Chiral resolution, or enantiomeric resolution, is a process in
stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereo ...
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
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. Circula ...
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 inhalati ...
s. 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 ...
resolution to obtain enantiomerically pure compounds has the disadvantage of necessarily discarding at least half of the starting racemic mixture.
Asymmetric synthesis
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...
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 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 such ...
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. Carboxylic ...
. 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 che ...
. The method was introduced (again) by
Louis Pasteur
Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization, the latter of which was named af ...
in 1853 by resolving racemic
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 ...
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
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 seroto ...
:
In one of its steps the
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. ...
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of se ...
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
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
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. Th ...
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
Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula NaOH. It is a white solid ionic compound consisting of sodium cations and hydroxide anions .
Sodium hydroxide is a highly caustic base and a ...
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 digesti ...
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 crystals.
Louis Pasteur
Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization, the latter of which was named af ...
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. Circula ...
. 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
In physical chemistry, supersaturation occurs with a solution when the concentration of a solute exceeds the concentration specified by the value of solubility at equilibrium. Most commonly the term is applied to a solution of a solid in a ...
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
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 heroin ...
.
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
Chiral column chromatography is a variant of column chromatography that is employed for the separation of enantiomers, e. g. in racemates. The stationary phase contains a single enantiomer of a chiral compound.
The chiral stationary phase can be ...
the stationary phase is made chiral with similar resolving agents as described above.
References
{{Authority control
Stereochemistry