Racemic species

The easiest combination of two chiral guests in the cylindrical capsule comes by the double encapsulation of racemic species with adequate size, shape and polarity to be accommodated in pairs, giving two diastereoisomeric complexes, the homochiral couple (R) - (R)/(S) - (S) and the heterochiral (R) -(S) combination. ( )-trans-1,2-Cyclohcxancdiol has all the above requisites and showed a 1.2 ratio between the two complexes in favor of the heterochiral combination [60]. This observation may be related to the preference in nature for centrosymmetric crystals or, alternatively stated, the higher melting points of racemates vs. enantiopure compounds where the resolution is driven by the less soluble pair [61,62], In the cylindrical capsule a single couple of chiral molecules is extrapolated from the bulk and the interactions between the two is governed by the shape of the cavity and their goodness of fit within the cavity. 

Li, Z. Zell, M.T. Munson, E.J. Grant, D.J.W. Characterization of racemic species of chiral drugs using thermal analysis, thermodynamic calculation and structural studies. J. Pharm. Sci. 1999, 88, 337-346. 

G. Properties of the racemic species of verapamil hydrochloride and gallopamil hydrochloride. Int. J. Pharm. 1999,178, III-I20. 

In section 2.2.1.3 the stereoselective reactions of an achiral substrate with a stoichiometric amount of a chiral non-racemic species were described. 

The generation of a racemic species from a phosphate monoester in t-butyl aleohol constitutes the only evidenee for free metaphosphate in solution. Under the conditions in which it is generated, there is no opportunity for observation of its properties. Studies of gas-phase reactions in the mass spectrometer (Meyerson et al., 1984) have indicated that the material can be generated by activation of phosphate (Henchman et al., 1985). Surprisingly, the material is not particularly reactive as either a nucleophile or electrophile in the gas phase. 

The different types of racemic species can be distinguished by their phase diagrams (Fig. 2). X-ray diffractometry (Fig. 3), and spectroscopic techniques (Figs. 4 and 5) may also distinguish these different types. The molecular basis of the different types of racemic species is the different intermolecular interactions in their crystals, as shown in Fig. 1. 

Figure 2 Typical phase diagrams of melting point against composition for (a-c) three types of racemic species, (a) racemic conglomerate, C, (b) racemic compound, R, (c) pseudoracemates, P (d-e) terminal solid solutions involving opposite enantiomers, (d) solid solution rich in an enantiomer, (e) solid solution rich in an enantiomer or rich in the racemic compound (f) a pair of diastereomers. (From Ref. 13. Reproduced by permission of John Wiley and Sons.)...

Less than 1% of racemic species are pseudoracemates, which show typical phase diagrams of continuous solid solutions. Figure 2c shows the three types of melting phase diagrams of pseudoracemates, which comprise ideal solid solutions, solid solutions with positive deviations from ideality, and solid solutions with negative deviations from ideality, respectively [13]. In real systems, the enantiomers and the racemic compound may display a small mutual solubility, even if they show eutectic behavior, which corresponds to terminal solid solutions for which the phase diagrams are shown in Figs. 2d and 2e. 

The enantiomer and the racemic compound possess different crystal structures, which correspond to different intermolecular interactions, as mentioned in Sec. 3. Therefore the enantiomer and the racemic compound exhibit different powder x-ray diffraction (PXRD) patterns, different infrared (IR) and Raman spectra, and different solid-state nuclear magnetic resonance (SSNMR) spectra. However, the opposite enantiomers give identical PXRD patterns, and identical IR, Raman, and SSNMR spectra. Consequently, the PXRD patterns and the above spectra of a conglomerate, which is a physical mixture of opposite enantiomers, are identical to that of the pure enantiomers. In contrast, the diffraction pattern and the various corresponding spectra of the racemic compound usually differ significantly from those of the pure enantiomers. Therefore the type of racemate can be easily determined by comparing the diffraction patterns or the various spectra of the racemic species with that of one of the pure enantiomers (Figs. 3 5). The enantiomeric composition in a racemic mixture may be determined by PXRD, or by IR or SSNMR spectroscopy. Quantitative PXRD has been applied to determine the relative... 

Polymorphism and pseudopolymorphism are known among chiral drugs. Whereas the enantiomers of chiral drugs may display ordinary polymorphism, the racemic species show a special type of polymorphism, namely conversion between the different types of racemate. For example, racemic sodium ibuprofen exhibits three polymorphs, the stable polymorph at room temperature being the conglomerate while the other two polymorphs, which are racemic compounds, are obtained by rapidly cooling the melt of the conglomerate [21]. 

For chiral drugs, it is usually necessary to apply several techniques to characterize both the enantiomer and the racemic species in order to interpret the origin of the polymorphism among the racemic species. For example, three monotropically related polymorphs of (R5)-nitrendipine were found [29]. Based on the melting phase diagram, IR spectra, and PXRD patterns, the thermodynamically stable form (I) of (R5)-nitrendipine was shown to be a racemic compound, while the other polymorphs, forms II and III, were both found to be conglomerates. Study of one of the pure... 

The enantiomeiically-pure cyclopropane 245 has been described,336 as has the adenine analogue of opposite chirality, together with other similar racemic species,337 and the analogue 246, prepared by treatment of 1-cyanomethyluracil with LDA, followed by q>ibromohydiin.338... 

Turner and Harris have discussed the more general problem of rotational changes when a species, stable with respect to racemization, is added to a solution containing an optically labile species (not necessarily a metal complex). When new rotations evolve, the authors describe the changes as occurring through asymmetric transformations. Using an equilibrium equation, in which the resolved stable species (base) is B and the racemic species (acid) is A, the fraction distribution (x) could be represented as... 

Racemic species contain equal amounts of two enantiomers and raise various issues concerning how to count the number of substances present in a sample. Most racemic species are distinct compounds (racemates) one solid compound forms, because heterochiral interactions dominate. Racemic molecules (or complexes ) may exist in the liquid state. Enantiomers may also form solid solutions or racemic conglomerates. The latter are eutectic mixtures of (-h) and (—) enantiomers two separate solid phases form, each crystal type comprises a single enantiomer (because homochiral interactions dominate). In practice, spectra of racemic and enantiomeric forms are indistinguishable, although one would be inclined to consider the racemate and the separate enantiomers as three different species. In the solid state, properties such as melting point, solubility behaviour, and density are different for the racemate and the respective enantiomers. Hence, some of their thermodynamic properties must be different. 

Because, in the end, substance is a proto-scientific concept (not defined in science) and identification (isolation, separation) depends on specific properties that are considered relevant and must be known, substance will remain a pragmatic notion and ambiguous situations may arise as to whether to count a sample as one, two, or three substances (cf. non-stoichiometric compounds, inclusion compounds, racemic species, tautomers, etc.). In ambiguous cases, substance identity is best correlated with its possible isolation, as distinct from phase rule substances (identification via a phase diagram) and individuation of chemical species. 

Li ZJ, ZeU MT, Munson EJ, Grant DJW. Characterization of racemic species of chiral drugs using thermal analysis. 

Zhang GGZ, Paspal SYL, Suryanarayanan R, Grant DJW. Racemic species of sodium ihuprofen characterization and polymorphic relationships. J. Pharm. Sci. 2003 92 1356-1366. 

The most important characteristic of the chiral recognition is that the chiral selector, either present in mobile phase or impregnated in the stationary phase, has to be compatible in size and structure with the racemic species to be resolved. This approach has been used by LuCid et al. [20] who developed a method for the separation of ( )-metoprolol tartrate. In order to approach the separation, the... 

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