Racemic mixture

In chemistry, a racemic mixture or racemate (/reɪˈsiːmeɪt, rə-, ˈræsɪmeɪt/),^[1] is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates.

History

The first known racemic mixture was racemic acid, which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid. He manually separated the crystals of a mixture, starting from an aqueous solution of the sodium ammonium salt of racemate tartaric acid. Pasteur benefited from the fact that ammonium tartrate salt gives enantiomeric crystals with distinct crystal forms (at 77 °F). Reasoning from the macroscopic scale down to the molecular, he reckoned that the molecules had to have non-superimposable mirror images.^[2] A sample with only a single enantiomer is an enantiomerically pure or enantiopure compound.^[3]

Etymology

From

Nomenclature

A racemic mixture is denoted by the prefix (±)- or dl- (for sugars the prefix dl- may be used), indicating an equal (1:1) mixture of dextro and levo isomers. Also the prefix rac- (or racem-) or the symbols RS and SR (all in italic letters) are used.

If the ratio is not 1:1 (or is not known), the prefix (+)/(−), d/l- or d/l- (with a slash) is used instead.

The usage of d and l is discouraged by

In contrast to the two pure enantiomers, which have identical physical properties except for the direction of rotation of plane-polarized light, a racemate sometimes has different properties from either of the pure enantiomers. Different melting points are most common, but different solubilities and boiling points are also possible.

Pharmaceuticals may be available as a racemate or as the pure enantiomer, which might have different potencies. Because biological systems have many chiral asymmetries, pure enantiomers frequently have very different biological effects; examples include glucose and methamphetamine.

Crystallization

There are four ways to crystallize a racemate; three of which H. W. B. Roozeboom had distinguished by 1899:

Conglomerate (sometimes racemic conglomerate)

If the molecules of the substance have a much greater affinity for the same enantiomer than for the opposite one, a mechanical mixture of enantiomerically pure crystals will result. The mixture of enantiomerically pure R and S crystals forms a eutectic mixture. Consequently, the melting point of the conglomerate is always lower than that of the pure enantiomer. Addition of a small amount of one enantiomer to the conglomerate increases the melting point. Roughly 10% of racemic chiral compounds crystallize as conglomerates.^[7]

Racemic compound (sometimes true racemate)

If molecules have a greater affinity for the opposite enantiomer than for the same enantiomer, the substance forms a single crystalline phase in which the two enantiomers are present in an ordered 1:1 ratio in the elementary cell. Adding a small amount of one enantiomer to the racemic compound decreases the melting point. But the pure enantiomer can have a higher or lower melting point than the compound. A special case of racemic compounds are kryptoracemic compounds (or kryptoracemates), in which the crystal itself has handedness (is enantiomorphic), despite containing both enantiomorphs in a 1:1 ratio.^[8]

Pseudoracemate (sometimes racemic solid solution)

When there is no big difference in affinity between the same and opposite enantiomers, then in contrast to the racemic compound and the conglomerate, the two enantiomers will coexist in an unordered manner in the crystal lattice. Addition of a small amount of one enantiomer changes the melting point slightly or not at all.

Quasiracemate

A quasiracemate is a co-crystal of two similar but distinct compounds, one of which is left-handed and the other right-handed. Although chemically different, they are sterically similar (isosteric) and are still able to form a racemic crystalline phase. One of the first such racemates studied, by Pasteur in 1853, forms from a 1:2 mixture of the bis

ammonium salt of (+)-tartaric acid and the bis ammonium salt of (−)-malic acid in water. Re-investigated in 2008,^[9] the crystals formed are dumbbell

-shape with the central part consisting of ammonium (+)-bitartrate, whereas the outer parts are a quasiracemic mixture of ammonium (+)-bitartrate and ammonium (−)-bimalate.

The separation of a racemate into its components, the individual enantiomers, is called a chiral resolution. Various methods exist for this separation, including crystallization, chromatography, and the use of various reagents.

Synthesis

Without a

Racemic pharmaceuticals

Some

While often only one enantiomer of the drug may be active, there are cases in which the other enantiomer is harmful, like salbutamol^[11] and thalidomide. The (R) enantiomer of thalidomide is effective against morning sickness, while the (S) enantiomer is teratogenic, causing birth defects. Since the drug racemizes, the drug cannot be considered safe for use by women of child-bearing age,^[12] and its use is tightly controlled when used for treating other illness.^[13]

• Chiral switch
• optical isomerism
  )
• Descriptor (chemistry)
• Racemic (protein) crystallography
• Racemization
• Skeletal formula#Stereochemistry which describes how stereochemistry is denoted in skeletal formulae

References