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Racemization

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In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic (optically inactive) form. This creates a 1:1 molar ratio of enantiomers and is referred to as a racemic mixture (i.e. contain equal amount of (+) and (−) forms). Plus and minus forms are called 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

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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 racemate. When there are both equal numbers of dextrorotating and levorotating molecules, the net optical rotation of a racemate is zero. Enantiomers should also be distinguished from 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

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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

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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. amphetamine is often dispensed as racemic salts while the more active dextroamphetamine is reserved for refractory cases or more severe indications; another example is methadone, of which one isomer has activity as an opioid agonist and the other as an 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

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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 NaOH or 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

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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

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References

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  1. ^ a b Kennepohl D, Farmer S (2019-02-13). "6.7: Optical Activity and Racemic Mixtures". Chemistry LibreTexts. Retrieved 2022-11-16.
  2. ^ Brooks WH, Guida WC, Daniel KG (2011). "The significance of chirality in drug design and development". Current Topics in Medicinal Chemistry. 11 (7): 760–770. doi:10.2174/156802611795165098. PMC 5765859. PMID 21291399.
  3. ^ Brown WH, Iverson BL, Anslyn E, Foote CS (2017). Organic chemistry (Eighth ed.). Boston, Mass.: Cengage Learning. ISBN 978-1-337-51640-2.
  4. ^ Mitchell AG (1998). "Racemic drugs: racemic mixture, racemic compound, or pseudoracemate?" (PDF). Journal of Pharmacy & Pharmaceutical Sciences. 1 (1): 8–12. PMID 10942967.
  5. ^ a b c Voet D, Voet JG, Pratt CW (2013). Fundamentals of Biochemistry: Life at the Molecular Level (4th ed.). Hoboken, NJ: John Wiley & Sons. ISBN 978-0-470-54784-7.
  6. ^ Arnold LE, Wender PH, McCloskey K, Snyder SH (December 1972). "Levoamphetamine and dextroamphetamine: comparative efficacy in the hyperkinetic syndrome. Assessment by target symptoms". Archives of General Psychiatry. 27 (6): 816–822. doi:10.1001/archpsyc.1972.01750300078015. PMID 4564954.
  7. ^ Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, et al. (2004). "Clinical pharmacokinetics of thalidomide". Clinical Pharmacokinetics. 43 (5): 311–327. doi:10.2165/00003088-200443050-00004. PMID 15080764. S2CID 37728304.
  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.
  10. ^ Moehler TM, Hillengass J, Glasmacher A, Goldschmidt H (December 2006). "Thalidomide in multiple myeloma". Current Pharmaceutical Biotechnology. 7 (6): 431–440. doi:10.2174/138920106779116919. PMID 17168659.
  11. ^ a b Nelson DL, Cox MM (2013). Lehninger Principles of Biochemistry (6th ed.). New York: W. H. Freeman. ISBN 978-1-4292-3414-6.
  12. ^ Jacquot C, David DJ, Gardier AM, Sánchez C (2007). "[Escitalopram and citalopram: the unexpected role of the R-enantiomer]". L'Encephale. 33 (2): 179–187. doi:10.1016/s0013-7006(07)91548-1. PMID 17675913.
  13. ^ Reist M, Testa B, Carrupt PA (2003). "Drug Racemization and Its Significance in Pharmaceutical Research". In Eichelbaum MF, Testa B, Somogyi A (eds.). Stereochemical Aspects of Drug Action and Disposition. Handbook of Experimental Pharmacology. Vol. 153. pp. 91–112. doi:10.1007/978-3-642-55842-9_4. ISBN 978-3-642-62575-6.
  14. ^ Streitwieser A, Heathcock CH (1985). Introduction to Organic Chemistry (3rd ed.). Maxwell MacMillan. ISBN 978-0-02-946720-6.
  15. ^ a b March J (1985). Advanced Organic Chemistry: reactions, mechanisms, and structure (3rd ed.). John Wiley & Sons. ISBN 978-0-471-85472-2.
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