Racemic compounds crystallization

For racemic compounds (Figure 4), pure enantiomers are obtained by crystallization only if the composition of the mixture (M) lies between D (or l) and E (eutectic composition). In the opposite case (M ), the racemic compound crystallizes from the solution. When E is located closer towards R, the potential yield of pure enantiomer increases. An extreme, but not uncommon case, is encountered if E is located very close to d (or l). The racemic mixture crystallizes from the solution (or melt) and the mother liquor contains practically pure enantiomer. An appropriate derivatization of the partially resolved compound is often helpful. 

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. 

Jacques has also concluded that among the 164 space groups possessing at least one element of inverse symmetry, it is found that 60-80% of racemic compounds crystallize in either the P2iC, C2/c, or P-1 space groups [13]. The most common group is monoclinic P2iC, where the unit cell contains two each of the opposite enantiomers related to one another by a center of symmetry and a binary screw axis. 

Splitting Racemic Compounds.—The methods by which racemic compounds may be split into their optically active components are several. The three methods used were all originated by Pasteur. The first method has been referred to and consists of the mechanical separation of the two oppositely hemi-hedral forms in which the salts of a racemic compound crystallize. This method is especially applicable in the case of tartaric acid when the sodium-ammonium salt is used. The crystallization and separation must be carried out under definite conditions. If the racemic acid salt is crystallized below 28° the two forms of crystals are produced and a separation can be accomplished. If, however, the crystallization takes place above 28° the two forms of crystals are not produced but the sodium-ammonium racemate crystallizes in unseparable crystals of one form. That is, above 28° the sodium-ammonium racemate crystallizes as such, while, below 28° the racemate splits into its two isomeric components and equal amouts of the sodium-ammonium dextro tartrate and the sodium-ammonium levo tartrate are formed. The second method for the splitting of a racemic compound into its optically active components consists of the formation of the cinchonine, strychnine, or other similar alkaloid salts. When the cinchonine salt of racemic acid is formed it splits into the... 

As discussed above, most racemic compounds crystallize in three space groups, namely F2i/c, C2/c, and P-1, which possess elements of inverse symmetry. On the other hand, enantiomers can crystallize only into dissymmetric space groups, which are devoid of inverse symmetry elements. The inverse symmetry in the racemic compound may lead to close packing and ultimately contributes to the greater stability of the racemic compound. 

Resolution of a racemic mixture was discovered by Pasteur in the last century. It remains an useful method to prepare enantiomerically pure compounds, although the yield in the desired enantiomw cannot exceed 50%. It is realized by the reaction of stoichiometric amounts of a chiral auxiliary which will produce a I I mixture of diastereomers, generally easy to separate. Removal of the chiral auxiliary graerates the desired enantiomer. A special case of resolution is one in which the racemic compound crystallizes as a conglomerate. Here, a chiral seed can propagate the production of... 

Although there is a priori no restriction in symmetry applicable to the space group of the racemic compound crystal lattice, a clear majority of these racemic compounds crystallize in one of the 92 centrosymmetric space groups among them Fife, P-l, C2/c, Pbca, Pnma are by far the most popular. . 

Some chiral racemic compounds crystallize in the 73 non-chiral and non-centrosymmetric space groups such as Pc, Pnali (form III of rae modafi-niii8,i9) Fddl (form IV rac-modafiniP°), and so on. Very rare examples... 

The racemic acid is not a primary product of plant processes but is formed readily from the dextrorotatory acid by heating alone or with strong alkaU or strong acid. The methods by which such racemic compounds can be separated into the optically active modifications were devised by Pasteur and were apphed first to the racemic acid. Racemic acid crystallizes as the dihydrate triclinic prisms. It becomes anhydrous on drying at 110°C... 

Specification in Table 9. b Yield of a mixture of 75 and 76 which was separated from the crude reaction product by a silica gel chromatography. All [a]D values were measured in CHC13 at c 1.0.d Optical purity was determined by HPLC on Chiralcel.e Since optically active 75 a and 76 a could not be separated, it is not clear whether both enantiomers are (—)-ones or not. Therefore, both are tentatively shown as (—)-enantiomers. Since [a]D value of each enantiomer is also not clear, [otJD value of the mixture is shown.f Compound is inert to irradiation. Optical purity was not determined. h When an acetone solution of the mixture of (+)— 75c and 76c was kept, racemic 76c crystallized out, mp 135-137 °C. 

For a number of the systems, comparisons were made between the effects of enantiomeric composition in the monolayer and corresponding melting-point-composition curves for the crystals. All of the latter gave clear evidence of racemic compound formation in the crystals, and this type of pattern was repeated in the monolayer properties. 

On the other hand, if the enantiomeric purity of the original solid is less than that of the eutectic (as in the case of M2 in Fig. 25b), crystallization results in a decrease in enantiomeric purity. For example, when sufficient solvent has been added to correspond to point P2, the tie line shows that the solid N2 contains less of the predominant enantiomer D than M2 and is in equilibrium with E, which corresponds to a saturated solution of the eutectic solid, e. When the system reaches the composition represented by point Q2, the solid that crystallizes out is the racemic compound, R, which is in equilibrium with the saturated solution, U2, containing the racemic compound and enantiomer D. 

Synthesis of the common intermediate C (4), and its further conversion to 2 and 3 is illustrated in Scheme 7-3. Two racemic compounds, ( )-7 and ( + )-10, are prepared from readily available starting materials 5 and 8, respectively (Scheme 7-2). Coupling of 7 and 10 gives a mixture of diastereomers 11. An intramolecular aldol reaction of 11 catalyzed by D-proline yields diastereomers 12 and 13 in equal molar ratios (about 36% ee for each diastereomer). Compound 12, the desired ketone, is converted to 14, which is further purified by crystallization to give the compound in the desired stereochemistry in sterically pure form. Reduction of the ketone carbonyl group and subsequent methoxy... 

Crystals composed of the R and S enantiomers of the same racemic mixture must be related by mirror symmetry in terms of both their internal structure and external shape. Enantiomorphous crystals may be sorted visually only if the crystals develop recognizable hemihedral faces. [Opposite (hid) and (hkl) crystal faces are hemihedral if their surface structures are not related to each other by symmetry other than translation, in which case the crystal structure is polar along a vector joining the two faces. Under such circumstances the hemihedral (hkl) and (hkl) faces may not be morphologically equivalent.] It is well known that Pasteur s discovery of enantiomorphism through die asymmetric shape of die crystals of racemic sodium ammonium tartrate was due in part to a confluence of favorable circumstances. In the cold climate of Paris, Pasteur obtained crystals in the form of conglomerates. These crystals were large and exhibited easily seen hemihedral faces. In contrast, at temperatures above 27°C sodium ammonium tartrate forms a racemic compound. 

Finally, reference must be made to the important and interesting chiral crystal structures. There are two classes of symmetry elements those, such as inversion centers and mirror planes, that can interrelate. enantiomeric chiral molecules, and those, like rotation axes, that cannot. If the space group of the crystal is one that has only symmetry elements of the latter type, then the structure is a chiral one and all the constituent molecules are homochiral the dissymmetry of the molecules may be difficult to detect but, in principle, it is present. In general, if one enantiomer of a chiral compound is crystallized, it must form a chiral structure. A racemic mixture may crystallize as a racemic compound, or it may spontaneously resolve to give separate crystals of each enantiomer. The chemical consequences of an achiral substance crystallizing in a homochiral molecular assembly are perhaps the most intriguing of the stereochemical aspects of solid-state chemistry. 

As illustrated for compounds 77 and 78 in Scheme 18, different methods were applied for the syntheses of 77-79 (79 was obtained analogously to 78 according to method a). The racemic products 77a 0.7CH3CN, 78 CH3CN, and 79 were isolated as crystalline solids. In addition, crystals of the racemic compound 77b (an isomer of 77a) were obtained. For the solvent-free compound 78 formation of enantiomorphic crystals was observed. The crystals studied by X-ray diffraction contained (just by accident) the (A)-enantiomer. 

The racemic compound forms crystals containing a 1 1 ratio of d- and /-molecules in a regular array. The pseudoracemate, eventually, forms crystals with both d- and /-molecules in an irregular arrangement and in any ratio. The corresponding phase diagrams are shown in Figure 13. 

The conglomerate shows a lower melting point (and hence, a higher solubility) than the individual enantiomers. From a melt or a solution with an enantiomeric ratio +1 1, the excess enantiomer crystallizes in pure form. The racemic compound may have a lower (curve 1) or a higher (curve 2) melting point (or solubility) than the corresponding enantiomers the eutectic mixture (E), however, always lies at a minimum. Finally, crystallization of pseudoracemates always yields enantiomerically impure samples. 

It must be emphasized that only conglomerates can be resolved into the enantiomers by direct crystallization. For racemic compounds, pure enantiomers can be crystallized only from partially resolved mixtures (vide infra). Which type is present in a given case is best decided by trial and error. For a complete list of conglomerates forming chiral compounds, see reference 5. 

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