Solubility, crystallization-based enantiomer separation

The second important observation on stereoisomer separation also involved ammonium sodium tartrate. Thirty-four years after Pasteur s observation, Jungfleisch (1882) observed that carefully introducing crystals of the individual isomers into different areas of a supersaturated solution of ammonium sodium tartrate resulted in the growth of isomerically pure crystals. These two observations form the basis for most industrial scale crystallizations for the purification of enantiomers or diastereoi-somers. However, it is more common for a solute to crystallize with the thermodynamically stable crystal form being a compound of the two isomers. This is typically denoted as a racemic compound. Secor (1963) made the first systematic review of optical isomer separation by crystallization, based upon phase behavior. Collet, Brienne, and Jacques (1980) applied systematic thermodynamics to the phase behavior, and developed straightforward methods for correlating the solubilities of isomers. 

Even nowadays, particularly in industrial processes, the separation of enantiomers of racemic acids and bases is based on this molecular chiral recognition. The less soluble, i.e. the more stable of these diastereomer salts crystallizes even if the chiral agent in the better soluble salt is replaced by an achiral reagent of similar chemical character, or eventually eliminated, or substituated by a solvent. In this case, a mixture enriched with the more stable diastereomer can be isolated by filtration from the solution of the achiral salt of the enantiomeric mixture or the free enantiomers [2,3]... 

The most classical of resolutions is exemplified by the separation, by crystallization, of the diastereomeric salts formed by treatment of a racemic acid with one enantiomer of a chiral base, typically an alkaloid such as quinine. Unfortunately, despite significant recent advances (3,6), the relative solubilities of two diastereomers, and thus the probability for success of a classical resolution, are difficult to predict. It thus remains, for most chemists, a largely empirical method. On the other hand, a successful resolution often provides both enantiomers, even when both enantiomers of the resolving agent are not at hand, by recovery from the enriched... 

Assume that the racemic alanine (47) must be resolved into pure 1-alanine. If racemic 53 (53mc) reacts with enantiopure 117, the salt of each enantiomer is formed 118 and 119. These diastereomeric salts are separated by fractional crystallization, assuming that one salt is more or less soluble in a given solvent than the other. If 118 can be crystallized from a solution, a highly purified 119 remains in solution. The salt 119 is isolated and recrystallized from a different solvent to high enantiopurity. When this process is complete, 118 is treated with dilute base to regenerate 117 and 1-alanine, 53. The other enantiomer, d-alanine, is similarly obtained from 119. 

Reaction of a racemic acid or base with an optically active base or acid gives a pair of diastereomeric salts. Members of this pair exhibit different physicochemical properties (e.g., solubility, melting peint, boiling point, adsorbtion, phase distribution) and can be separated owing to these differences. The most important method for the separation of enantiomers is the crystallization. This is the subject of this chapter. 

Pasteur also recognized, that more efficient separation of the enantiomers of racemic tartaric acid could be achieved by application of another chiral base (Quinotoxine (Q)) as resolving agent to the enantiomers of tartaric acid was obtained a better enantiomeric separation. In this case a diastereoisomeric salt ((R,R)-TA.Q.6H20) crystallized while the better soluble diastereoisomeric salt((S,S)-TA.Q) remained in solution. 

The racemic mixture to be resolved in Figure 8.19 is designated Aj Ag- The optically active compound selected as the resolving agent is represented Xj. The choice of X over X is arbitrary in this discussion. The choice we make in the laboratory is based on the configuration of the available resolving agent. The diastereomeric compounds made from the racemic mixture are Aj -Xj and Aj-Xj. After the diastereomers are separated, one or the other or both can be reacted to liberate the pure enantiomers. In practice, only one of the enantiomers is easily obtained. For example, the least soluble diastereomer may crystallize from solution and yield one of the enantiomers in the subsequent step. Because some of the less soluble diastereomer remains in solution with the more soluble diastereomer, it is difficult to obtain the second enantiomer in optically pure form. 

Diastereomeric salts are formed between enantiomeric acids or bases and a chiral resolving bases or acids, respectively. Unlike enantiomers, diastereomers do not exhibit mirror symmetry therefore, they have different physicochemical properties including solubility. This difference in solubility makes the separation of the two diastereomers by crystallization possible. Furthermore, the extent of the difference in solubility determines the efficiency of the separation. 

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