Crystallization enantiomeric separation

Through luck, in 1848, Louis Pasteur was able to separate or resolve racemic tartaric acid into its (+) and (—) forms by crystallization. Two enantiomers of the sodium ammonium salt of tartaric acid give rise to two distinctly different types of chiral crystal that can then be separated easily. However, only a very few organic compounds crystallize into separate crystals (of two enantiomeric forms) that are visibly chiral as are the crystals of the sodium ammonium salt of tartaric acid. Therefore, Pasteur s method of separation of enantiomers is not generally applicable to the separation of enantiomers. 

In 1848, Louis Pasteur noticed that a salt of racemic ( )-tartaric acid crystallizes into mirror-image crystals. Using a microscope and a pair of tweezers, he physically separated the enantiomeric crystals. He found that solutions made from the left-handed crystals rotate polarized light in one direction and solutions made from the right-handed crystals rotate polarized light in the opposite direction. Pasteur had accomplished the first artificial resolution of enantiomers. Unfortunately, few racemic compounds crystallize as separate enantiomers, and other methods of separation are required. 

The history of enantiomeric separation starts with the work of Pasteur. In 1848 he discovered that the spontaneous resolution of racemic ammonium sodium tartrate yielded two enantiomorphic crystals. Individual solutions of these enantiomorphic crystals led to a levo and dextro rotation of the polarized light. Because the difference of the optical rotation was observed in solution, Pasteur suggested that like the two sets of crystals, the molecules are... 

The first method of enantiomeric separation by direct crystallization is the mechanical technique use by Pasteur, where he separated the enan-tiomorphic crystals that were simultaneously formed while the residual mother liquor remained racemic. Enantiomer separation by this particular method can be extremely time consuming, and not possible to perform unless the crystals form with recognizable chiral features (such as well-defined hemihedral faces). Nevertheless, this procedure can be a useful means to obtain the first seed crystals required for a scale-up of a direct crystallization resolution process. When a particular system has been shown to be a conglomerate, and the crystals are not sufficiently distinct so as to be separated, polarimetry or circular dichroism spectroscopy can often be used to establish the chirality of the enantiomeric solids. 

Even a few seed crystals, mechanically separated, can be used to produce larger quantities of resolved enantiomerically pure material. A second method of resolution by direct crystallization involves the localized crystallization of each enantiomer from a racemic, supersaturated solution. With the crystallizing solution within the metastable zone, oppositely handed enantiomerically pure seed crystals of the compound are placed in geographically distant locations in the crystallization vessel. These serve as nuclei for the further crystallization of the like enantiomer, and enantiomerically resolved product grows in the seeded locations. 

Enantiomeric ( )-(+)- and (R)-(-)-BNP acids are useful resolving agents, which give well crystallized, easily separated salts with a variety of amines. They have been used In the preparation of the enantiomers of... 

The 1,4-dihydrazinotetrasilane 21, obtained from 6 and anhydrous hydrazine, also exists in the solid state as a conglomerate of enantiomerically pure crystals. The separations between the two pairs of nitrogen atoms are very short (303 pm and 315 pm) and thus suggest the presence of two dynamic NH-N bridges.f ... 

Despite the overall decline in output, the year has produced ftirther interesting developments in the fteld of hypervalent phosphorus chemistry. These include phosphoranes containing acetylenic links, the synthesis and enantiomeric separation of a bicyclic phosphorane with chirality only at phosphorus, and a wide range of phosphoranes incorporated within macrocyclic ring systems (Houlla et al). In addition Lattman has reported on phosphoranes bound to transition metals or enclosed within calixarene skeletons and Holmes and his co-workers have made further substantial contributions on the X-ray crystal structures of phosphoranes containing eight-membered rings. 

Preparation of enantiomerically active hydrocarbons is difficult and only a few examples of the preparation of chiral hydrocarbons have been reported. For example, chiral 3-phenylcyclohexene has been derived from tartaric acid through eight synthetic steps. Enantiomeric separation by host-guest complexation with a chiral host is more fruitful for the preparation of chiral hydrocarbons. For example, when a solution of fR,Rh( )-t ws-4,5-bis(hydroxydiphenylmethyl)-l,4-dioxaspiro[4.4]-nonane (lb) [2] (3 g, 6.1 mmol) and rac-3-methylcyclohexene (2a) (0.58 g, 6.1 mmol) in ether (15 ml) was kept at room temperature for 12 h, a 2 1 inclusion complex of lb and 2a (2.5 g, 75%) was obtained as colorless prisms in the yield indicated. The crystals were purified by recrystallization from ether to give the inclusion complex (2.4 g, 71%), which upon heating in vacuo gave (-)-2a of 75% ee by distillation (0.19 g, 71%) [3]. By the same inclusion complexation, (-i-)-4-methyl- (2b) (33% ee, 55%), (-)-4-vinylcyclohexene (2c) (28% ee, 73%), (-)-bicyclo[4.3]-nonane-2,5-diene... 

The binaphthol host 10b was found to be very effective for enantiomeric separation of some sulfoxides. When a solution of 10b and two molar equivalents of rac-me-thyl m-methylphenyl sulfoxide (85c) in benzene-hexane was kept at room temperature for 12 h, a 1 1 complex of 10b and (-i-)-85c was obtained, after one recrystallization from benzene, as colorless prisms in 77% yield. Chromatography of the complex on sihca gel gave (-i-)-85c of 100% ee in 77% yield [32]. By the same procedure, rac-85d was separated by 10b to give (-i-)-85d of 100% ee in good yield. However, rac-85a was poorly separated with 10b, giving approximately 5% ee enantiomer, while 85b and 85e did not form complexes with 10b. In order to establish why the chirality of the m-substituted derivatives 85c and 85d is so precisely recognized by 10b, the crystal structure of the complex of 10b and (-i-)-85c was studied by X-ray analysis [33]. 

The title compound (107) [42] has been found to form inclusion complexes with a wide variety of solvent molecules [43]. In the complexation, racemates or conglomerates of 107 were formed, depending on the choice of solvent. In the latter case, the inclusion crystals consisting of one enantiomer of 107 were formed preferentially and the enantiomeric separation of 107 could be performed. For example, recrystallization of rac-107 from the solvents shown in Table 3.3-10 gave a 1 1 complex of the rac-107 with the solvent as yellow crystals. On the other hand, recrystal-lization of the rac-107 from the solvents shown in Table 3.3-11 gave a 1 1 complex... 

Scheme 3.3-3 Enantiomeric separation of 10a by inciusion com-piexation with 111 in the presence of chiral seed crystals.

The economic interest is very important in the development of the drugs. The separation methods are more economical than the asymmetric synthetic methods, and hence the development of rapid, reproducible, and inexpensive resolution methods is a demanding area. Conventionally, enantiomeric separation is performed by fractional crystallization, microbiological methods, kinetic enzymatic resolution, or by chromatographies [Ilisz et al., 2006), which have the problems of robustness, reproducibility, ease, and cost effectiveness. 

The first enantiomeric separation was credited to Louis Pasteur, who in 1848 manually sorted crystals of sodium ammonium tartrate based on their different crystalline appearances. Advances in technology and separation science have been paralleled by similar advances in enantiomeric separation methods. These have included preferential crystallization, crystallization from optically active solvents, fractional crystallization of diaslereo-... 

Although a wide variety of derivatizations has been used to facilitate the enantiomeric separation of carbonyl compounds, the final step has inevitably involved crystallization and relatively few have used chromatography. 

In this procedure the single enantiomer of an amine, (i )-l-phenylethylamine, is added to a solution of the racemic form of an acid. The salts that form are diastereomers. The chirality centers of the acid portion of the salts are enantiomericaUy related to each other, but the chirality centers of the amine portion are not. The diastereomers have different solubilities and can be separated by careful crystallization. The separated salts are then acidified with hydrochloric acid and the enantiomeric acids are obtained from the separate solutions. The amine remains in solution as its hydrochloride salt. 

In terms of zeolites, chiral pores exist only in a low-temperature form of zeolite /3 [112]. Therefore, zeolites are not inherently suitable for either enantiomeric separations or stereospecific catalysis. As noted recently by Ball [6], the development of a new generation of chiral porous material represents one of the major challenges and objectives that faces crystal engineering. Such materials could find widespread application. Furthermore, coordination polymers have the potential to be inherently catalytically active because the metal centers used as nodes could be selected for their known catalytic activity. The issue of how to design and build chiral porous solids is closely related to that of how to design and build polarity into a solid. The subject of polarity is discussed below. 

Combining the structural specificity of FT-IR spectroscopy with the slereosensitivity of circular dichroism, VCD allows the determination of optical purity without enantiomeric separation or de-rivatization, as well as of absolute configuration without crystallization. Simultaneous monitoring of the optical purity of multiple chiral species, such as reactant and product molecules in a reaction process is also possible, as is the determination of conformations of biological molecules such as proteins, peptides, and DNA [131], [132J. 

When the same experiment, namely crystallization of the non-racemic enantiomeric mixture of sodium-ammonium tartarate, was effectuated at a temperature above 27 °C, the racemic fraction (the racemate) crystallized, because the sodium-ammonium salts of racemic tartaric acid have a racemate like behaviour at around 30 °C. In this case the derivative of tartaric acid (the mixed salt) was suitable for fractioned enantiomeric separation, but only at a lower temperature than 27 °C (influence of temperature). 

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. 

In other cases, the use of solvent mixtures could influence which diasteieoisomer can be found in the crystalline phase. In such cases, either the crystallizing diasteieoisomer or the one remained in the mother liquor form stable solvate with one of the solvents. After a short summaiy of the theoretical background, it will be shown via examples, how can we use the influence of pH, solvent polarity, and solvate formation, respectively, to imptrove the efficiency of enantiomeric separation. 

Although the methods based on fractionated crystallization suggest that during crystallization the less soluble diastereomer is crystallized, but at the enantiomeric separations realized by fractionated crystallization, or precipitation, respectively, was observed in some cases that instead of expected racemate behaviour was crystallized the... 

---