Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of

racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

compounds into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term with the same meaning is optical resolution. The use of

chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...

resolution to obtain enantiomerically pure compounds has the disadvantage of necessarily discarding at least half of the starting racemic mixture. 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 In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have di ...

derivatives by reacting them with

chiral derivatizing agent A chiral derivatizing agent (CDA) also known as a chiral resolving reagent, is a chiral auxiliary used to convert a mixture of enantiomers into diastereomers in order to analyze the quantities of each enantiomer present within the mix. Analysis can ...

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 for reuse. It is common to test several resolving agents. Typical derivatization involves salt formation between an

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen Hydrogen is the chemical element wi ...

and a carboxylic acid. Simple deprotonation then yields back the pure enantiomer. Examples of chiral derivatizing agents are

tartaric acid Tartaric acid is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes, but also in bananas, tamarinds, and citrus. Its salt, potassium bitartrate, commonly known as cream of tartar, develops naturally ...

and the amine

brucine Brucine, is an alkaloid closely related to strychnine, most commonly found in the ''Strychnos nux-vomica'' tree. Brucine poisoning is rare, since it is usually ingested with strychnine, and strychnine is more toxic than brucine. In synthetic ch ...

. The method was introduced (again) by Louis Pasteur in 1853 by resolving racemic

with optically active (+)- cinchotoxine.

Case study

One modern-day method of chiral resolution is used in the organic synthesis of the drug

duloxetine Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth. It is a seroton ...

In one of its steps the

alcohol 1 is dissolved in a mixture of

toluene Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) a ...

and methanol to which solution is added optically active (S)-

mandelic acid Mandelic acid is an aromatic alpha hydroxy acid with the molecular formula C6H5CH(OH)CO2H. It is a white crystalline solid that is soluble in water and polar organic solvents. It is a useful precursor to various drugs. The molecule is chiral. T ...

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 liberates free (S)-alcohol. In the meanwhile the (R)-alcohol remains in solution unaffected and is recycled back to the racemic mixture by

epimerization In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is t ...

with

hydrochloric acid Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid Acid strength is the tendency of an acid, symbol ...

in toluene. This process is known as RRR synthesis in which the R's stand for Resolution-Racemization-Recycle.

Common resolving agents

Antimony potassium tartrate Antimony potassium tartrate, also known as potassium antimonyl tartrate, potassium antimontarterate, or tartar emetic, has the formula K2Sb2(C4H2O6)2. The compound has long been known as a powerful emetic, and was used in the treatment of schistoso ...

, an anion, that forms diastereomeric salts with chiral cations. *

Camphorsulfonic acid Camphorsulfonic acid, sometimes abbreviated CSA or 10-CSA is an organosulfur compound. Like typical sulfonic acids, it is a relatively strong acid that is a colorless solid at room temperature and is soluble in water and a wide variety of organic ...

, an acid that forms diastereomeric salts with chiral amines * 1-Phenylethylamine, a base that forms diastereomeric salts with chiral acids. Many related chiral amines have been demonstrated. The

chiral pool The chiral pool is a "collection of abundant enantiopure building blocks provided by nature" used in synthesis. In other words, a chiral pool would be a large quantity of common organic enantiomers. Contributors to the chiral pool are amino acids, s ...

consists of many widely available resolving agents.

Spontaneous resolution and related specialized techniques

Via the process known as spontaneous resolution, 5-10% of all racemates are known to crystallize as mixtures of

enantiopure In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...

crystals. Louis Pasteur exploited this phenomenon by the manual separation of left-handed and right-handed

sodium ammonium tartrate Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable is ...

crystals in 1849. These experiments underpinned his discovery of optical activity. In 1882 he went on to demonstrate that by

seeding The term seeding and related terms such as seeded are used in several different contexts: *Sowing, planting seeds in a place or on an object *Cloud seeding, manipulating cloud formations *Seeding (computing), a concept in computing and peer-to-pee ...

a supersaturated solution of

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 Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroi ...

. In a typical setup 50 grams dl-methadone is dissolved in

petroleum ether Petroleum ether is the petroleum fraction consisting of aliphatic hydrocarbons and boiling in the range 35–60 °C, and commonly used as a laboratory solvent. Despite the name, petroleum ether is not classified as an ether; the term is used ...

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 Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

solution of (±)- hydrobenzoin.

Chiral column chromatography

*In chiral column chromatography the stationary phase is made chiral with similar resolving agents as described above.

References

{{Authority control Stereochemistry