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In chemistry, racemization refers to the conversion of an enantiomerically pure mixture (one where only one enantiomer is present) into a mixture where more than one of the enantiomers are present. If the racemization results in a mixture where the enantiomers are present in equal quantities, the resulting sample is described as racemic or a racemate.^[1]

Stereochemistry

Chiral molecules have two forms (at each point of asymmetry), which differ in their optical characteristics: The levorotatory form (the (−)-form) will rotate the plane of polarization of a beam of light to the left, whereas the dextrorotatory form (the (+)-form) will rotate the plane of polarization of a beam of light to the right. The two forms, which are non-superimposable when rotated in 3-dimensional space, are said to be enantiomers.

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.^[1]

Physical properties

Racemate may have different physical properties from either of the pure enantiomers because of the differential intermolecular interactions. 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. Crystalization of a racemate can result in separate (+) and (−) forms, or a single racemic compound.

Biological significance

In general, only one form of a chiral molecule will participate in biochemical reactions 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. Additionally, 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.

Racemization of pharmaceutical drugs, however, can occur in vivo. An example is thalidomide, its (R) enantiomer is effective against morning sickness, while the (S) enantiomer is teratogenic, causing birth defects. If only one enantiomer is administered to a human subject, both forms may be found later in the blood serum.^[2] 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.^[3]^[4]

Formation of racemic mixtures

On a trivial level, 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.^[5] 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.

Substitution reactions that proceed through a free carbocation intermediate, such as unimolecular substitution reactions, lead to non-stereospecific addition of substituents which results in racemization.
Unimolecular elimination reactions also proceed through a carbocation, but they do not result in a chiral center. Rather, they result in a set of geometric isomers in which trans/cis or E/Z forms will result.
In an 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.^[6]
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.^[7]

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.

References

^ ^a ^b Andrew Streitwieser, Clayton H. Heathcock (1985). Introduction to Organic Chemistry (3rd ed.). Maxwell MacMillan. pp. 122–124. ISBN 0029467209.
^ Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL (2004). "Clinical pharmacokinetics of thalidomide". Clin Pharmacokinet. 43 (5): 311–327. doi:10.2165/00003088-200443050-00004. PMID 15080764.
^ Sheryl Gay Stolberg (17 July 1998). "Thalidomide Approved to Treat Leprosy, With Other Uses Seen". New York Times. Retrieved 8 January 2012.
^ "Use of thalidomide in leprosy". WHO:leprosy elimination. WHO. Retrieved 22 April 2010.
^ Andrew Streitwieser, Clayton H. Heathcock (1985). Introduction to Organic Chemistry (3rd ed.). Maxwell MacMillan. p. 373. ISBN 0029467209.
^ Jerry March (1985). Advanced Organic Chemistry: reactions, mechanisms, and structure (3rd ed.). John Wiley & Sons. pp. 517–518. ISBN 0-471-85472-7.
^ Jerry March (1985). Advanced Organic Chemistry: reactions, mechanisms, and structure (3rd ed.). John Wiley & Sons. p. 610. ISBN 0-471-85472-7.

English Journal

Copper, nickel, and zinc cyclam-amino acid and cyclam-peptide complexes may be synthesized with "click" chemistry and are noncytotoxic.

Yu M, Price JR, Jensen P, Lovitt CJ, Shelper T, Duffy S, Windus LC, Avery VM, Rutledge PJ, Todd MH.SourceSchool of Chemistry, The University of Sydney, NSW 2006, Australia.
Inorganic chemistry.Inorg Chem.2011 Dec 19;50(24):12823-35. Epub 2011 Nov 23.
We describe the synthesis of cyclam metal complexes derivatized with amino acids or a tripeptide using a copper(I)-catalyzed Huisgen "click" reaction. The linker triazole formed during the synthesis plays an active coordinating role in the complexes. The reaction conditions do not racemize the amino
PMID 22111787

Resolution of enantiomers of a series of chiral alkoxy-modified phthalocyaninato nickel(II) complexes by enantioselective HPLC.

Robinson JR, Bahr KA, Bierman MJ, Guzei IA, Kieler-Ferguson HM, McCoy AM, McGaff RW.SourceUniversity of Wisconsin- La Crosse Department of Chemistry, WI 54601, USA.
Dalton transactions (Cambridge, England : 2003).Dalton Trans.2011 Nov 28;40(44):11809-14. Epub 2011 Oct 3.
We have resolved the enantiomers of a series of chiral modified metallophthalocyaninato complexes of nickel bearing alkoxy groups at the 14 and 28 positions on what would otherwise be a normal phthalocyaninato ligand and conforming to the general formula [14,28-(RO)(2)Pc]Ni(ii), where R = Me, Et, or
PMID 21964596

Japanese Journal

光学活性カルコゲニン酸およびその誘導体の単離, 構造と性質

中島勇介,清水敏夫,上方宣政
有機合成化学協会誌 : JOURNAL OF Synthetic Organic Chemistry JAPAN 64(2), 151-162, 2006-02-01
… Kinetic studies of the racemization, oxygen exchange reaction using H218O, and theoretical studies clarified that optically active sulfinic acids and seleninic acids racemize via … an achiral chalcogeninate anion, whereas optically active tellurinic acids racemize via … Both of the optically active seleninamides and seleninate esters were found to racemize via …
NAID 10017252449