Conglomerate racemates

Crystalline states of racemates are generally classified into the following three forms racemic mixture (conglomerate), racemic compound, and racemic solid solution (Figure 1). 

Of the three types of racemates,11 conglomerate, racemic compound, and solid solution, 3-(1,2-dihydroxyethyl)-1,5-dihydro-3H-2,4-benzodioxepine shows melting point behavior characteristic of a racemic compound. The racemic diol is much higher melting than the enantiomerically enriched diol as shown in the Figure 1. Therefore the diol of lower ee precipitates first during recrystallization and the enantiomerically enriched diol remains in the mother liquor. High ee diol (97% ee) is then obtained upon recrystallization of this mother liquor. 

This is the method which allowed Pasteur to discover molecular chirality 150 years ago [2]. The prerequisite for working of this technique is the occurrence of a chiral compound as a crystalline conglomerate (racemic mixture) rather than a racemic compound. In bulk, such a conglomerate is optically inactive. However, individual crystals contain only one enantiomer. This is not the case for a racemic compound which does not form a conglomerate. In the latter case crystals contain equal amounts of both enantiomers. 

Since conglomerate systems consist of totally independently formed enantiomer crystals and are therefore mere physical mixtures of the enantiomer components, these constitute a binary system. Such binary mixtures are easily described by the phase rule and can be profitably characterized by their melting point phase diagrams [10]. Since the components of a conglomerate racemate will melt indepen-... 

In the case of a chiral monomer, sequences of the resultant polymer should be directly influenced by the stereoselectivity of these interactive moieties." if the interactive moiety prefers homochiral association, two enantiomeric polymers of individual optical antipodes should be afforded. Contrary to this, when the interactive moiety possesses a strong tendency to adhere another monomer with opposite handedness, an alternative eopolymer of each enantiomer is expected to arise. On the other hand, the monomer with no stereoselectivity will give a random copolymer. Studies on the supramolecular polymerization of racemic monomers are of significant importance, because these three extreme cases are regarded as the simplest models of the molecular arrangements in crystalline states, conglomerates, racemic compounds, and racemic mixtures, respectively. 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

Plouvier then prepared the previously unknown racemic form of proto-quercitol by mixing equal weights of the two enantiomers. The melting point (237°C.) of the mixture was not depressed, and its (presumably solid state) infrared spectrum reportedly (36) was identical with that of either active form. It thus appears that DL-proto-quercitol exists as a solid solution, not a racemic compound or conglomerate. 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

The first resolution of an octahedral complex into its enantiomers was achieved in 1911 by A. Werner, who got the Nobel Prize in 1913, with the complex [Co(ethylenediamine)(Cl)(NH3)] [10]. Obviously, resolution is to be considered only in the case of kinetically inert complexes whose enantiomers do not racemize quickly after separation. This is a very important remark since, as noted above, the interesting complexes are those containing exchangeable sites required for catalytic activity and thus more sensitive to racemization. We will not discuss here the very rare cases of spontaneous resolution during which a racemic mixture of complexes forms a conglomerate (the A and A enantiomers crystallize in separate crystals) [11,12]. 

As typical examples of crystal-to-crystal thermal reactions, the cyclization of allene derivatives to four-membered ring compounds and the transformation of a racemic complex into a conglomerate complex are described. 

Racemic Crystal-to-Conglomerate Crystal Transformation Reactions in 2,2 -Dihydroxy-1,1 -binaphthyl-l /le4N+CI Complex... 

Figure 24 shows the ternary phase diagram (solubility isotherm) of an unsolvated conglomerate that consists of physical mixtures of the two enantiomers that are capable of forming a racemic eutectic mixture. It corresponds to an isothermal (horizontal) cross section of the three-dimensional diagram shown in Fig. 21. Examples include A-acetyl-leucine in acetone, adrenaline in water, and methadone in water (each at 25°C) [141].

Fig. 23 Tie lines associated with different systems (1) a solid phase D (pure enantiomer) in the presence of mother liquor of variable composition, (2) a solid phase L, (solvated enantiomer) in mother liquor of variable composition, (3) a solid phase R (pure racemic compound) in mother liquor of variable composition, (4) a solid phase Rs (solvated racemic compound) in mother liquor of variable composition, (5) two solid phases, one enantiomer and the racemic compound (or two enantiomers if E is on SR, i.e., for a conglomerate) in mother liquor of fixed composition E (eutectic), and (6) the tie lines do not converge one solid phase is present (solid solution of D and L) in mother liquor of variable composition. (Reproduced with permission of the copyright owner, John Wiley and Sons, Inc., New York, from Ref. 141, p. 177.)...

Fig. 24 Isothermal solubility diagrams for a racemic conglomerate, i.e., a eutectic system of the two opposite enantiomers. The appearance of the tie lines is shown in (b). Symbols are defined in the text. (Reproduced with permission of the copyright owner, John Wiley and Sons, Inc., New York, from Ref. 141, p. 178.)...

If the molecular species of the solute present in solution is the same as those present in the crystals (as would be the case for nonelectrolytes), then to a first approximation, the solubility of each enantiomer in a conglomerate is unaffected by the presence of the other enantiomer. If the solutions are not dilute, however, the presence of one enantiomer will influence the activity coefficient of the other and thereby affect its solubility to some extent. Thus, the solubility of a racemic conglomerate is equal to twice that of the individual enantiomer. This relation is known as Meyerhoffer s double solubility rule [147]. If the solubilities are expressed as mole fractions, then the solubility curves are straight lines, parallel to sides SD and SL of the triangle in Fig. 24. 

If a solute of the general formula AX (A is the chiral ion and X is an achiral ion) dissociates completely into ions once dissolved, then the solubility of the racemic conglomerate, SR, is equal to n%V2-SA (where SA is concentration of A in a solution saturated with AX ). If the solute is of the type AX, then 5 = V2-5a. The subscript n refers to the achiral ion and may be fractional, and so A2X must be represented by AXi/. If dissociation of AX is incomplete, SA lies between n i/2-SA and 2SA. For weakly dissociated electrolytes (such as carboxylic acids), SR is approximately 2SA. 

This situation changed dramatically in 1996 with the discovery of strong electro-optic (EO) activity in smectics composed of bent-core, bowshaped, or banana-shaped achiral molecules.4 Since then, the banana-phases exhibited by such compounds have been shown to possess a rich supermolecular stereochemistry, with examples of both macroscopic racemates and conglomerates represented. Indeed, the chiral banana phases formed from achiral or racemic compounds represent the first known bulk fluid conglomerates, identified 150 years after the discovery of their organic crystalline counterparts by Pasteur. A brief introduction to LCs as supermolecular self-assemblies, and in particular SmC ferroelectric and SmCA antiferroelectric LCs, followed by a snapshot of the rapidly evolving banana-phase stereochemistry story, is presented here. 

A young Louis Pasteur observed that many salts of tartaric acid formed chiral crystals (which he knew was related to their ability to rotate the plane of polarization of plane-polarized light). He succeeded in solving the mystery of racemic acid when he found that the sodium ammonium salt of racemic acid could be crystallized to produce a crystal conglomerate. After physical separation of the macroscopic enantiomers with a dissecting needle, Pasteur... 

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