Chemicals that used in purification: Amines

(a) Picrates:
The most versatile derivative from which the free base can be readily recovered is the picrate. This is very satisfactory for primary and secondary aliphatic amines and aromatic amines and is particularly so for heterocyclic bases. The amine, dissolved in water, alcohol or benzene, is treated with excess of a saturated solution of picric acid in water, alcohol or benzene, respectively, until separation of the picrate is complete. If separation does not occur, the solution is stirred vigorously and warmed for a few minutes, or diluted with a solvent in which the picrate is insoluble. Thus, a solution of the amine and picric acid in ethanol or benzene can be treated with benzene or light petroleum, repectively, to precipitate the picrate. Alternatively, the amine can be dissolved in alcohol and aqueous picric acid added. The picrate is filtered off, washed with water, ethanol or benzene, and recrystallised from boiling water, ethanol, methanol, aqueous ethanol or methanol, chloroform or benzene. The solubility of picric acid in water, ethanol and benzene is 1.4, 6.23 and 5.27% respectively at 20'.

It is not advisable to store large quantities of picrates for long periods, particularly when they are dry due to their potential EXPLOSIVE nature. The free base should be recovered as soon as possible. The picrate is suspended in an excess of 2N aqueous NaOH and warmed a little. Because of the limited solubility of sodium picrate, excess hot water must be added. Alternatively, because of the greater solubility of lithium picrate, aqueous 10% lithium hydroxide solution can be used. The solution is cooled, the amine is extracted with a suitable solvent such as ethyl ether or toluene, washed with 5N NaOH until the alkaline solution remains colourless, then with water, and the extract is dried with anhydrous sodium carbonate. The solvent is distilled off and the amine is fractionally distilled (under reduced pressure if necessary) or recrystallised.

If the amines are required as their hydrochlorides, picrates can often be decomposed by suspending them in much acetone and adding two equivalents of 10N HCl. The hydrochloride of the base is filtered off, leaving the picric acid in the acetone. Dowex No 1 anion-exchange resin in the chloride form is useful for changing solutions of the more
soluble picrates (for example, of adenosine) into solutions of their hydrochlorides, from which sodium hydroxide precipitates the free base .


(b) Salts:
Amines can also be purified via their salts, e.g. hydrochlorides. A solution of the amine in dry toluene, ether, methylene chloride or chloroform is saturated with dry hydrogen chloride (generated by addition of concentrated sulphuric acid to dry sodium chloride, or to concentrated HCI followed by drying the gas through sulphuric acid, or from a hydrogen chloride cylinder) and the insoluble hydrochloride is filtered off and dissolved in water. The solution is made alkaline and the amine is extracted, as above. Hydrochlorides can also be prepared by dissolving the amine in ethanolic HCl and adding ether or light petroleum. Where hydrochlorides are too hygroscopic or too soluble for satisfactory isolation, other salts, e.g. nitrate, sulphate, bisulphate or oxalate, can be used.

(c) Double Salts:
The amine (lmol) is added to a solution of anhydrous zinc chloride (lmol) in concentrated hydrochloric acid (421x11) in ethanol (200m1, or less depending on the solubility of the double salt). Thesolution is stirred for lh and the precipitated salt is filtered off and recrystallised from ethanol. The free base is recovered by adding excess of 5-10N NaOH (to dissolve the zinc hydroxide that separates) and is steam distilled. Mercuric chloride in hot water can be used instead of zinc chloride and the salt is crystallized from 1% hydrochloric acid. Other double salts have been used, e.g. cuprous salts, but are not as convenient as the above salts.

(d) N-Acetyl derivatives:
Purification as their N-acetyl derivatives is satisfactory for primary, and to a limited extent secondary, amines. The base is refluxed with slightly more than one equivalent of acetic anhydride for half to one hour, cooled and poured into ice-cold water. The insoluble derivative is filtered off, dried, and recrystallised from water, ethanol, aqueous ethanol, benzene or benzene-light petroleum. The derivative is then hydrolysed by


refluxing with 70% sulphuric acid for a half to one hour. The solution is cooled, poured onto ice, and made alkaline. The amine is steam distilled or extracted as above. Alkaline hydrolysis is very slow.

(e) N-Tosyl derivatives:
Primary and secondary amines are converted into their tosyl derivatives by
mixing equimolar amounts of amine and toluene-p-sulphonyl chloride in dry pyridine (ca 5-lhols) and allowing to stand at room temperature overnight. The solution is poured into ice-water and the pH adjusted to 2 with HCI. The solid derivative is filtered off, washed with water, dried (vac. desiccator) and recrystallised from an alcohol or aqueous alcohol solution to a sharp melting point. The derivative is decomposed by dissolving in liquid ammonia (fume cupboard) and adding sodium metal (in small pieces with stirring) until the blue colour persists for 10-15min.

Ammonia is allowed to evaporate (fume cupboard), the residue treated with water and the solution checked that the pH is above 10. If the pH is below 10 then the solution has to be basified with 2N NaOH. The mixture is extracted with ether or toluene, the extract is dried (KzCO~), evaporated and the residual amine recrystallised if solid or distilled if liquid.