Resolution by entrainment

For practical use the conglomerate is most favorable as pure enantiomers may be obtained by direct crystallization, either by localization of crystallization or by resolution by entrainment . 

Figure3. Apparatus for resolution by entrainment in a supercooled melt77.

Typically, resolution by entrainment involves a sequence of alternate crystallizations of both enantiomers interrupted by loading the mixture with racemic material. A continuous resolution may be performed with supercooled melts in the apparatus shown in Figure 3. 

Amiard, G. Resolution by entrainment. The idea of "residual" supersaturation. Experienta 1959, 15, 38-40. 

Resolution by entrainment is best illustrated through the use of an example, and the laboratory scale resolution of hydrobenzoin [38] is an appropriate example. Initially, 1100 mg of racemic material is dissolved along with 370 mg of (—)-hydrobenzoin in 85 g of 95% ethanol, and then the solution is cooled down to 15 °C. Ten milligrams of the (—)-isomer is added in the form of seed crystals, and a crop of additional crystalline material is allowed to form. After 20 minutes, 870 mg of (—)-hydroben-zoin was recovered. Then, 870 mg of racemic hydrobenzoin was dissolved with heating. The resulting solution was cooled to 15 °C and seeded with 10 mg of the (+)-isomer. The quantity of (+)-hydrobenzoin recovered at this time was 900 mg. The process was cycled 15 times, and ultimately yielded 6.5 g of (—)-hydrobenzoin and 5.7 g of ( )-hydrobenzoin. Each isomer was obtained as approximately 97% enantiomerically pure. 

Resolution by entrainment can sometimes be used to separate racemic mixtures when there are distinct differences in the rates of crystallization of the two optical isomers. This preferential crystallization is initiated by seeding with the crystals of one enantiomer. This technique has been shown to be effective in the production of thiamphenicol (21). 

J. Jacques, A, CoUet, and S. H, Whilen, Resolution by entrainment. Enantiomers, Racemates and Resolutions, Wiley, New York, 1981. 

The creation of dissymmetry at a molecular level, that is the preparation of enantiopure compounds, inevitably requires either the resolution of racemic compounds or asymmetric synthesis, so we shall pay particular attention to the problems associated with these two methods. The formation of enantiopure crystals by spontaneous resolution during crystallization, whether the crystals are separable or not, is of undeniable theoretical and practical importance to the technique of resolution by entrainment. In general, however, we will not consider this in itself as a technique for resolution. 

This experiment was in fact a rediscovery, several years later, of the work of Gernez (a student of Pasteur) on the crystallization of one of the enantiomeric tartrates from a supersaturated solution by seeding with a pure enantiomeric crystal.This method is known as resolution by entrainment. 

This direct separation of enantiomers is named resolution by entrainment. Kostya-novsky uses the term conglomerator for one element (ion) which is able to initiate the crystallization of a conglomerate instead of a racemic crystal. For example Na is a conglomerator for the NaNELj tartrate salt (2.5) because it is responsible for the formation of a conglomerate while the diammonium tartrate salt crystallizes as a true racemic compound. 

Srivastava RP, Zjawiony JK, Peterson JR, McChesney JD (1994) N-Benzoyl-(2R,3S)-Phenylisoserine Methyl Ester A Facile and Convenient Synthesis and Resolution by Entrainment. Tetrahedron Asymmetry 5 1683... 

Another important but non-synthetic method involves harvesting crops of enan-tioenriched crystals by seeding a supersaturated racemate and is known as resolution by entrainment, or preferential crystallization. These approaches have been well reviewed and will not be covered here [8]. Rare (but spectacular) examples where crystallizations of conglomerates are observed combined with racemization events in solution, leading to total spontaneous resolutions [9], are briefly mentioned in Chapter 7 as there have been interesting recent developments on that front. Included therein are special cases where diastereomeric interactions in solution combined with racemization may yield more than a 50% yield of one enantiomer. 

Preferential crystallization (or resolution by entrainment)—stereospecihc growth of each isomer in two different crystallizers from solution. This process requires no resolving agent. 

Another form of a direct crystallization is a preferential crystallization, which is also called resolution by entrainment of one enantiomer. The process involves solution formation, e.g., under elevated temperature that will then be subcooled and seeded with crystals of the preferred species. Preferential crystallization is a potent method for the improvement of the product quality and at the same time achievement of a higher yield and productivity. For example, by preferential crystallization of DL-threonine from the aqueous solution, it is possible already during a simple batch to gain highly pure enantiomers up to a certain point after which the opposite enantiomer nucleates from the solution and leads to a purity drop. If (—)-hydrobenzoin seed crystals are added to an ethanol solution of ( )-hydrobenzoin, the ( )-enantiomer will crystallize out and after 15 cycles, 97% optical purity can be obtained. 

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