Racemization

Source: Wikipedia, the free encyclopedia.

In

Dextrorotation and levorotation.[1] The D and L enantiomers are present in equal quantities, the resulting sample is described as a racemic mixture
or a racemate. Racemization can proceed through a number of different mechanisms, and it has particular significance in pharmacology as different enantiomers may have different pharmaceutical effects.

Stereochemistry

Two enantiomers of a generic amino acid that is chiral

Chiral molecules have two forms (at each point of asymmetry), which differ in their optical characteristics: The levorotatory form (the (−)-form) will rotate counter-clockwise on the plane of polarization of a beam of light, whereas the dextrorotatory form (the (+)-form) will rotate clockwise on the plane of polarization of a beam of light.[1] The two forms, which are non-superposable when rotated in 3-dimensional space, are said to be enantiomers. The notation is not to be confused with D and L naming of molecules which refers to the similarity in structure to D-glyceraldehyde and L-glyceraldehyde. Also, (R)- and (S)- refer to the chemical structure of the molecule based on Cahn–Ingold–Prelog priority rules of naming rather than rotation of light. R/S notation is the primary notation used for +/- now because D and L notation are used primarily for sugars and amino acids.[2]

Racemization occurs when one pure form of an enantiomer is converted into equal proportion of both enantiomers, forming a

diastereomers which are a type of stereoisomer that have different molecular structures around a stereocenter
and are not mirror images.

Partial to complete racemization of stereochemistry in solutions are a result of SN1 mechanisms. However, when complete inversion of stereochemistry configuration occurs in a substitution reaction, an SN2 reaction is responsible.[3]

Physical properties

In the solid state, racemic mixtures may have different physical properties from either of the pure enantiomers because of the differential intermolecular interactions (see Biological Significance section). The change from a pure enantiomer to a racemate can change its density, melting point, solubility, heat of fusion, refractive index, and its various spectra. Crystallization of a racemate can result in separate (+) and (−) forms, or a single racemic compound. However, in liquid and gaseous states, racemic mixtures will behave with physical properties that are identical, or near identical, to their pure enantiomers.[4]

Biological significance

In general, most

biochemical reactions are stereoselective, so only one stereoisomer will produce the intended product while the other simply does not participate or can cause side-effects. Of note, the L form of amino acids and the D form of sugars (primarily glucose) are usually the biologically reactive form. This is due to the fact that many biological molecules are chiral and thus the reactions between specific enantiomers produce pure stereoisomers.[5] Also notable is the fact that all amino acid residues exist in the L form. However, bacteria produce D-amino acid residues that polymerize into short polypeptides which can be found in bacterial cell walls. These polypeptides are less digestible by peptidases and are synthesized by bacterial enzymes instead of mRNA translation which would normally produce L-amino acids.[5]

The stereoselective nature of most biochemical reactions meant that different enantiomers of a chemical may have different properties and effects on a person. Many psychotropic drugs show differing activity or efficacy between isomers, e.g.

NMDA antagonist.[6]

Racemization of

pharmaceutical drugs can occur in vivo. Thalidomide as the (R) enantiomer is effective against morning sickness, while the (S) enantiomer is teratogenic, causing birth defects when taken in the first trimester of pregnancy. If only one enantiomer is administered to a human subject, both forms may be found later in the blood serum.[7] The drug is therefore not considered safe for use by women of child-bearing age, and while it has other uses, its use is tightly controlled.[8][9] Thalidomide can be used to treat multiple myeloma.[10]

Another commonly used drug is ibuprofen which is only anti-inflammatory as one enantiomer while the other is biologically inert. Likewise, the (S) stereoisomer is much more reactive than the (R) enantiomer in citalopram (Celexa), an antidepressant which inhibits serotonin reuptake, is active.[11][5][12] The configurational stability of a drug is therefore an area of interest in pharmaceutical research.[13] The production and analysis of enantiomers in the pharmaceutical industry is studied in the field of chiral organic synthesis.

Formation of racemic mixtures

Racemization can be achieved by simply mixing equal quantities of two pure enantiomers. Racemization can also occur in a chemical interconversion. For example, when (R)-3-phenyl-2-butanone is dissolved in aqueous ethanol that contains

HCl, a racemate is formed. The racemization occurs by way of an intermediate enol form in which the former stereocenter becomes planar and hence achiral.[14]: 373  An incoming group can approach from either side of the plane, so there is an equal probability that protonation
back to the chiral ketone will produce either an R or an S form, resulting in a racemate.

Racemization can occur through some of the following processes:

The rate of racemization (from L-forms to a mixture of L-forms and D-forms) has been used as a way of dating biological samples in tissues with slow rates of turnover, forensic samples, and fossils in geological deposits. This technique is known as amino acid dating.

Discovery of optical activity

In 1843, Louis Pasteur discovered optical activity in paratartaric, or racemic, acid found in grape wine. He was able to separate two enantiomer crystals that rotated polarized light in opposite directions.[11]

See also

References

  1. ^ a b Kennepohl D, Farmer S (2019-02-13). "6.7: Optical Activity and Racemic Mixtures". Chemistry LibreTexts. Retrieved 2022-11-16.
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  8. ^ Stolberg SG (17 July 1998). "Thalidomide Approved to Treat Leprosy, With Other Uses Seen". The New York Times. Retrieved 8 January 2012.
  9. ^ "Use of thalidomide in leprosy". WHO:leprosy elimination. World Health Organization. Archived from the original on November 10, 2006. Retrieved 22 April 2010.
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