In chemistry, a racemic mixture or racemate (
History
The first known racemic mixture was
racemic acid, which
Louis Pasteur found to be a mixture of the two enantiomeric
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.
A sample with only a single enantiomer is an
enantiomerically pure or
enantiopure compound.
Etymology
The word
racemic derives from Latin racemus, meaning pertaining to a bunch of grapes.
, when naturally produced in grapes, is only the right-handed version of the molecule, better known as
tartaric acid. In many Germanic languages racemic acid is called "grape acid", e.g. German Traubensäure and Swedish druvsyra.
Carl Linnaeus gave
red elderberry the scientific name
Sambucus racemosa as the Swedish name, druvfläder, means 'grape elder', so called because its berries grow in a grape-like cluster.
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 IUPAC.[ Nomenclature of Carbohydrates (Recommendations 1996), 2-Carb-4. – Configurational symbols and prefixes]
Properties
A racemate is
Optical rotation (
achiral), meaning that such materials do not rotate the polarization of plane-polarized light. Although the two enantiomers rotate plane-polarized light in opposite directions, the rotations cancel each other out because they are present in equal amounts of negative (-) counterclockwise (
levorotatory) and positive (+) clockwise (
dextrorotatory) enantiomers.
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 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:
- 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
- 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
Resolution
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 chiral influence (for example a chiral
catalyst,
solvent or starting material), a chemical reaction that makes a chiral product will always yield a racemate. That can make the synthesis of a racemate cheaper and easier than making the pure enantiomer, because it does not require special conditions. This fact also leads to the question of how biological
homochirality evolved on what is presumed to be a racemic primordial earth.
The reagents of, and the reactions that produce, racemic mixtures are said to be "not stereospecific" or "not stereoselective", for their indecision in a particular stereoisomerism. A frequent scenario is that of a planar species (such as an sp2 carbon atom or a carbocation intermediate) acting as an electrophile. The nucleophile will have a 50% probability of 'hitting' either of the two sides of the planar grouping, thus producing a racemic mixture:
Racemic pharmaceuticals
Some
Small molecule are chiral, and the enantiomers have different effects on biological entities. They can be sold as one enantiomer or as a racemic mixture. Examples include
thalidomide,
ibuprofen,
cetirizine and
salbutamol. A well known drug that has different effects depending on its ratio of enantiomers is
amphetamine.
Adderall is an unequal mixture of both
amphetamine enantiomers. A single Adderall dose combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and D/L-amphetamine aspartate monohydrate. The original
Benzedrine was a racemic mixture, and isolated dextroamphetamine was later introduced to the market as Dexedrine. The prescription analgesic
tramadol is also a racemate.
In some cases (e.g., ibuprofen and thalidomide), the enantiomers interconvert or racemize in vivo. This means that preparing a pure enantiomer for medication is largely pointless. However, sometimes samples containing pure enantiomers may be made and sold at a higher cost in cases where the use requires specifically one isomer (e.g., for a stereospecific reagent); compare omeprazole and esomeprazole. Moving from a racemic drug to a chiral specific drug may be done for a better safety profile or an improved therapeutic index. This process is called chiral switching and the resulting enantiopure drug is called a chiral switch.
While often only one enantiomer of the drug may be active, there are cases in which the other enantiomer is harmful, like salbutamol
Methamphetamine is available by prescription under the brand name Desoxyn. The active component of Desoxyn is dextromethamphetamine hydrochloride. This is the right-handed isomer of methamphetamine. The left-handed isomer of methamphetamine, levomethamphetamine, is an OTC drug that is less centrally-acting and more peripherally-acting. Methedrine during the 20th century was a 50:50 racemic mixture of both methamphetamine isomers (levo and dextro).
Wallach's rule
Wallach's rule (first proposed by
Otto Wallach) states that
racemic crystals tend to be denser than their chiral counterparts.
This rule has been substantiated by crystallographic database analysis.
See also
-
Chiral switch
-
Chirality (same as optical isomerism)
-
Descriptor (chemistry)
-
Racemic (protein) crystallography
-
Racemization
-
which describes how stereochemistry is denoted in skeletal formulae
