Editing Racemization

{{Short description|Conversion of an optically active chemical compound into an inactive form}}
In [[chemistry]], '''racemization''' is a conversion, by heat or by chemical reaction, of an [[Optical rotation|optically active]] compound into a [[Racemic mixture|racemic]] (optically inactive) form. This creates a 1:1 molar ratio of [[enantiomer]]s 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]].<ref name = "Kennepohl_2019">{{Cite web | vauthors = Kennepohl D, Farmer S |date=2019-02-13 |title=6.7: Optical Activity and Racemic Mixtures |url=https://chem.libretexts.org/Courses/Sacramento_City_College/SCC%3A_Chem_420_-_Organic_Chemistry_I/Text/06%3A_Stereochemistry_at_Tetrahedral_Centers/6.07%3A_Optical_Activity_and_Racemic_Mixtures |access-date=2022-11-16 | work = Chemistry LibreTexts |language=en}}</ref> 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 inasmuch as different enantiomers may have different pharmaceutical effects.

== Stereochemistry ==
[[File:Chirality with hands.svg|Two enantiomers of a generic amino acid that is chiral|thumbnail]]
[[Chirality (chemistry)|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 [[Polarization (waves)|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.<ref name = "Kennepohl_2019" /> 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 <small>D</small> and <small>L</small> naming of molecules which refers to the similarity in structure to [[Glyceraldehyde|<small>D</small>-glyceraldehyde]] and <small>L</small>-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.<ref>{{cite journal | vauthors = Brooks WH, Guida WC, Daniel KG | title = The significance of chirality in drug design and development | journal = Current Topics in Medicinal Chemistry | year = 2011 | volume = 11 | issue = 7 | pages = 760–770 | pmid = 21291399 | pmc = 5765859 | doi = 10.2174/156802611795165098 }}</ref>

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 reaction|SN1 mechanisms]]. However, when complete inversion of stereochemistry configuration occurs in a [[substitution reaction]], an [[SN2 reaction]] is responsible.<ref>{{cite book | vauthors = Brown WH, Iverson BL, Anslyn E, Foote CS |title=Organic chemistry |date=2017 |publisher=Cengage Learning |location=Boston, Mass. |isbn=978-1-337-51640-2 |edition=Eighth}}</ref>

== 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 [[enantiomer]]s.<ref name="Mitchell_1988">{{cite journal | vauthors = Mitchell AG | title = Racemic drugs: racemic mixture, racemic compound, or pseudoracemate? | journal = Journal of Pharmacy & Pharmaceutical Sciences | volume = 1 | issue = 1 | pages = 8–12 | date = 1998 | pmid = 10942967 | doi = | url = https://sites.ualberta.ca/~csps/JPPS1(1)/A.Mitchell/Mitchell.pdf }}</ref>

== Biological significance ==
In general, most [[biochemical reaction]]s 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 <small>L</small> form of amino acids and the <small>D</small> 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.<ref name="Voet_2013">{{cite book| vauthors = Voet D, Voet JG, Pratt CW |author-link1 = Donald Voet|author-link2 = Judith G. Voet|title = Fundamentals of Biochemistry: Life at the Molecular Level|year = 2013|publisher = [[John Wiley & Sons]]|location = Hoboken, NJ|isbn = 978-0-470-54784-7|edition = 4th}}</ref> Also notable is the fact that all amino acid residues exist in the <small>L</small> form. However, bacteria produce <small>D</small>-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 <small>L</small>-amino acids.<ref name="Voet_2013"/>

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]].<ref>{{cite journal | vauthors = Arnold LE, Wender PH, McCloskey K, Snyder SH | title = Levoamphetamine and dextroamphetamine: comparative efficacy in the hyperkinetic syndrome. Assessment by target symptoms | journal = Archives of General Psychiatry | volume = 27 | issue = 6 | pages = 816–822 | date = December 1972 | pmid = 4564954 | doi = 10.1001/archpsyc.1972.01750300078015 }}</ref>

Racemization of [[pharmaceutical drugs]] can occur ''in vivo''. [[Thalidomide]] as the (''R'') enantiomer is effective against [[morning sickness]], while the (''S'') enantiomer is [[teratology|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.<ref>{{cite journal | vauthors = Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL | display-authors = 6 | title = Clinical pharmacokinetics of thalidomide | journal = Clinical Pharmacokinetics | volume = 43 | issue = 5 | pages = 311–327 | year = 2004 | pmid = 15080764 | doi = 10.2165/00003088-200443050-00004 | s2cid = 37728304 }}</ref> 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.<ref name="nyt-fda">{{cite news|url = https://www.nytimes.com/1998/07/17/us/thalidomide-approved-to-treat-leprosy-with-other-uses-seen.html|title = Thalidomide Approved to Treat Leprosy, With Other Uses Seen|newspaper = [[The New York Times]]| vauthors  = Stolberg SG |access-date = 8 January 2012|date = 17 July 1998}}</ref><ref>{{cite web |url =https://www.who.int/lep/research/thalidomide/en/index.html|archive-url =https://web.archive.org/web/20061110083549/http://www.who.int/lep/research/thalidomide/en/index.html|url-status =dead|archive-date =November 10, 2006|title = Use of thalidomide in leprosy|work = WHO:leprosy elimination|publisher = [[World Health Organization]]|access-date = 22 April 2010}}</ref> Thalidomide can be used to treat [[multiple myeloma]].<ref>{{cite journal | vauthors = Moehler TM, Hillengass J, Glasmacher A, Goldschmidt H | title = Thalidomide in multiple myeloma | journal = Current Pharmaceutical Biotechnology | volume = 7 | issue = 6 | pages = 431–440 | date = December 2006 | pmid = 17168659 | doi = 10.2174/138920106779116919 }}</ref>

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.<ref name="Lehninger_2013">{{cite book | vauthors = Nelson DL, Cox MM |title=Lehninger Principles of Biochemistry |publisher=[[W. H. Freeman]] |year=2013 |isbn=978-1-4292-3414-6 |edition=6th |location=New York}}</ref><ref name="Voet_2013"/><ref>{{cite journal | vauthors = Jacquot C, David DJ, Gardier AM, Sánchez C | title = [Escitalopram and citalopram: the unexpected role of the R-enantiomer] | journal = L'Encephale | volume = 33 | issue = 2 | pages = 179–187 | year = 2007 | pmid = 17675913 | doi = 10.1016/s0013-7006(07)91548-1 }}</ref> The configurational stability of a drug is therefore an area of interest in pharmaceutical research.<ref name="Reist_2003">{{cite book | vauthors = Reist M, Testa B, Carrupt PA |chapter=Drug Racemization and Its Significance in Pharmaceutical Research | veditors = Eichelbaum MF, Testa B, Somogyi A  |title=Stereochemical Aspects of Drug Action and Disposition|volume =153| series =Handbook of Experimental Pharmacology  |chapter-url=https://books.google.com/books?id=0U_xCAAAQBAJ&pg=PA91 |pages= 91–112 |year =2003|doi= 10.1007/978-3-642-55842-9_4 |isbn =978-3-642-62575-6}}</ref> 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 [[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.<ref name = "Streitwieser_1985">{{cite book| vauthors = Streitwieser A, Heathcock CH |author-link1 = Andrew Streitwieser |author-link2 = Clayton Heathcock|title = Introduction to Organic Chemistry|edition = 3rd|publisher = [[Macmillan Publishers|Maxwell MacMillan]]|year = 1985|isbn = 978-0-02-946720-6 |url-access = registration|url = https://archive.org/details/introductiontoor0003stre}}</ref>{{rp|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:
* Substitution reactions that proceed through a free [[carbocation]] intermediate, such as [[SN1 reaction|unimolecular substitution reactions]], lead to non-stereospecific addition of substituents which results in racemization. 
* Although [[Elimination reaction|unimolecular elimination reactions]] also proceed through a carbocation, they do not result in a chiral center.  They result instead in a set of [[Cis–trans isomerism|geometric isomers]] in which ''trans''/''cis'' (''E''/''Z'') forms are produced, rather than racemates.
* In a unimolecular aliphatic [[electrophilic substitution]] reaction, if the [[carbanion]] is planar or if it cannot maintain a pyramidal structure, then racemization should occur, though not always.<ref name = "March_1985">{{cite book| vauthors = March J |author-link = Jerry March|title = Advanced Organic Chemistry: reactions, mechanisms, and structure|publisher = [[John Wiley & Sons]]|edition = 3rd|year = 1985|isbn = 978-0-471-85472-2 }}
</ref>{{rp|517–518}} 
* In a [[free radical substitution]] reaction, if the formation of the free radical takes place at a chiral carbon, then racemization is almost always observed.<ref name = "March_1985" />{{rp|610}}

The rate of racemization (from <small>L</small>-forms to a mixture of <small>L</small>-forms and <small>D</small>-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.<ref name="Lehninger_2013"/>

== See also ==
* [[Dextrorotation and levorotation]]
* [[Enantiomer]]
* [[Racemic mixture]]

== References ==
{{reflist|33em}}

{{Chiral synthesis}}
{{Protein posttranslational modification}}

{{Authority control}}

[[Category:Chemical reactions]]
[[Category:Stereochemistry]]
[[Category:Protein structure]]
[[Category:Post-translational modification]]