Editing Racemic mixture

{{Short description|Mixture with equal amounts of left- and right-handed chiral isomers}}
{{Use dmy dates|date=July 2018}}
In [[chemistry]], a '''racemic mixture''' or '''racemate''' ({{IPAc-en|r|eɪ|ˈ|s|iː|m|eɪ|t|,_|r|ə|-|,_|ˈ|r|æ|s|ɪ||m|eɪ|t}}<ref>{{cite Merriam-Webster|racemate|access-date=8 July 2018}}</ref>) is a mixture that has equal [[Amount of substance|amounts]] (50:50) of left- and right-handed [[enantiomer]]s of a [[Chirality (chemistry)|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]] found to be a mixture of the two enantiomeric [[isomer]]s of [[tartaric acid]]. He manually separated the crystals of a mixture, starting from an aqueous solution of the sodium ammonium salt of racemate tartaric acid.  Pasteur benefited from the fact that ammonium tartrate salt gives enantiomeric crystals with distinct crystal forms (at 77&nbsp;°F). Reasoning from the macroscopic scale down to the molecular, he reckoned that the molecules had to have non-superimposable mirror images.<ref>{{cite book |doi=10.1016/B978-0-444-51675-6.50018-9 |chapter=Substances |title=Philosophy of Chemistry |year=2012 |last1=Brakel |first1=Jaap van |pages=191–229 |isbn=978-0-444-51675-6 }}</ref>
A sample with only a single enantiomer is an ''enantiomerically pure'' or ''enantiopure'' compound.<ref>{{cite book|last=Moss|first=Gerry P.|title=Basic terminology of stereochemistry (IUPAC Recommendations 1996)|year=1996|publisher=Blackwell Scientific Publications|location=Department of Chemistry, Queen Mary University of London|pages=8, 11|url=http://www.chem.qmul.ac.uk/iupac/stereo/}}</ref>

==Etymology==
The word ''racemic'' derives from Latin {{lang|la|racemus}}, meaning pertaining to a [[bunch of grapes]].<ref>{{cite web |title=Racemic |url=https://www.etymonline.com/search?q=racemic |website=Online Etymology Dictionary}}</ref> [[Racemic acid]], when naturally produced in grapes, is only the right-handed version of the molecule, better known as [[tartaric acid]]. In many Germanic languages racemic acid is called "grape acid", e.g. German {{lang|de|Traubensäure}} and Swedish {{lang|sv|druvsyra}}. [[Carl Linnaeus|Carl von Linné]] gave [[red elderberry]] the scientific name ''Sambucus racemosa'' as the Swedish name, {{lang|sv|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 '''{{smallcaps|dl}}-''' 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  '''(+)/(−)''', '''{{smallcaps|d/l}}-''' or '''d/l-''' (with a slash) is used instead.

The usage of d and l is discouraged by [[IUPAC]].<ref>{{cite journal |last1=Moss |first1=G. P. |title=Basic terminology of stereochemistry (IUPAC Recommendations 1996) |journal=Pure and Applied Chemistry |date=1 January 1996 |volume=68 |issue=12 |pages=2193–2222 |doi=10.1351/pac199668122193 |s2cid=98272391 |doi-access=free }}</ref><ref>[http://www.chem.qmul.ac.uk/iupac/2carb/03n04.html#04 Nomenclature of Carbohydrates] (Recommendations 1996), 2-Carb-4. – Configurational symbols and prefixes</ref>

==Properties==
A racemate is [[Optical rotation|optically inactive]] ([[achiral]]), meaning that such materials do not rotate the polarization of plane-[[Polarization (waves)|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.<ref>{{cite web | url=https://www.chemistrysteps.com/racemic-mixtures/ | title=Racemic Mixtures | date=15 November 2021 }}</ref>

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]]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]] and [[methamphetamine]].

==Crystallization==
There are four ways to crystallize a racemate; three of which [[Hendrik Willem Bakhuis Roozeboom|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 system|eutectic]] mixture. Consequently, the [[melting point]] 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.<ref>{{cite book |last1=Jacques |first1=Jean |last2=Collet |first2=André |last3=Wilen |first3=Samuel H. |title=Enantiomers, racemates, and resolutions |date=1981 |publisher=Wiley |isbn=978-0-471-08058-9 |oclc=7174200 }}{{page needed|date=July 2022}}</ref>
;Racemic compound (sometimes ''true racemate''):If molecules have a greater affinity for the opposite [[enantiomer]] 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 [[Kryptoracemic compounds|kryptoracemates]]), in which the crystal itself has handedness (is enantiomorphic), despite containing both enantiomorphs in a 1:1 ratio.<ref>{{cite journal |last1=Fábián |first1=László |last2=Brock |first2=Carolyn Pratt |title=A list of organic kryptoracemates |journal=Acta Crystallographica Section B: Structural Science |date=1 February 2010 |volume=66 |issue=1 |pages=94–103 |doi=10.1107/S0108768109053610 |pmid=20101089 }}</ref>
;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]] and the bis ammonium salt of (−)-[[malic acid]] in water. Re-investigated in 2008,<ref>{{cite journal |last1=Wheeler |first1=Kraig A. |last2=Grove |first2=Rebecca C. |last3=Davis |first3=Raymond E. |last4=Kassel |first4=W. Scott |title=Rediscovering Pasteur's Quasiracemates |journal=Angewandte Chemie International Edition |date=January 2008 |volume=47 |issue=1 |pages=78–81 |doi=10.1002/anie.200704007 |pmid=18022885 }}</ref> 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 [[Chirality (chemistry)|chiral]] influence (for example a chiral [[catalyst]], [[solvent]] 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]]" or "not [[stereoselective]]", for their indecision in a particular [[stereoisomerism]]. A frequent scenario is that of a planar species (such as an sp<sup>2</sup> carbon atom or a [[carbocation]] 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:

[[File:Carbocation attack to racemic product.svg|700px|frameless|center]]

==Racemic pharmaceuticals==
{{see also|Enantiopure drug}}

Some [[Small molecule|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]], [[cetirizine]] and [[salbutamol]]. A well known drug that has different effects depending on its ratio of enantiomers is [[amphetamine]]. [[Adderall]] is an unequal mixture of both [[amphetamine]] enantiomers. A single Adderall 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]] was a racemic mixture, and isolated dextroamphetamine was later introduced to the market as Dexedrine. The prescription analgesic [[tramadol]] is also a racemate.

In some cases (e.g., [[ibuprofen]] and [[thalidomide]]), the enantiomers interconvert or [[racemize]] ''[[in vivo]]''. 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]] 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]].<ref>{{cite journal |last1=Agranat |first1=Israel |last2=Wainschtein |first2=Silvya R. |title=The strategy of enantiomer patents of drugs |journal=Drug Discovery Today |date=March 2010 |volume=15 |issue=5–6 |pages=163–170 |doi=10.1016/j.drudis.2010.01.007 |pmid=20116449 }}</ref> As examples, [[esomeprazole]] is a chiral switch of  (±)-omeprazole and [[levocetirizine]] 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]]<ref>{{cite journal |last1=Ameredes |first1=Bill T. |last2=Calhoun |first2=William J. |title=(R)-Albuterol for Asthma: Pro [a.k.a. (S)-Albuterol for Asthma: Con] |journal=American Journal of Respiratory and Critical Care Medicine |date=November 2006 |volume=174 |issue=9 |pages=965–969 |doi=10.1164/rccm.2606001 |pmid=17060667 }}</ref> 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,<ref>{{cite journal |last1=de Jesus |first1=Soraya Machado |last2=Santana |first2=Rafael Santos |last3=Leite |first3=Silvana Nair |title=Comparative analysis of the use and control of thalidomide in Brazil and different countries: is it possible to say there is safety? |journal=Expert Opinion on Drug Safety |date=2 January 2022 |volume=21 |issue=1 |pages=67–81 |doi=10.1080/14740338.2021.1953467 |pmid=34232089 |s2cid=235759079 }}</ref> and its use is tightly controlled when used for treating other illness.<ref name="nyt-fda">{{cite news |last1=Stolberg |first1=Sheryl Gay |title=Thalidomide Approved to Treat Leprosy, With Other Uses Seen |url=https://www.nytimes.com/1998/07/17/us/thalidomide-approved-to-treat-leprosy-with-other-uses-seen.html |work=The New York Times |date=17 July 1998 }}</ref>

[[Methamphetamine]] is available by prescription under the brand name [[Desoxyn]]. The active component of Desoxyn is [[dextromethamphetamine (medical)|dextromethamphetamine hydrochloride]]. This is the right-handed isomer of methamphetamine. The left-handed isomer of methamphetamine, [[levomethamphetamine]], is an [[Over-the-counter drug|OTC]] drug that is less centrally-acting and more peripherally-acting. Methedrine during the 20th century was a 50:50 racemic mixture of both methamphetamine isomers (levo and dextro).

==Wallach's rule==
Wallach's rule (first proposed by [[Otto Wallach]]) states that [[racemic]] crystals tend to be denser than their [[Chirality (chemistry)|chiral]] counterparts.<ref>{{cite journal |last1=Wallach |first1=O. |title=Zur Kenntniss der Terpene und der ätherischen Oele |trans-title=On the knowledge of terpenes and essential oils |language=de |journal=Justus Liebig's Annalen der Chemie |date=1895 |volume=286 |issue=1 |pages=90–118 |doi=10.1002/jlac.18952860105 }}</ref> This rule has been substantiated by crystallographic database analysis.<ref>{{cite journal |last1=Brock |first1=Carolyn Pratt |last2=Schweizer |first2=W. Bernd |last3=Dunitz |first3=Jack D. |title=On the validity of Wallach's rule: on the density and stability of racemic crystals compared with their chiral counterparts |journal=Journal of the American Chemical Society |date=December 1991 |volume=113 |issue=26 |pages=9811–9820 |doi=10.1021/ja00026a015 |bibcode=1991JAChS.113.9811B }}</ref>

==See also==
* [[Chiral switch]]
* [[Chirality (chemistry)|Chirality]] (same as [[optical isomerism]])
* [[Descriptor (chemistry)]]
* [[Racemic crystallography|Racemic (protein) crystallography]]
* [[Racemization]]
* {{slink|Skeletal formula|Stereochemistry}} which describes how stereochemistry is denoted in skeletal formulae

==References==
{{Reflist}}

{{Chiral synthesis}}
{{Navbox stereochemistry}}

{{DEFAULTSORT:Racemic Mixture}}
[[Category:Stereochemistry]]
[[Category:Racemic mixtures| ]]
[[Category:Chemical nomenclature]]
[[Category:Organic chemistry]]