Partially racemic compounds

A 50 50 mixture of enantiomers is called a racemate a partially racemized compound, e.g. a mixture that contains, say, a 73 27 ratio of enantiomers is called scalemic. In this latter case the constitution of a mixture is described numerically by an enantiomeric excess or by an enantiomeric ratio. 

In the case of partially racemic compounds i.e, the compound of a racemate with an optically active substance) the type of curve will... 

As has already been pointed out, the formation of racemic compounds from the two enantiomorphous isomerides, is analogous to the formation of double salts. The isothermal solubility curves also have a similar form. In the case of the latter, indeed, the relationships are simplified by the fact that the two enantiomorphous forms have identical solubility, and the solubility cur 7-es are therefore symmetrical to the line bisecting the angle of the co-ordinates. Further, with the exception of the partially racemic compounds to be mentioned later, there is no transition interval. 

Partially racemic compounds, —In this case we are no longer dealing with enantiomorphous forms, and the solubility of the two oppositely active isomerides is no longer the same. The symmetry of the solubility curves therefore disappears, and a figure is obtained which is identical in its general form with that found in the case of ordinary double salts (Fig. 129). In this case there is a transition interval. 

The curves acb belong to a temperature at which the partially racemic compound cannot be formed a dfb to the temperature at which the compound just begins to be stable in contact with water, and a"ed fb" belongs to a temperature at which the partially racemic compound is quite stable in contact with water. Suppose solubility determinations made, in the first case, with the original material alone, and then with the original body plus each of the two compounds, formed from the enantiomorphous substances separately, then if the original body was a mixture, identical solutions will be obtained in all three cases (point c) if it was a partially racemic compound, three different solutions [e, d / ) will be obtained if the temperature was outside the transition interval, and two solutions, d and /, if the temperature belonged to the transition interval. 

C. By Oxidation.—This year s literature has been notable for attempts to study the details of certain phosphine oxidation reactions. In one such investigation nitric acid was found to oxidize phosphines, or phosphine sulphides, to phosphine oxides with inversion of configuration at phosphorus, whereas dinitrogen tetroxide, in the absence of acid, was found to oxidize the same compounds with predominant retention. The partial racemization observed with the latter reagent was probably due to the racemization of the oxides, since methylphenyl-n-propylphosphine oxide... 

Partial or complete separation of enantiomers within a racemic mixture as a result of unequal rates of reaction with another agent. The latter reagent, catalyst, solvent, or micelle must itself exhibit chirality, resulting in its stereoselective or stereospecific action on the racemic compound. 

Comparison of the configuration of the stannane with the prodncts of reaction reveals that primary alkyl halides that are not benzyhc or a to a carbonyl react with inversion at the lithium-bearing carbon atom. In the piperidine series, the best data are for the 3-phenylpropyl compound, which was shown to be >99 1 er. In the pyrrolidine series, the er of the analogous compound indicates 21-22% retention and 78-79% inversion of configuration. Activated alkyl halides such as benzyl bromide and teri-butyl bromoacetate afford racemic adducts. In both the pyrrolidine and piperidine series, most carbonyl electrophiles (i.e. carbon dioxide, dimethyl carbonate, methyl chloroformate, pivaloyl chloride, cyclohexanone, acetone and benzaldehyde) react with virtually complete retention of configuration at the lithium-bearing carbon atom. The only exceptions are benzophenone, which affords racemic adduct, and pivaloyl chloride, which shows some inversion. The inversion observed with pivaloyl chloride may be due to partial racemization of the ketone product during work-up. 

The (2R,3R,4R) diastereomer results from partial racemization of one or both of the allenylmetal intermediates. This point was confirmed by comparison to authentic material as the (S)-MPA ((S)-(2-methoxy)phenylacetic acid-Mosher s acid) derivative. The optical rotations of these compounds are small, and thus correlation by comparison of [ajp... 

An interesting new group of flavan-3-ol analogs containing an additional C6-C2 unit at C-5 (A-ring) has been isolated from the tubes of Pleione bulbocodioides Shanciol, called a dihydrophenanthropyran, was obtained in partially racemized form (93)/(94), and is accompanied by shanciol A (95), shanciol B (96), and shanciol E (97). These compounds are... 

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. 

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. 

Despite the highly selective alkylations of azaenolates, the optical purity of the final products is rather low in several cases, due to partial racemization during hydrolysis of the alkylated imines. In general, racemization occurs very fast in basic media, whereas in acidic solutions, especially in two-phase systems, the degree of racemization is rather low and depends on the nature of the carbonyl compounds. 

Pyrrolizid-l-one, obtained from the ethyl ester of L-proline (see Section II,E), was condensed with methylenetriphenylphosphorane to give 1-methylenepyrrolizidine, [a] 8 —33°, the IR spectrum of the latter compound was identical with that of the naturally occurring alkaloid. Notwithstanding the partial racemization of the base during... 

NMR Spectra. Uskokovic was probably the first to report the difference in the H-NMR spectra of an optically pure compound and its racemate (53). As illustrated in Scheme 32, the spectra of optically pure dihy-droquinine and the racemate differ significantly when taken at the same concentration in chloroform-d. The spectrum of the partially resolved compound affords two sets of peaks whose areas are proportional to the relative amount of each enantiomer. These observations can be understood by considering the presence of the solute-solute interactions of the enantiomers. Thus, to the extent that there is some solute aggregation, enantiomers may exhibit different spectra. 

Initially, only the nitrile of L-mannonic acid was found on addition of hydrocyanic acid to L-arabinose this acid retained the original arabinose in the asymmetry centers 3, 4, and 5. The new center of asymmetry created in this way at C-2 was first considered by Fischer to be racemic. This would have meant that the L-mannonic acid should be a partial racemate however, attempts to separate it into two stereoisomers failed. The idea of a partial racemate led to the question as to whether L-mannonic acid and D-gluconic acid (which are enantiomorphous on carbon atoms 3, 4, and 5) could form such a partial racemate (which would still be optically active). Such a compound could not be isolated, but negative results have only limited values as proof. ... 

Cook and co-workers suggested that partial racemization had occurred in the acid/base mediated isolation of (-)-tetrahydroroeharmine (41), Fig. (10) [35]. Proof was obtained by treating 41 with TFA/CH2CI2 at room temperature, which resulted in racemization of 41. In an experiment with TFA-rf, deuterium was incorporated only at C-5 and C-8, not at the epimeric centre, indicating that a mechanism analogous to Mechanism 1 was not active. Reddy and Cook, in contrast, proposed that the mechanism depicted in Scheme (10) was responsible for the racemization of (-)-tetrahydroroeharmine (41). This mechanism is analogous to Mechanism 3. Interestingly, compounds with more than one asymmetric... 

Two laboratories, those of Walborsky and of Goering, simultaneously investigated the stereochemistry of solvolysis of optically active bicyclo[2.2.2]-octyl arenesulfonates, and both found that the product consists of only two compounds 2-bicyclo[2.2.2]octyl and exo-2-bicyclo[3.2.1] derivatives.The [2.2.2] system is largely retained although there is some attendant racemization, and the [3.2.1] system is also chiral but again partially racemized. Both groups concluded that ionization at C2 is assisted by the —C6 bond ajH that flip product... 

The properties of partially acetylated cellulose for the separation of enantiomers were recognized in 1966 by Luttringhaus and Peters [14]. But the full potential of cellulose acetate was developed by Hesse and Hagel in 1973 [15]. Since then, this stationary phase has been frequently used for the resolution of various racemic compounds. Native cellulose acetylated heterogeneously yields a crystallographic form of cellulose triacetate (CTA) known as CTA-I, which corresponds to its source, an indication that the original supramolecular structure of the starting... 

A single CSP cannot be used for the chiral resolution of all racemic compounds. Therefore, different CSPs were used for the chiral resolution of different racemates. To make this part easy and clear, Table 1 includes the names of 20 CSPs and their most frequent applications. However, some other interesting applications are possible. Upon screening about 510 racemic compounds described in the literature, we observed that 229 of them resolved completely and 86 partially on cellulose tris(3,5-dimethylphenylcarbamate), and the rest not at all. For amylose tris(3,5-dimethylphenylcarbamate) CSP, we screened 384 racemic compounds and observed that 107 resolved completely and 102 partially. Clearly, cellulose and amylose tris(3,5-diphenylcarbamate) CSPs have the ability to resolve about 80% of the racemic compounds investigated. 

ISOLATION OF PURE ENANTIOMERS FROM PARTIALLY RESOLVED COMPOUNDS BY USE OF CRYSTALLIZING CHARACTERISTICS OF RACEMIC MIXTURES... 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

Fig. 10.28. The addition of a Grignard reagent to aromatic carbonyl compounds proceeds via SET in part, which is demonstrated by the partial racemizations observed here the sec-alkyl radical that occurs as an intermediate undergoes an extremely rapid racemiza-tion. The more stable the simultaneously formed magnesium-bound ketyl radical is, the larger is the share of the racemization.

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