Racemic mixture properties

The Cahn-Ingold-Prelog (CIP) rules stand as the official way to specify chirahty of molecular structures [35, 36] (see also Section 2.8), but can we measure the chirality of a chiral molecule. Can one say that one structure is more chiral than another. These questions are associated in a chemist s mind with some of the experimentally observed properties of chiral compounds. For example, the racemic mixture of one pail of specific enantiomers may be more clearly separated in a given chiral chromatographic system than the racemic mixture of another compound. Or, the difference in pharmacological properties for a particular pair of enantiomers may be greater than for another pair. Or, one chiral compound may rotate the plane of polarized light more than another. Several theoretical quantitative measures of chirality have been developed and have been reviewed elsewhere [37-40]. 

A much more serious drawback to using chiral drugs as racemic mixtures is illustrated by thalidomide briefly employed as a sedative and antinausea drug in Europe during the period 1959-1962 The desired properties are those of (/ ) thalidomide (S) Thalido mide however has a very different spectrum of bio logical activity and was shown to be responsible for over 2000 cases of serious birth defects in children born to women who took it while pregnant... 

Section 7 4 Optical activity, or the degree to which a substance rotates the plane of polarized light is a physical property used to characterize chiral sub stances Enantiomers have equal and opposite optical rotations To be optically active a substance must be chiral and one enantiomer must be present m excess of the other A racemic mixture is optically inactive and contains equal quantities of enantiomers... 

Many of the physical properties are not affected by the optical composition, with the important exception of the melting poiat of the crystalline acid, which is estimated to be 52.7—52.8°C for either optically pure isomer, whereas the reported melting poiat of the racemic mixture ranges from 17 to 33°C (6). The boiling poiat of anhydrous lactic acid has been reported by several authors it was primarily obtained duriag fractionation of lactic acid from its self-esterification product, the dimer lactoyUactic acid [26811-96-1]. The difference between the boiling poiats of racemic and optically active isomers of lactic acid is probably very small (6). The uv spectra of lactic acid and dilactide [95-96-5] which is the cycHc anhydride from two lactic acid molecules, as expected show no chromophores at wavelengths above 250 nm, and lactic acid and dilactide have extinction coefficients of 28 and 111 at 215 nm and 225 nm, respectively (9,10). The iafrared spectra of lactic acid and its derivatives have been extensively studied and a summary is available (6). 

DUactide (5) exists as three stereoisomers, depending on the configurations of the lactic acid monomer used. The enantiomeric forms whereia the methyl groups are cis are formed from two identical lactic acid molecules, D- or L-, whereas the dilactide formed from a racemic mixture of lactic acid is the opticaUy iaactive meso form, with methyl groups trans. The physical properties of the enantiomeric dilactide differ from those of the meso form (6), as do the properties of the polymers and copolymers produced from the respective dilactide (23,24). 

Although most anesthetics are achiral or are adininistered as racemic mixture, the anesthetic actions are stereoselective. This property can define a specific, rather than a nonspecific, site of action. Stereoselectivity is observed for such barbiturates as thiopental, pentobarbital, and secobarbital. The (3)-enantiomer is modestly more potent (56,57). Additionally, the volatile anesthetic isoflurane also shows stereoselectivity. The (3)-enantiomer is the more active (58). Further evidence that proteins might serve as appropriate targets for general anesthetics come from observations that anesthetics inhibit the activity of the enzyme luciferase. The potencies parallel the anesthetic activities closely (59,60). 

When additional substituents ate bonded to other ahcycHc carbons, geometric isomers result. Table 2 fists primary (1°), secondary (2°), and tertiary (3°) amine derivatives of cyclohexane and includes CAS Registry Numbers for cis and trans isomers of the 2-, 3-, and 4-methylcyclohexylamines in addition to identification of the isomer mixtures usually sold commercially. For the 1,2- and 1,3-isomers, the racemic mixture of optical isomers is specified ultimate identification by CAS Registry Number is fisted for the (+) and (—) enantiomers of /n t-2-methylcyclohexylamine. The 1,4-isomer has a plane of symmetry and hence no chiral centers and no stereoisomers. The methylcyclohexylamine geometric isomers have different physical properties and are interconvertible by dehydrogenation—hydrogenation through the imine. 

In many cases only the racemic mixtures of a-amino acids can be obtained through chemical synthesis. Therefore, optical resolution (42) is indispensable to get the optically active L- or D-forms in the production of expensive or uncommon amino acids. The optical resolution of amino acids can be done in two general ways physical or chemical methods which apply the stereospecific properties of amino acids, and biological or enzymatic methods which are based on the characteristic behavior of amino acids in living cells in the presence of enzymes. 

Pirmenol. Pirmenol hydrochloride, a pyridine methanol derivative, is a racemic mixture. It has Class lA antiarrhythmic activity, ie, depression of fast inward sodium current, phase 0 slowing, and action potential prolongation. The prolongation of refractory period may be a Class III property. This compound has shown efficacy in converting atrial arrhythmias to normal sinus rhythm (34,35). 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Discrimination between the enantiomers of a racemic mixture is a complex task in analytical sciences. Because enantiomers differ only in their structural orientation, and not in their physico-chemical properties, separation can only be achieved within an environment which is unichiral. Unichiral means that a counterpart of the race-mate to be separated consists of a pure enantiomeric form, or shows at least enrichment in one isomeric form. Discrimination or separation can be performed by a wide variety of adsorption techniques, e.g. chromatography in different modes and electrophoresis. As explained above, the enantioseparation of a racemate requires a non-racemic counterpart, and this can be presented in three different ways ... 

Meso compounds contain chirality centers but are achiral overall because they have a plane of symmetry. Racemic mixtures, or racemates, are 50 50 mixtures of (+) and (-) enantiomers. Racemic mixtures and individual diastereomers differ in their physical properties, such as solubility, melting point, and boiling point. 

In general the metal complexes are charged. It is thus possible to convert the racemic mixture of such a complex into a pair of diastereoisomeric species with different physico-chemical properties, in particular solubihty, by association with an enantiomerically pure chiral coimterion [19]. Examples of frequently used such ions are shown in Fig. 3. Then the separation can be achieved by ... 

Aliphatic acids such as butyric acid have been previously implicated as being allelopathic compounds (46, 47, 23). Chou and Patrick (23) isolated butyric acid from soil amended with rye and showed that it was phytotoxic. Hydroxy acids have also been shown to possess phytotoxic properties (48) but have not been implicated in any allelopathic associations. Since SHBA is a stereo isomer, and the enantiomer was not identified because of impurity, all bioassays were run using a racemic mixture. The D-(-) stereo isomer of SHBA has been isolated from both microorganisms and root nodules of legumes and is suspected to be a metabolic intermediate in these systems (49). It is likely that only one enantiomer was present in the extract therefore, the true phytotoxic potential of this compound awaits clarification of the phytotoxicity of the individual enantiomers. 

Lactide (LA), the cyclic diester of lactic acid, has two stereogenic centers and hence exists as three stereoisomers L-lactide (S,S), D-lactide (R,R), and meso-lactide (R,S). In addition, rac-lactide, a commercially available racemic mixture of the (R,R) and (S,S) forms, is also frequently studied. PLA may exhibit several stereoregular architectures (in addition to the non-stereoregular atactic form), namely isotactic, syndiotactic, and heterotactic (Scheme 15). The purely isotactic form may be readily prepared from the ROP of L-LA (or D-LA), assuming that epimerization does not occur during ring opening. The physical properties, and hence medical uses, of the different stereoisomers of PLA and their copolymers vary widely and the reader is directed to several recent reviews for more information.736 740-743... 

The implications for films cast from mixtures of enantiomers is that diagrams similar to those obtained for phase changes (i.e., melting point, etc.) versus composition for the bulk surfactant may be obtained if a film property is plotted as a function of composition. In the case of enantiomeric mixtures, these monolayer properties should be symmetric about the racemic mixture, and may help to determine whether the associations in the racemic film are homochiral, heterochiral, or ideal. Monolayers cast from non-enantiomeric chiral surfactant mixtures normally will not exhibit this feature. In addition, a systematic study of binary films cast from a mixture of chiral and achiral surfactants may help to determine the limits for chiral discrimination in monolayers doped with an achiral diluent. However, to our knowledge, there has never been any other systematic investigation of the thermodynamic, rheological and mixing properties of chiral monolayers than those reported below from this laboratory. 

In the bulk crystalline phases, large differences exist in the properties of the racemic mixture and the pure enantiomers. X-ray powder diffraction patterns showed that the racemic mixture was a true racemate, and the melting transition points and heats of fusion of the racemate were markedly different from those of the pure enantiomers [which were identical (Arnett and Thompson, 1981)]. 

Taken together, the equilibrium spreading pressures of films spread from the bulk surfactant, the dynamic properties of the films spread from solution, the shape of the Ylj A isotherms, the monolayer stability limits, and the dependence of all these properties on temperature indicate that the primary mechanism for enantiomeric discrimination in monolayers of SSME is the onset of a highly condensed phase during compression of the films. This condensed phase transition occurs at lower surface pressures for the R( —)- or S( + )-films than for their racemic mixture. 

Most of the time, enantiomers are found equally mixed together. Equally mixed enantiomers are not optically active because the rotation in one direction by one structure is canceled by the rotation in the opposite direction by the other structure. Hence, a sample of 2-butanol, for example, as normally obtained from a chemical vendor, is not optically active. An equimolar mixture of two enantiomers is called a racemic mixture and is optically inactive. Separation of a racemic mixture is not possible by conventional methods because the enantiomers are identical with respect to properties that are used to effect the separation. However, it may be possible to separate them by chemical methods, meaning that one may undergo a chemical reaction that the other does not. Some biological reactions are such reactions, and hence a single enantiomeric structure is sometimes found in nature. 

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