# Chiral resolution > Mediated Wiki article. Canonical URL: https://mediated.wiki/source/Chiral_resolution > Markdown URL: https://mediated.wiki/source/Chiral_resolution.md > Source: https://en.wikipedia.org/wiki/Chiral_resolution > Source revision: 1344265643 > License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/) {{Short description|Separation of a sample of a chiral compound into its enantiomers}} '''Chiral resolution''', or '''enantiomeric resolution''',{{cite journal |last1=Kuhn |first1=Reinhard. |last2=Erni |first2=Fritz. |last3=Bereuter |first3=Thomas. |last4=Haeusler |first4=Johannes. |title=Chiral recognition and enantiomeric resolution based on host-guest complexation with crown ethers in capillary zone electrophoresis |journal=Analytical Chemistry |date=1992-11-15 |volume=64 |issue=22 |pages=2815–2820 |doi=10.1021/ac00046a026 }} is a process in [stereochemistry](/source/stereochemistry) for the separation of [racemic mixture](/source/racemic_mixture) into their [enantiomer](/source/enantiomer)s.{{March6th|page=173-179}} It is an important tool in the production of [optically active](/source/optically_active) compounds, including [drug](/source/drug)s.{{cite journal |title=Resolution of chiral drugs |last=Porter |first=William H. |work=[Pure Appl. Chem.](/source/Pure_Appl._Chem.) |volume=63 |issue=8 |pages=1119–1122 |year=1991 |url=https://publications.iupac.org/pac/1991/pdf/6308x1119.pdf |doi=10.1351/pac199163081119 |s2cid=35860450 }} Another term with the same meaning is '''optical resolution'''. The use of [chiral](/source/chirality) resolution to obtain enantiomerically pure compounds has the disadvantage of necessarily discarding at least half of the starting racemic mixture. [Asymmetric synthesis](/source/Asymmetric_synthesis) of one of the enantiomers is one means of avoiding this waste. ==Crystallization of diastereomeric salts== The most common method for chiral resolution involves conversion of the racemic mixture to a pair of [diastereomeric](/source/diastereomeric) derivatives by reacting them with '''[chiral derivatizing agent](/source/chiral_derivatizing_agent)s''', also known as '''chiral resolving agents'''. The derivatives which are then separated by conventional crystallization, and converted back to the enantiomers by removal of the resolving agent. The process can be laborious and depends on the divergent solubilities of the diastereomers, which is difficult to predict. Often the less soluble diastereomer is targeted and the other is discarded or [racemized](/source/racemization) for reuse. It is common to test several resolving agents. Typical derivatization involves salt formation between an [amine](/source/amine) and a [carboxylic acid](/source/carboxylic_acid). Simple deprotonation then yields back the pure enantiomer. Examples of chiral derivatizing agents are [tartaric acid](/source/tartaric_acid) and the amine [brucine](/source/brucine). The method was introduced (again) by [Louis Pasteur](/source/Louis_Pasteur) in 1853 by resolving racemic [tartaric acid](/source/tartaric_acid) with optically active (+)-[cinchotoxine](/source/cinchotoxine). === Half-equivalent method in diastereomeric salt resolution === A modern refinement of classical diastereomeric salt resolution was introduced by Hans‑Joachim Gais and Jochen Brandt in their comprehensive treatment of racemate resolution in the Houben–Weyl series. They demonstrated that the formation of diastereomeric salts between a racemic compound and an enantiopure resolving agent does not require equimolar amounts of the resolving agent. Because a racemate contains equal quantities of both enantiomers, only 0.5 equivalents of a chiral acid or base are stoichiometrically necessary to form the corresponding diastereomeric salt.H.-J. Gais, J. Brandt: ''Racematespaltung''. In: ''Methoden der Organischen Chemie (Houben–Weyl)'', Vol. E21a: ''Stereoselektive Synthesen I'', Georg Thieme Verlag, Stuttgart (2001). Using half the amount of a chiral resolving agent (e.g., camphorsulfonic acid) can simplify crystallization, reduce the formation of mixed diastereomeric species, improve separation efficiency, and lower the consumption of the resolving agent. This half-equivalent method is now recognized as a logical and resource‑efficient refinement of traditional diastereomeric salt resolution. ===Case study=== One modern-day method of chiral resolution is used in the [organic synthesis](/source/organic_synthesis) of the drug [duloxetine](/source/duloxetine):{{cite journal |title= Synthesis of (S)-3-(N-Methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly's Resolution-Racemization-Recycle Synthesis of Duloxetine for Its Robust Processes |author1=Yoshito Fujima |author2=Masaya Ikunaka |author3=Toru Inoue |author4=Jun Matsumoto |journal= [Org. Process Res. Dev.](/source/Org._Process_Res._Dev.) |year= 2006 |volume= 10 |issue= 5 |pages= 905–913 |doi= 10.1021/op060118l}} center|400px|RRR synthesis In one of its steps the [racemic](/source/racemic) [alcohol](/source/Alcohol_(chemistry)) '''1''' is dissolved in a mixture of [toluene](/source/toluene) and [methanol](/source/methanol) to which solution is added optically active (S)-[mandelic acid](/source/mandelic_acid) '''3'''. The alcohol (S)-enantiomer forms an insoluble diastereomeric salt with the mandelic acid and can be filtered from the solution. Simple deprotonation with [sodium hydroxide](/source/sodium_hydroxide) liberates free (S)-alcohol. In the meanwhile the (R)-alcohol remains in solution unaffected and is recycled back to the racemic mixture by [epimerization](/source/epimerization) with [hydrochloric acid](/source/hydrochloric_acid) in toluene. This process is known as '''RRR synthesis''' in which the R's stand for '''Resolution-Racemization-Recycle'''. ===Common resolving agents=== {{Main|Chiral derivatizing agent}} *[Antimony potassium tartrate](/source/Antimony_potassium_tartrate), an anion, that forms diastereomeric salts with chiral cations.{{cite book |doi=10.1002/9780470132371.ch62|title=Resolution of ''cis''-Dinitrobis(ethylenediamine)cobalt Ion |author=F. P. Dwyer |author2=F. L. Garvan|chapter=Resolution of cis -Dinitrobis(ethylenediamine)cobalt Ion|year=1960|series=Inorganic Syntheses|volume=6|page=195-197|isbn=978-0-470-13237-1}} *[Camphorsulfonic acid](/source/Camphorsulfonic_acid), an acid that forms diastereomeric salts with chiral amines *[1-Phenylethylamine](/source/1-Phenylethylamine), a base that forms diastereomeric salts with chiral acids.{{cite journal |doi=10.15227/orgsyn.017.0080|title=D- and l-α-Phenylethylamine|journal=Organic Syntheses|year=1937|volume=17|page=80|author=A. W. Ingersoll}} Many related chiral amines have been demonstrated.{{cite journal|title=(S)-(−)-α-(1-Naphthyl)ethylamine|first1=E.|last1=Mohacsi|first2=W.|last2=Leimgruber|journal=Org. Synth.|year=1976|volume=55|page=80|doi=10.15227/orgsyn.055.0080}} The [chiral pool](/source/chiral_pool) consists of many widely available resolving agents.{{cite journal|journal=Org. Synth.|year=1989|volume=67|page=1|doi= 10.15227/orgsyn.067.0001|title=Enantiomeriic (''S'')-(+)- and (''R'')-(−)-1,1'-Binaphthyl-2,2'-diyl Hydrogen Phosphate|first1=J.|last1=Jacques|first2=C.|last2=Fouquey}} ==Spontaneous resolution and related specialized techniques== Via the process known as '''spontaneous resolution''', 5-10% of all [racemates](/source/racemates) crystallize as mixtures of enantiopure crystals.{{cite book|title=Enantiomers, racemates, and resolutions|author=Jean Jacques, André Collet, Samuel H Wilen|year=1981|publisher=Wiley |isbn=0-471-08058-6}} This phenomenon allowed [Louis Pasteur](/source/Louis_Pasteur) to separate left-handed and right-handed [sodium ammonium tartrate](/source/sodium_ammonium_tartrate) crystals. These experiments underpinned his discovery of [optical activity](/source/optical_activity). In 1882 he went on to demonstrate that by [seeding](/source/seed_crystal) a [supersaturated](/source/supersaturation) solution of sodium ammonium tartrate with a d-crystal on one side of the reactor and a l-crystal on the opposite side, crystals of opposite handedness will form on the opposite sides of the reactor. Spontaneous resolution has also been demonstrated with racemic [methadone](/source/methadone).{{cite journal |title= A Mechanical Resolution of dl-Methadone Base |author= Harold E. Zaugg |journal= [J. Am. Chem. Soc.](/source/J._Am._Chem._Soc.) |year= 1955 |volume= 77 |issue= 10 |page= 2910 |doi= 10.1021/ja01615a084|bibcode= 1955JAChS..77.2910Z}} In a typical setup 50 grams dl-methadone is dissolved in [petroleum ether](/source/petroleum_ether) and concentrated. Two millimeter-sized d- and l-crystals are added and after stirring for 125 hours at 40 °C two large d- and l-crystals are recovered in 50% yield. Another form of direct crystallization is preferential crystallization also called '''resolution by entrainment''' of one of the enantiomers. For example, seed crystals of (−)-hydrobenzoin induce crystallization of this enantiomer from an [ethanol](/source/ethanol) solution of (±)-[hydrobenzoin](/source/hydrobenzoin). ==Chiral column chromatography== In [chiral column chromatography](/source/chiral_column_chromatography) the stationary phase is made chiral with similar resolving agents as described above. == Further reading == * {{Cite book |last=[Sheldon](/source/Roger_A._Sheldon) |first=Roger Arthur |title=Chirotechnology: industrial synthesis of optically active compounds |date=1993 |publisher=Dekker |isbn=978-0-8247-9143-8 |location=New York, NY}} ==References== {{Reflist}} {{Chiral synthesis}} {{Authority control}} Category:Stereochemistry --- Adapted from the Wikipedia article [Chiral resolution](https://en.wikipedia.org/wiki/Chiral_resolution) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Chiral_resolution?action=history)). 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