a technical chemical balance and triturate it in a mortar. Pour the powdered salt into a chemical beaker, and add 50 ml of water. Place the beaker on an asbestos gauze and heat with the flame of a gas burner almost to boiling while mixing the solution with a glass rod. Why is the solution heated almost to boiling and only then filtered  

To separate the insoluble impurities, filter the hot solution through a fluted filter into another beaker, using a funnel for hot filtration. While continuously stirring, cool the filtrate to room temperature, and then in a bath with ice to 0 C. 

Why does the intensity of the solution s colour change Filter off the precipitated crystals through a Buchner funnel. What is contained in the mother solution  

Insoluble material anti-bumping granules, pieces of filter paper, traces of drying agents, grit, hair and other materials which may have been present in the starting chemicals. 

Small quantities of unreacted starting chemicals and/or by-products from side reactions or other isomers. 

Very small amounts of coloured by-products resulting from oxidation or polymerization of the chemicals used. 

Organic chemists devote considerable effort to isolating pure products, the ultimate goal being to obtain a substance that cannot be further purified by any known experimental techniques. This chapter focuses on the purification of solids by recrystallization and their characterization by the physical property of melting points. 

Recrystallization of solids is a valuable technique to master, because it is one of the most common methods used to purify solids. Other techniques for purifying solids include sublimation (Sec. 2.20), extraction (Chap. 5), and chromatography (Chap. 6). Nevertheless, even when one of these alternative methods of purification has been used, the solid material thus isolated may still be recrystallized to achieve a higher state of purity. 

Almost all solids are more soluble in a hot than in a cold solvent, and solution crystallization takes advantage of this fact. Thus, if you first dissolve a solid in an amount of hot solvent insufficient to dissolve it when cold, crystals should form when the hot solution is allowed to cool. The extent to which the solid precipitates depends on the difference in its solubility in the particular solvent at temperatures between the extremes used. The upper extreme is determined by the boiling point of the solvent, whereas the lower limit is usually dictated by experimental convenience. For example, an ice-water bath is often used to cool the solution to 0 °C, whereas ice-salt and dry ice-acetone baths are commonly used to cool solutions to -20 °C and -78 °C, respectively (Sec. 2.10). The solid should be recovered with greater efficiency at these temperatures, provided the solvent itself does not freeze. 

If the impurities present in the original solid mixture have dissolved and remain dissolved after the solution is cooled, isolation of the crystals that have formed should ideally provide pure material. Alternatively, the impurities may not dissolve at all in the hot solution and may be removed by filtration before the solution is cooled. The crystals that subsequently form should be purer than the original solid mixture. Solution recrystallization is seldom quite so simple in practice, but these two idealized generalizations do outline the basic principles of the technique. 

Even after a solid has been recrystallized, it may still not be pure. Thus, it is important to determine the purity of the sample, and one of the easiest methods to do this is by determining the melting point of the solid. This technique is described in Section 3.3. 

Of the three goals, the first two are standard to any purification and are covered in this subsection. The last goal is perhaps less obvious but provides the foundation for later subsections. 

Almost any solvent is possible for a recrystallization. Table 13.1 shows some of the most frequently used solvents in the pharmaceutical industry. Mixtures of solvents, binary or even ternary, are also common. The burden of checking many solvents and solvent mixtures for use in recrystallizations can be mitigated with automated high-throughput screening tools. A drug s solubility is tested in each solvent and reasonable solvent mixture at various 

Acetone, methyl isopropyl ketone, ethyl acetate 

According to Section 5.3.3, crystalline polymers can occur in different polymorphic forms. When a polymer melt is cooled to a given crystallization temperature, the crystal modification that is thermodynamically stable at this temperature is not always formed (because of kinetic reasons). In many cases, the modifications only transform into one another very slowly, which 

However, the melting point is defined as that temperature at which the crystalline layer is in thermodynamic equilibrium with the melt. It must of necessity depend on the lamellar thickness before the onset of the melting process. Each monomeric unit contributes an enthalpy of fusion (A//a ) to the observed enthalpy of fusion The enthalpy of fusion is also 

the entropy of fusion of a lamella of JV monomeric units is 

Inserting equations (10-35)-( 10-37) into each other leads to 

Fiywv ()- 0. Mean lengths of the crystalline and amorphous portions of the lamellar height of polylethylene) as inferred from small-angle X-ray measurements carried out at different temperatures. All experiments were carried out on the same material (after K. V. Fulcher, D. S- Brown, and R. E. Wetioii). 

Solid substances are often purified by a procedure known as recrystaUization. The impure solid is dissolved in the minimum amount of an appropriate hot solvent and, after filtration of the hot solution to remove any insoluble impurities, the solution is allowed to cool. Crystals of the required substance start to crystallize out, leaving the soluble impurities in solution. When cool, the crystals can be filtered off. 

At some point in the near future you should watch the video entitled RecrystaUization in the multimedia activity Practical techniques on the Experimental techniques CD-ROM that accompanies this book. The sequence shows this technique in practice, and discusses the theory of the procedure. 

The product that is recrystallized in this sequence is benzoic acid, which was obtained by the oxidation of benzyl alcohol. This activity should take approximately 10 minutes to complete. 

It is the same with a filtration in the laboratory — the solid (crystals) remains in the funnel on the filter paper while the liquid runs off and into a collection flask. 

There are several different methods for the filtration of a material the two primary methods being filtration under gravity and filtration under suction. You should recall the contrasting appearance of the samples of suction-filtered and gravity-filtered crystals of benzoic acid. 

What s the Difference between Recovery and Recrysta Ilization  

during recrystalhzation, the mechanical properties that were changed as a result of cold working are restored to their precold-worked values—that is, the metal becomes softer and weaker, yet more ductile. Some heat treatments are designed to allow recrystallization to occur with these modifications in the mechanical characteristics (Section 11.7). 

It shoiUd be noted that because recrystaUization rate depends on several variables, as discussed previously, there is some arbitrariness to recrystaUization temperatures cited in the Uterature. Furthermore, some degree of recrystaUization may occur for an alloy that is heat treated at temperatures below its recrystaUization temperature. 

Photomicrographs showing several stages of the recrystallization and grain growth of brass. 

Plastic deformation operations are often carried out at temperatures above the recrystallization temperature in a process termed hot working, described in Section 11.4. The material remains relatively soft and ductile during deformation because it does not strain harden, and thus large deformations are possible. 

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In principle, then, small crystals should show a higher solubility in a given solvent than should large ones. A corollary is that a mass of small crystals should eventually recrystallize to a single crystal (see Ostwald ripening. Section IX-4). 

Frequently the recrystallized azobenzeno has m.p. 61°, which is unaffected by recrystallisation from alcohol. Upon distillation from a. 50 ml. distilling flask fitted with a short air condenser, the m.p. is raised to 67-5° and the recovery is about 90 per cent. one recrystallisation from diluted alcohol (as above) then gives perfectly pure azobenzene of m.p. 68-5°. 

Phenylacetic acid. Use 5 0 g. of magnesium, 25 g, (23 ml.) of redistilled benzyl chloride (Section IV,22) and 75 ml. of sodium-dried ether. Allow the reaction mixture to warm to 15° and then decompose it with dilute hydrochloric or sulphuric acid. Filter off the crude acid and recrystallize it from water. The yield of pure phenylacetic acid, m.p. 76-77°, is 11 g. 

It was originally separated from zirconium by repeated recrystallization of the double ammonium or potassium fluorides by von Hevesey and Jantzen. Metallic hafnium was first prepared by van Arkel and deBoer by passing the vapor of the tetraiodide over a heated tungsten filament. Almost all hafnium metal now produced is made by reducing the tetrachloride with magnesium or with sodium (Kroll Process). 

Once the reaction mix has cooled after reflux, 500mL of room temperature dHsO can be added and the whole solution extracted with DCM. The DCM layer is separated and the solvent removed by distillation to give the li-nitropropene as an oil of all things. This oil can then be recrystallized in hot methanol just like the crystalline form was [38]. 

They isolated their products after conversion into the solid semi-carbazone, which included recrystallizations (more losses). This and the fact that they distilled those tiny amounts make me believe that yield will be even higher (at least with the HgCl2 route). 

Phenylpropanolamine. - With catalyst prepared as previously described from 0.5g of palladium chloride and 3g of charcoal, it was possible to reduce two portions of 9.8g of isonitrosopropio-phenone (0.06 mol), dissolved in 150 cc. of absolute alcohol containing 7. Og of hydrogen chloride, to phenylpropanolamine in from 145 - 190 minutes with yields of the isolated chloride from 9.4g to 11. Og, or 84 to 98% of the theoretical. After recrystallization from absolute alcohol the salt melted at 191°. The free base was obtained by treating an aqueous solution of the hydrochloride with alkali on cooling, the liberated amino alcohol solidified and after recrystallization from water melted at 103°."... 

The way the chemist knows that she has methylamine and not ammonium chloride is that she compares the look of the two types of crystals. Ammonium chloride crystals that come from this reaction are white, tiny and fuzzy. The methylamine hydrochloride crystals are longer, more crystalline in nature and are a lot more sparkly. The chemist leaves the methylamine crystals in the Buchner funnel of the vacuum filtration apparatus and returns the filtrate to the distillation set up so it can be reduced one last time to afford a second crop. The combined methylamine hydrochloride filter cake is washed with a little chloroform, scraped into a beaker of hot ethanol and chilled. The methylamine hydrochloride that recrystallizes in the cold ethanol is vacuum filtered to afford clean, happy product (yield=50%). 

Synthesis of (A) started with the combination of 2,4,6-trimethylphenol and allyl bromide to give the or/Ao-allyl dienone. Acid-catalyzed rearrangement and oxidative bydroboration yielded the dienone with a propanol group in porlactone ring were irons in the product as expected (see p. 275). Treatment with aqueous potassium hydroxide gave the epoxy acid, which formed a crystalline salt with (R)-l-(or-naphthyl)ethylamine. This was recrystallized to constant rotation. 

Bromo-2-nitrophenylacetic acid (26 g, 0.10 mol) was dissolved in a mixture of 50% HjSO (400 ml) and ethanol (600 ml) and heated to 90°C. Over a period of 1 h, zinc dust (26.2 g, 0.40 mol) was added. slowly and then heating was continued for 2 h. The excess ethanol was removed by distillation. The solution was cooled and filtered. The filtrate was extracted with EtOAc. The filtered product and extract were combined, washed with 5% NaCOj and brine and then dried (MgSO ). The solvent was removed in vacuo and the residue recrystallized from methanol to give 20.5 g (97% yield) of the oxindole. 

Sodium hydride (9.3 g, 0.22 mol) was washed with petroleum ether and DMSO (200 ml) was added and the mixture was heated to 100°C. A solution of diethyl malonate (35.2 g, 0.22mol) in DMSO (50 ml) was then added and stirred for 10 min to give a clear solution. A solution of 4-bromo-3-nitrobenzophenone (30.6 g, 0.10 mol) in DMSO (100 ml) was added and the resulting dark solution kept at 100 C for 1 h. The solution was poured into water (3 1) and extracted (2x) with ether. The extract was washed with water, dried (NajSOj and concentrated in vacuo to give an oil which crystallized. The solid was recrystallized from isopropyl alcohol to give 35.4 g (92% yield) of the product. 

A stirred solution of o-methylpivalanilide (50 mmol) in dry THE (100 ml) was maintained at 15°C under a nitrogen atmosphere. A 1.5 M solution of n-butyllithium in hexane (3 equiv.) was added dropwise. The solution was then maintained at room temperature for 16h. The solution was cooled in an ice-bath and treated with 2 N HCl (60 ml). The organic layer was separated and the aqueous layer was further extracted with benzene. The combined layers were dried (MgS04). The product was obtained in 87% yield and recrystallized from ether-cyclohexane. 

The cinnamate ester prepared as above (23.2 g. 79 mmol) was added as a solid slowly to refluxing xylene (500 ml) over a period of 3 h at a rate that prevented accumulation of unreacted azidocinnamate in the solution (monitored by gas evolution through a gas bubbler). The solution was refluxed for an additional 2 h after gas evolution ceased. The reaction mixture was cooled and the solvent removed in vacuo. The residue was recrystallized from methanol to give pure product (20.7 g, 99% yield). 

Phenyl-3-oxopropanoic acid (25 mmol) and EtjN (87.5 mmol) were dissolved in THF (150 ml) and cooled to —40°C. Ethyl chloroformate (27.5 mmol) was added dropwise to this solution and then the reaction mixture was stirred for 30 min at —20°C. Di-n-hexylamine (27.5 mmol) was added to the suspension and it was stirred at room temperature for an additional hour. The reaction mixture was diluted with water (100 ml) and extracted with ether (400 ml). The extract was washed with aq. 5% HCl (100 ml) and brine (2 X 100 ml) and dried over NajSO. The crude amide was obtained by removal of the solvent in vacuo and phenylhydrazine (25 mmol) was added. The mixture was heated to 100°C for 30 min. The residue was held in vacuo to remove the water formed and then powdered ZnCl2 (125 mmol) was added. The mixture was heated at 170"C with manual stirring for 5 min. The cooled residue was dissolved in acetone (100 ml) and diluted with ether (500 ml). Water (100 ml) was added. The organic layer was separated and washed successively with 5% aq. HCl (100 ml) and brine (2 x 100 ml) and dried over NajSO. The solvent was removed in vacuo, and the residue was recrystallized from EtOAc-hexane. The yield was 79%. 

The hydrazone prepared above (153 g. 0.42 mol) was heated at reflux for 5 h in 5% H2SO4 (750ml). The solution was cooled to 4 "C and after 12h the precipitate was collected by filtration. Recrystallization from MeOH/water (70 30) gave the product (145 g, 99%). 

The above intermediate (8 g, 0.03 mol) in THF (80 ml) was stirred with Raney nickel (40g) for 2h and then carefully filtered. [CAUTION Raney nickel can ignite during filtrationf Cone. HCl (2 drops) was added to the filtrate and it was evaporated in vacuo. Recrystallization of the residue from 2-propanol gave the product (6,0 g) in 89% yield. 

A solution of 2,3-dibromo-5-methoxyaniline (32 g, 0.17 mol) in CHjClj (300 ml) was stirred and cooled in an icc bath. Boron trichloride (1 M in CH2CI2, 180 ml, 0.18 mol), chloroacetonitrile (14.3 g, 0.19 mol) and TiC (1 M in CH CIj, 190ml, 0.19 mol) were added. The resulting mixture was refluxed for 1.5 h. The solution was cooled to room temperature and poured carefully on to a mixture of icc and 20% aq. HCl (700 ml). The organic layer was separated and the CH Clj removed by distillation. The residue was heated to 90°C on a water bath for 30 min. The solution was cooled and the solid collected by filtration. It was partitioned between ether (1.41) and 1 N NaOH (500 ml). The ether layer was washed with brine, dried over Na2S04 and evaporated. The residue was recrystallized from ethanol to give 2-amino-3,4-dibromo-6-methoxy-a-chloroacetophenone (55 g) in 90% yield. 

The above product (24 g, 0.067 mol) was dissolved in 90 10 dioxane-water (300 ml) and sodium borohydride (92.5 g, 0.067 mol) was added. The mixture was refluxed for 4h. The cooled solution was poured into 0.1 N HCl (1.11). A solid precipitated and was collected by filtration, dried and recrystallized from ether hexane to give 6,7-dibromo-4-methoxyindole (18.5 g, 90%). 

Phenylmagnesium bromide (2.8 mol) was prepared in anhydrous ether (21) from bromobenzene (440 g, 2.9 mol) and magnesium turnings (68.0 g 2.8 g-atom). To this solution was added dropwise a solution of indole (328 g, 2.8 mol) in benzene (8(X)ml). The resulting solution was stirred for 10 min and then a solution of cyclopentanoyl chloride (322 g, 2.4 mol) in benzene (800 ml) was added dropwise. The solution was stirred for 1 h and then water (11) was added carefully. The precipitate which formed was collected by filtration and dried to give 169 g of crude product. Additional product (97 g) was obtained by evaporation of the organic layer of the filtrate. The combined products were recrystallized from toluene to give 250 g (49% yield) of pure product. 

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