The racemic modification

Figure 11.3 The acid-catalyzed hydrolysis of one trans-2,3-dimethyloxirane enantiomer produces the meso (21 ,3 S)-2,3-butanediol by path (a) or path (b). Hydrolysis of the other enantiomer (or the racemic modification) would yield the same product.

TYPICAL PROCESSES OF PREFERENTIAL CRYSTALLIZATION If a conglomerate derivative is found, a moderate supersaturated solution of the racemic modification is prepared. Then, appropriate quantity of the (+) or (-) seed crystal of the optically active compound is inoculated into the solution, and it is left standing or stirred gently to crystallize. If a certain amount of the optically active compound (e.g. 1 g) was crystallized out by the first inoculation, then we can obtain about 2 g each of the optically active compounds after adding 2 g each of the racemic modification and repeating the operation. 

Even for such a quantity of crystallization, separating the crystals while at the same preventing the crystallization of the opposite enantiomer is often difficult because the solution is supersaturated with the opposite enantiomer. In this case, the stability of the supersaturated solution can be improved remarkably by dissolving a readily soluble salt derivative of the racemic modification (Fig. 8). 

In Figure 8, the salt to be resolved by preferential crystallization is shown as A B, and the readily soluble co-existing salt is shown as A C. Starting with a mixture of composition I, the composition of the mother liquor becomes like composition II when the (+)-isomer is crystallized out from the solution. If the racemic salt ( )-A B is then added, the composition of the mother liquor becomes III. When (-)-isomer is crystallized out from III, it is possible that almost twice as much of the (-)-isomer is crystallized out from the solution shown as IV. Thereafter, we can obtain the optically active salts alternatively by adding the racemic modification salt ( )-A-B and repeating the same operations. 

Camphor is of considerable importance technically, being used in the manufacture of celluloid and medicinal products. It is manufactured industrially from a-pinene, obtained from turpentine, by several processes (66-107) which differ mainly in detail. Synthetic camphor is usually obtained as the racemic modification. The formation of camphor involves the Wagner-Meerwein rearrangements, e.g. ... 

A direct consequence of the stereospecific nature of many metabolic processes is that racemic modifications must be treated as though they contained two different drugs, each with its own pharmacokinetic and pharmacodynamic properties. Investigation of these properties must include an investigation of the metabolites of each of the enantiomers of the drug. Furthermore, if a drug is going to be administered in the form of a racemic modification, the metabolism of the racemic modification must also be determined, since this could be different from that observed when the pure enantiomers are administered separately. 

Table 10.1 Examples of the pure enantiomers used to resolve racemic modifications by forming diastereoisomers. In all regeneration processes there is a danger of the racemic modification being reformed by racemization...

A purely organic chiral nitroxide which shows liquid crystalline behaviour as well as intriguing magnetic properties and a dependence on the enantiomeric nature has been reported [180]. The reason for studying the compounds was to increase the sensitivity of mesophases to magnetic and electric fields. The racemic modification of the radical, which displays a nematic phase, proved to be more sensitive to alignment than the cholesteric phase with the enantiomers present. It was proposed that the compounds may also be used to study the dynamic nature of mesophases by electron paramagnetic resonance spectroscopy. 

Chand S, Banwell MG (2007) Biomimetic Preparation of the Racemic Modifications of the Stilbenolignan Aiphanol and Three Congeners. Aust J Chem 60 243... 

To end this section and the review, we mention briefly the first results from the simulation on laboratory-frame cross-correlation of the type (v(f)J (0)). Here v is the molecular center-of-mass linear velocity and J is the molecular angular momentum in the usual laboratory frame of reference. For chiral molecules the center-of-mass linear velocity v seems to be correlated directly in the laboratory frame with the molecule s own angular momentum J at different points r in the time evolution of the molectilar ensemble. This is true in both the presence and absence of an external electric field. These results illustrate the first direct observation of elements of (v(r)J (0)) in the laboratory frame of reference. The racemic modification of physical and molecular dynamical properties depends, therefore, on the theorem (v(r)J (0)) 0 in both static and moving frames of reference. An external electric field enhances considerably the magnitude of the cross-correlations. 

Given a mixture of all four stereoisomeric 2,3-dichloropentanes, we could separate it, by distillation, for example, into two fractions but no further. One fraction would be the racemic modification of I plus II the other fraction would be the racemic modification of III plus IV. Further separation would require resolution of the racemic modifications by use of optically active reagents (Sec. 7.9). 

Each enantiomer should, of course, be optically active. Now, if we were to put the jec-butyl chloride actually prepared by the chlorination of -bulane into a polarimeter, would it rotate the plane of polarized light The answer is no, because prepared as described it would consist of the racemic modification. The next question is why is the racemic modificcUion formed ... 

In the first step of the reaction, a chlorine atom abstracts hydrogen to yield hydrogen chloride and a j c-butyl free radical. The carbon that carries the odd electron in the free radical is jp. j ybridized trigonal, Sec. 2.21), and hence a part of the molecule is flat, the trigonal carbon and the three atoms attached to it lying in the same plane. In the second step, the free radical abstracts chlorine from a chlorine molecule to yield jec-butyl chloride. But chlorine may become attached to either face of the flat radical, and, depending upon which face, yield either of two products R or S (see Fig. 7.1). Since the chance of attachment to one face is exactly the same as for attachment to the other face, the enantiomers are obtained in exactly equal amounts. The product is the racemic modification. 

The randomness of attack that yields the racemic modification from achiral reactants is not necessarily due to the symmetry of any individual reactant molecule, but rather to the random distribution of such molecules between mirror-image conformations (or to random selection between mirror-image transition states). 

We know (Sec. 7.3) that when optically inactive reactants form a chiral compound, the product is the racemic modification. We know that the enantiomers making up a racemic modification have identical physical properties (except for direction of rotation of polarized light), and hence cannot be separated by the usual methods of fractional distillation or fractional crystallization. Yet throughout this book are frequent references to experiments carried out using-... 

Addition of bromine to the 2-butenes involves a/ir/-addition. If we start (Fig. 7.4) with cw-2-butene, we can attach the bromine atoms to opposite faces of the alkene either as in a) or in (b) and thus obtain the enantiomers. Since, whatever the mechanism, ( i) and b) should be equally likely, we obtain the racemic modification. 

Now bromonium ion III is attacked by bromide ion. A new carbon-bromine bond is formed, and an old carbon-bromine bond is broken. This attack occurs on the bottom face of 111, so that the bond being formed is on the opposite of carbon from the bond being broken. Attack can occur by path (a) to yield structure IV or by path (b) to yield structure V. We recognize IV and V as enantiomers. Since attack by either (a) or (b) is equally likely, the enantiomers are formed in equal amounts, and thus we obtain the racemic modification. The same results are obtained if positive bromine initially becomes attached to the bottom face of c -2-butene. (Show with models that this is so.)... 

The environments of the two protons are the same in V. The environments arc different for the two in VI and VII, but average out the same because of the equal populations of these enantiomeric conformations. (Here, however, we cannot say just what the average environment is, unless we know the ratio of V to the racemic modification (VI plus VII).)... 

The product has the opposite configuration from the starting materials, as in the Sn2 reaction, but this time there is a loss in optical purity. Optically pure bromide yields alcohol that is only about two-thirds optically pure. Optically pure starting material contains only the one enantiomer, whereas the product clearly must contain both. The product is thus a mixture of the inverted compound and the racemic modification, and we say that the reaction has proceeded with partial racemization. How can we account for these stereochemical results ... 

If the attack were purely random, we would expect equal amounts of the two isomers that is to say, we would expect only the racemic modification. But the product is not completely racemized, for the inverted product exce ds its enantiomer. How do we account for this The simplest explanation is that attack by the nucleophilic reagent occurs before the departing halide ion has completely left the neighborhood of the carbonium ion to a certain extent the departing ion thus shields the front side of the ion from attack. As a result, back-side attack is somewhat preferred. 

Even in the best case, some racemic product is produced and must be separated out. This separation is easy or hard, depending on the nature of the racemate. If the racemic modification has a different crystalline form to that of the pure d or l, then separation of the pure excess enantiomer will be inefficient. If one achieves a 90% ee value, then it is quite possible to get out only 75-80% pure enantiomer. With lower ee values, the losses become prohibitive. For such a system, a catalyst of very high efficiency must be used. Unfortunately, most compounds are of this type their racemic modifications do not crystallize as pure d- or l-forms. If, on the other hand, the racemic modification is a conglomerate or an equal mix of d- and L-crystals, then recovery of the excess the L-form can be achieved with no losses. Since the l- and D,L-forms are not independently soluble, a 90% ee value easily gives a 90% recovery of pure isomer. In our L-dopa process, the intermediate is just such a conglomerate and separations are efficient. This lucky break was most welcome. If one thinks back, ours was the same luck that Pasteur encountered in his classical tartaric acid separations, 150 years ago. 

Whereas the optically pure compound 6c resembles the racemic modification in the solid state, the opposite was found to be the case for racemic 6d which proved to be isostructural with optically active 6a (19a-b,20) this material crystallizes in the chiral space group PI with the two enantiomers randomly distributed throughout the lattice. Crystals of unequal R/S composition could be prepared by recrystallizing various mixtures of the optical antipodes. Irradiation of these crystals gave a diastereomeric mixture of optically active dimers, trimers and oligomers, the optical purities of which varied from 0 to 100% depending on the R/S composition of the sample photolyzed. This... 

When the salt derived from the hydrogenation products is crystallized, a part of the racemic modification crystallizes as a racemate but not conglomerate, while a part of the excess enantiomer gives crystals of a single enantiomer. In all cases, the former crystals are much soluble than the latter. Hence crystals of a single enantiomer are effectively isolated from racemic modification. This optical enrichment procedure is effectively applied for 3-hydroxyalkanoic acids of more than 80% e.e. on a practical scale. 

The reactions between MeP(S)Cl2 and amines have been utilized in a novel way the products from chiral amines, e.g. aminocarboxylic acids, consist of mixtures of dia-stereoisomeric methylphosphonothioic diamides, two of meso structure, 102 and its mirror image, together with the racemic modification 103 the proton-decoupled P NMR spectra of such mixtures display three well separated singlets from which the enantiomeric purity of the amines can be determined. ... 

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