Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic compounds into their

enantiomer 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 ant ...

s. It is an important tool in the production of

optically active Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circular ...

compounds, including

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...

s. Another term with the same meaning is optical resolution. The use of chiral 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 agents, 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 Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...

and a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...

. 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 Salt is a mineral composed primarily of sodium chloride (NaCl), a c ...

and the amine brucine. 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 Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...

of the drug duloxetine: RRRsynthesis

In one of its steps the racemic 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) ...

and methanol to which solution is added optically active (S)- 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 liberates free (S)-alcohol. In the meanwhile the (R)-alcohol remains in solution unaffected and is recycled back to the racemic mixture by epimerization 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. It is a component of the gastric acid in the dig ...

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, 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 organi ...

, 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 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 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. ...

are known to crystallize as mixtures of enantiopure crystals. Louis Pasteur exploited this phenomenon by the manual separation of left-handed and right-handed sodium ammonium tartrate crystals in 1849. These experiments underpinned his discovery of

optical activity Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circular ...

. In 1882 he went on to demonstrate that by seeding a supersaturated 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. In a typical setup 50 grams dl-methadone is dissolved in 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 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 h ...

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