Racemic compound solid solution

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. 

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.)...

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. 

If solvent is added to either of the solid eutectics represented by e or e in Fig. 25a or b, the undissolved solid retains this composition while the saturated solution maintains the composition E or E, respectively. Again, Gibbs phase rule [145,146] can provide further insight into these systems. If the solid enantiomers are solvated, the compositions of the equilibrium solids are displaced symmetrically along the DS or LS axes to an extent determined by the stoichiometry of the solvates. Similarly, if the racemic compound is solvated, the stoichiometry of the equilibrium solid is displaced from R along the line RS to an extent determined by the stoichiometry of the solvate. 

Racemate - Traditionally, a 1 1 mixture of enantiomers was denoted racemic mixture. In order to describe precisely the solid state according to distinct phases racemates (or racemic compounds), conglomerates and solid solutions were distinguished. Thus, the term race-mate had a very specific function. However, currently the term racemate is almost exclusively used in the general sense of racemic mixture. It appears sensible to comply to current usage and reserve the term racemic compound to a distinct solid phase. 

The fact that the racemization of[Co(en)3]X3MH20 salts proceeds more rapidly for the hydrated complexes than for the anhydrous ones cannot be due to the nucleophilicity of HzO toward the cobalt atom because [Co(en)3]I3H20 is found to racemize faster in the solid state than in solution 23 Instead, the dehydration process is thought to produce an open crystal structure with many defects in which inversion can occur in a less restricted fashion than is possible in the presumably more compact and defect free anhydrous compound. Interestingly, [Co(en)3]Cl3-H20, which does not change crystal structure upon dehydration, does not racemize either as the hydrate or anhydrous compound. It is further observed (based on X-ray powder patterns) that the racemic compounds obtained from solution have different crystal structures than those obtained by solid-phase racemization. 

The method relies on the p and n salts having different solubilities, and they must not form solid solutions or double salts. The more insoluble salt is filtered and the purified acid recovered by adding mineral acid. This method of chiral resolution is well established, and lists of resolving agents for many classes of racemic compounds are available [22], Inclusion chemistry may be employed for the same purpose by preparing host-guest compounds with a chiral host ... 

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

The formation of two-dimensional nanocrystals, by peptide amphiphiles is also influenced by the chirality of the peptide building block.125 Three types of two-dimensional crystals were observed after the assembly of the functionalized peptide amphiphiles 17-19 shown in Figure 7.11 (above) at the air-water interface, which was followed by polymerization. These two dimensional crystals include (/) a racemic compound, in which each enantiomer is packed with its mirror image in a crystalline order, (it) enantiomorphous conglomerates, in which each enantiomer is segregated into small domains, and (iii) a solid solution, in which all molecules are randomly distributed without crystalline order. Interestingly, in the case of the two-dimensional system arising from the racemic compound,... 

C and 28 inches of Hg for 2 hours as (R)-4-benzyl albuterol D-DBTA salt (22.9 g, 37.1% yield, 99.3% ee). The salt (22.9 g) is then treated with 204 mL of 5 wt % aq. Na2C03 solution in 570 mL of ethyl acetate. The solid is worked-up, and recrystallization from 30 mL of ethyl acetate and 30 mL of n-heptane gives optically pure (R)-4-benzyl albuterol free base as a white powder (10.1 g, 34.1% yield from racemic compound 99.6% ee and 99.8% purity). 

Both modifications of the method depend upon a natural segregation of the molecules of each active component into their individual crystal lattices. Experience has shown that such segregation, though common for dissimilar solutes, seldom occurs in the solution of a racemic substance and then usually in a narrow range of conditions that cannot be predicted or attained readily. In the great majority of instances the molecules of both active components combine in equal numbers to form one species of crystals known as a racemic compound or combine in variable proportions to form a series of solid solutions. Also, when segregation does occur, the experimental procedure necessary to produce distinguishable crystals or a uniform deposit of one variety is usually troublesome and slow. Hence the method has assumed practical value only in a few instances in which all the circumstances are especially favorable. 

For convenience, a phase diagram of a pair of diastereomeric crystals is ordinarily studied in detail, and the mechanism of the diastereomeric resolution is interpreted in terms of the thermodynamic and physical properties of the bulk of the diastereomeric crystals.4,7-10 Such studies reveal the importance for diastereomeric resolution of the type of mixture of diastereomers in a target system. There are three types of diastereomer mixtures an eutectic mixture, a 1 1 addition compound, and a solid solution. To achieve successful resolution, it is essential that the mixture of the diastereomeric crystals of a target racemate with a resolving agent be an eutectic mixture. The classic studies are thoroughly reviewed by Collet and co-workers.4,12... 

The compounds in this report usually contain a chirotopic stereogenic carbon ring atom, and were prepared as racemic mixtures. Hypothetically, if the BC conformation prevails, then one can imagine two enantiomers in solution (reference, 5)-BC 9 and (retro-inverso,R)-BC 9-bar. Since this stereochemistry is complicated, it will be helpful if we refer to the descriptor for only one enantiomer. Therefore, in an arbitrary but consistent manner in this report, we will always define the reference ring chirality and label tropicity to be that of the (S)-enantiomer. For example, suppose a racemic mixture of (reference,S)-BC 9 and (retro-inverso,R)-BC 9-bar affords crystals belonging to an achiral space group so that both enantiomers in the racemic compound are present in the crystal lattice. Let us further suppose that dissolution of these crystals will give the same solution-state conformation. We will write that the solid-state (reference,S)-BC 9... 

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. 

A brief description of the type of "racemic" compounds is necessary for the reader to better understand the principles behind the application of crystallization methods to the separation of enantiomers. Three fundamental types of crystalline racemates exist. In the first, the crystalline racemate is a conglomerate, which exists as a mechanical mixture of crystals of two pure enantiomers. The second, which is the most common, consists of the two enantiomers in equal proportions in a well-defined arrangement within the crystal lattice this is termed racemic compound. The third possibility occurs with the formation of a solid solution between the two enantiomers that coexist in an unordered manner in the crystal. This kind of racemate is called a pseu-... 

Enantiomers are stereoisomers, which are mirror images of eath another. An equimolecular mixture of two enantiomers is called a racemate. Crystalline race-mates occur in three different types. The first is termed a conglomerate, that is, a mechanical mixture of crystals of pure enantiomers that is formed from two solid phases. The most common type is the racemic compound, which consists only of one crystalline phase in which the two enantiomers are present in equal quantities. The third type is the pseudoracemate in which a solid solution of the two enantiomers is present. 

Fig. 16 Phase diagrams for enantiomers (A) conglomerate, (B) and (C) racemic compound, (D) solid solution.

In general, kinetic resolution requites the presence of a racemic mixture (conglomerate) and the absence of a (generally lower-solubility) racemic compound (both enantiomers in the crystal lattice). This is not always the case, however, and depending on the relative rates of nucleation and crystal growth of the respective forms, a kinetic (nonthermodynamic) isomer separation can sometimes be effected even when a racemic compound is possible. In the case of solid solution of the enantiomers (no lattice fit requirement), an equilibrium process will essentially always be requited. 

A description of an amplification procedure based on the different solubility of the D-enantiomer and that of the corresponding d, L-racemate of ribonucleosides follows. When the melting points and solubilities of crystalline d, L-ribonucleosides and the pure D-ribonucleoside were determined, it was found that solution-based amplification of a slight ee of D-cytidine and D-adenosine, in a mixture with the d, L-racemates, is sufficiently large to produce solutions with at least 99% ee of the D-enantiomer (Breslow et al. 2010 and references cited therein). The 96% excess of D-uridine could also be sufficient to allow for the selection of the d isomer in solution under prebiotic conditions. In contrast, d, L-ribose itself forms a solid solution and d, l-guanosine a conglomerate (Breslow et al. 2010). This work is based on the mechanism for the amplification of fluctuations in racemic mixtures of the corresponding compounds (Morowitz 1969). 

In cases where the active components can form mixed crystals or solid solutions, the freezing-point curve will exhibit one of the forms given in Figs. 43 and 48. The inactive mixed crystal containing 50 per cent, of the dextro and laevo compound, is known as a pseudo-racemic mixed crystal. So far, only curves of the types I. and II. have been obtained. 

In the case of the carvoximes solid solutions are also formed, but the equilibrium curve in this case exhibits a maximum (Fig. 58). At this maximum point the composition of the solid and of the liquid solution is the same. Since the curve must be symmetrical, this maximum point must occur in the case of the solution containing 50 per cent, of each component, which will therefore be inactive. Further, this inactive solid solution will melt and solidify at the same temperature, and behave, therefore, like a chemical compound (p. 121). The melting-point of the active compounds is 72° that of the inactive pseudo-racemic mixed crystal is 91-4°... 

That is, no compound capable of existing as solid phase in equilibrium with liquid mixtures. A racemic compound may be formed which 3delds solid solutions with the optically active isomerides. 

From these curves, now, it will be evident that it will be possible, in any given case, to decide whether or not an inactive solid is a mixture or a racemic compound- For this purpose, two solubility determinations are made, first with the inactive material alone (in excess), and then with the inactive material plus excess of one of the optically active forms. If we are dealing with a mixture, the two solutions thus obtained will be identical both will have the composition corre-... 

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