Chiral resolution
Encyclopedia
Chiral resolution in stereochemistry
is a process for the separation of racemic
compounds into their enantiomer
s. It is an important tool in the production of optically active drug
s. Other terms with the same meaning are optical resolution and mechanical resolution.
One disadvantage of chiral resolution of racemates compared to direct asymmetric synthesis of one of the enantiomers is that only 50% of a desired enantiomer is obtained. Several methods exist.
was the first to conduct chiral resolution when he discovered the concept of optical activity in the first place by the manual separation of left-handed and right-handed tartaric acid
crystals in 1849. Later 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 side of the reactor.
This type of resolution called 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 an added seed of (-)-hydrobenzoin to an ethanol
solution of (±)-hydrobenzoin will have the (-)-enantiomer crystallizing out and after 15 cycles 97% optical purity can be obtained.
s which can be separated by conventional techniques in physical chemistry
. Derivatization is possible by salt formation between an amine
and a carboxylic acid
. Simple deprotonation affords the pure enantiomer. Examples of so-called chiral resolving agents are tartaric acid
and brucine
. The method was introduced (again) by Louis Pasteur
in 1853 by resolving racemic tartaric acid
with optically active (+)-cinchotoxine.
One modern-day method of chiral resolution is used in the organic synthesis
of the drug Duloxetine
:
In one of its steps the racemic
alcohol
1 is dissolved in a mixture of toluene
and methanol
to which solution is added optically active (S)-mandelic acid
3. The alcohol (S)-enantiomer forms an insoluble diastereomer
ic 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
in toluene. This process is known as RRR synthesis in which the R's stand for Resolution-Racemization-Recycle.
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
is a process for the separation of racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
compounds into their enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s. It is an important tool in the production of optically active drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s. Other terms with the same meaning are optical resolution and mechanical resolution.
One disadvantage of chiral resolution of racemates compared to direct asymmetric synthesis of one of the enantiomers is that only 50% of a desired enantiomer is obtained. Several methods exist.
Resolution by crystallization
Typically 5-10% of all racemates are known to crystallize as mixtures of enantiopure crystals, so-called conglomerates . Louis PasteurLouis Pasteur
Louis Pasteur was a French chemist and microbiologist born in Dole. He is remembered for his remarkable breakthroughs in the causes and preventions of diseases. His discoveries reduced mortality from puerperal fever, and he created the first vaccine for rabies and anthrax. His experiments...
was the first to conduct chiral resolution when he discovered the concept of optical activity in the first place by the manual separation of left-handed and right-handed tartaric acid
Tartaric acid
Tartaric acid is a white crystalline diprotic organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds; is commonly combined with baking soda to function as a leavening agent in recipes, and is one of the main acids found in wine. It is added to other foods to...
crystals in 1849. Later in 1882 he went on to demonstrate that by seeding
Seed crystal
A seed crystal is a small piece of single crystal/polycrystal material from which a large crystal of the same material typically is to be grown...
a supersaturated
Supersaturation
The term supersaturation refers to a solution that contains more of the dissolved material than could be dissolved by the solvent under normal circumstances...
solution of sodium ammonium tartrate
Tartrate
A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. Its formula is O−OC-CH-CH-COO− or C4H4O62−.As food additives, tartrates are used as antioxidants, acidity regulators, and emulsifiers...
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 side of the reactor.
This type of resolution called spontaneous resolution has also been demonstrated with racemic methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
. In a typical setup 50 grams dl-methadone is dissolved in petroleum ether
Petroleum ether
Petroleum ether, also known as benzine, VM&P Naphtha, Petroleum Naphtha, Naphtha ASTM, Petroleum Spirits, X4 or Ligroin, is a group of various volatile, highly flammable, liquid hydrocarbon mixtures used chiefly as nonpolar solvents...
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 an added seed of (-)-hydrobenzoin to an ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
solution of (±)-hydrobenzoin will have the (-)-enantiomer crystallizing out and after 15 cycles 97% optical purity can be obtained.
Chiral resolving agents
Derivatization of racemic compounds is possible with optically pure reagents forming pairs of diastereomerDiastereomer
Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...
s which can be separated by conventional techniques in physical chemistry
Physical chemistry
Physical chemistry is the study of macroscopic, atomic, subatomic, and particulate phenomena in chemical systems in terms of physical laws and concepts...
. Derivatization is possible by salt formation between an amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
and a carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
. Simple deprotonation affords the pure enantiomer. Examples of so-called chiral resolving agents are tartaric acid
Tartaric acid
Tartaric acid is a white crystalline diprotic organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds; is commonly combined with baking soda to function as a leavening agent in recipes, and is one of the main acids found in wine. It is added to other foods to...
and brucine
Brucine
Brucine is a bitter alkaloid closely related to strychnine. It occurs in several plant species, the most well known being the Strychnos nux-vomica tree, found in South-East Asia.While brucine is related to strychnine, it is not as poisonous...
. The method was introduced (again) by Louis Pasteur
Louis Pasteur
Louis Pasteur was a French chemist and microbiologist born in Dole. He is remembered for his remarkable breakthroughs in the causes and preventions of diseases. His discoveries reduced mortality from puerperal fever, and he created the first vaccine for rabies and anthrax. His experiments...
in 1853 by resolving racemic tartaric acid
Tartaric acid
Tartaric acid is a white crystalline diprotic organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds; is commonly combined with baking soda to function as a leavening agent in recipes, and is one of the main acids found in wine. It is added to other foods to...
with optically active (+)-cinchotoxine.
One modern-day method of chiral resolution is used in the organic synthesis
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
of the drug Duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
:
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
1 is dissolved in a mixture of toluene
Toluene
Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...
and methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
to which solution is added optically active (S)-mandelic acid
Mandelic acid
Mandelic acid is an aromatic alpha hydroxy acid with the molecular formula C6H5CHCO2H. It is a white crystalline solid that is soluble in water and polar organic solvents. It is a useful precursor to various drugs...
3. The alcohol (S)-enantiomer forms an insoluble diastereomer
Diastereomer
Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...
ic 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
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
in toluene. This process is known as RRR synthesis in which the R's stand for Resolution-Racemization-Recycle.
Chiral column chromatography
- In chiral column chromatographyChiral column chromatographyChiral column chromatography is a variant of column chromatography in which the stationary phase contains a single enantiomer of a chiral compound rather than being achiral...
the stationary phase is made chiral with similar resolving agents as described above.