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In
chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, structure, proper ...
, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
s 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 Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization, the latter of which was named afte ...
found to be a mixture of the two enantiomeric
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Is ...
s of
tartaric acid Tartaric acid is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes, but also in bananas, tamarinds, and citrus. Its salt, potassium bitartrate, commonly known as cream of tartar, develops naturally ...
. He manually separated the crystals of a mixture by hand, starting from an aqueous solution of the sodium ammonium salt of racemate tartaric acid. Pasteur benefited from the fact that ammonium tartrate salt that 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

From racemic acid found in grapes; from Latin ''racemus'', meaning a bunch of grapes. This acid, when naturally produced in grapes, is only the right-handed version of the molecule, better known as
tartaric acid Tartaric acid is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes, but also in bananas, tamarinds, and citrus. Its salt, potassium bitartrate, commonly known as cream of tartar, develops naturally ...
. In many Germanic languages racemic acid is called “grape acid” e.g. German ''traubensäure'' and Swedish ''druvsyra''. Carl von Linné 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 - 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 (+)/(−), - or d/l- (with a slash) is used instead. The usage of d and l is discouraged by
IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...
.


Properties

A racemate is optically inactive (
achiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...
), meaning that such materials do not rotate 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
boiling point The boiling point of a substance is the temperature at which the vapor pressure of a liquid equals the pressure surrounding the liquid and the liquid changes into a vapor. The boiling point of a liquid varies depending upon the surrounding env ...
s 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 Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
and
methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
.


Crystallization

There are four ways in which a racemate can be crystallized, depending on the substance; 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 The melting point (or, rarely, liquefaction point) of a substance is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depen ...
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. ;Racemic compound (sometimes true racemate):If molecules have a greater affinity for the opposite
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
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. ;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 Tartaric acid is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes, but also in bananas, tamarinds, and citrus. Its salt, potassium bitartrate, commonly known as cream of tartar, develops naturally ...
and the bis ammonium salt of (−)- malic acid in water. Re-investigated in 2008, 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.


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 Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
,
solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
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 In chemistry, stereospecificity is the property of a reaction mechanism that leads to different stereoisomeric reaction products from different stereoisomeric reactants, or which operates on only one (or a subset) of the stereoisomers."Overlap Con ...
" 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 A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encount ...
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 drug molecules 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 Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus ar ...
, cetirizine and
salbutamol Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing rel ...
. A well known drug that has different effects depending on its ratio of enantiomers is
amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
. Adderall is an unequal mixture of both
amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
enantiomers. A single amphetamine 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 Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
was a racemic mixture. The prescription analgesic
tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...
is also a racemate. In some cases (e.g.,
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus ar ...
and thalidomide), the enantiomers interconvert or racemize ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
''. 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 In chemistry, stereospecificity is the property of a reaction mechanism that leads to different stereoisomeric reaction products from different stereoisomeric reactants, or which operates on only one (or a subset) of the stereoisomers."Overlap Con ...
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. As examples, esomeprazole is a chiral switch of (±)-omeprazole and
levocetirizine Levocetirizine, sold under the brand name Xyzal among others, is a second-generation antihistamine used for the treatment of allergic rhinitis (hay fever) and long term hives of unclear cause. It is less sedating than older antihistamines. It is ...
is a chiral switch of (±)-cetirizine. While often only one enantiomer of the drug may be active, there are cases in which the other enantiomer is harmful, like
salbutamol Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing rel ...
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, and its use is tightly controlled when used for treating other illness.
Methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
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.


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 Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...
(same as optical isomerism) * Descriptor (chemistry) * Racemic (protein) crystallography * Racemization * Skeletal formula#Stereochemistry which describes how stereochemistry is denoted in skeletal formulae


References

{{DEFAULTSORT:Racemic Mixture Stereochemistry Chemical nomenclature Organic chemistry