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Atropisomers are stereoisomers arising because of hindered rotation about a
single bond In chemistry, a single bond is a chemical bond between two atoms involving two valence electrons. That is, the atoms share one pair of electrons where the bond forms. Therefore, a single bond is a type of covalent bond. When shared, each of ...
, where
energy In physics, energy (from Ancient Greek: ἐνέργεια, ''enérgeia'', “activity”) is the quantitative property that is transferred to a body or to a physical system, recognizable in the performance of work and in the form of ...
differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. They occur naturally and are important in pharmaceutical design. When the substituents are achiral, these conformers are
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 anti ...
s (''atropoenantiomers''), showing
axial chirality Axial may refer to: * one of the anatomical directions describing relationships in an animal body * In geometry: :* a geometric term of location :* an axis of rotation * In chemistry, referring to an axial bond * a type of modal frame, in music ...
; otherwise they are diastereomers (''atropodiastereomers'').


Etymology and history

The word ''atropisomer'' ( el, άτροπος, , meaning "without turn") was coined in application to a theoretical concept by German biochemist Richard Kuhn for Karl Freudenberg's seminal ''Stereochemie'' volume in 1933. Atropisomerism was first experimentally detected in a tetra substituted biphenyl, a
diacid In organic chemistry, a dicarboxylic acid is an organic compound containing two carboxyl groups (). The general molecular formula for dicarboxylic acids can be written as , where R can be aliphatic or aromatic. In general, dicarboxylic acids show ...
, by George Christie and James Kenner in 1922. Michinori Ōki further refined the definition of atropisomers taking into account the temperature-dependence associated with the interconversion of conformers, specifying that atropisomers interconvert with a
half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...
of at least 1000 seconds at a given temperature, corresponding to an
energy barrier In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...
of 93 kJ mol−1 (22 kcal mol −1) at 300 K (27 °C).


Energetics

The stability of individual atropisomers is conferred by the repulsive interactions that inhibit rotation. Both the steric bulk and, in principle, the length and rigidity of the bond connecting the two subunits contribute. Commonly, atropisomerism is studied by dynamic nuclear magnetic resonance spectroscopy, since atropisomerism is a form of
fluxionality In chemistry and molecular physics, fluxional (or non-rigid) molecules are molecules that undergo dynamics such that some or all of their atoms interchange between symmetry-equivalent positions. Because virtually all molecules are fluxional in som ...
. Inferences from
theory A theory is a rational type of abstract thinking about a phenomenon, or the results of such thinking. The process of contemplative and rational thinking is often associated with such processes as observational study or research. Theories may ...
and results of reaction outcomes and yields also contribute. Atropisomers exhibit
axial chirality Axial may refer to: * one of the anatomical directions describing relationships in an animal body * In geometry: :* a geometric term of location :* an axis of rotation * In chemistry, referring to an axial bond * a type of modal frame, in music ...
( planar chirality). When the barrier to racemization is high, as illustrated by the BINAP ligands, the phenomenon becomes of practical value in asymmetric synthesis. Methaqualone, the anxiolytic and hypnotic-sedative, is a classical example of a drug molecule that exhibits the phenomenon of atropisomerism.


Stereochemical assignment

Determining the axial stereochemistry of biaryl atropisomers can be accomplished through the use of a
Newman projection A Newman projection is a drawing that helps visualize the 3-dimensional structure of a molecule. This projection most commonly sights down a carbon-carbon bond, making it a very useful way to visualize the stereochemistry of alkanes. A Newman pro ...
along the axis of hindered rotation. The ortho, and in some cases
meta Meta (from the Greek μετά, '' meta'', meaning "after" or "beyond") is a prefix meaning "more comprehensive" or "transcending". In modern nomenclature, ''meta''- can also serve as a prefix meaning self-referential, as a field of study or end ...
substituents are first assigned priority based on Cahn–Ingold–Prelog priority rules. One scheme of nomenclature in based on envisioning the helicity defined by these groups. Starting with the substituent of highest priority in the closest ring and moving along the shortest path to the substituent of highest priority in the other ring, the absolute configuration is assigned ''P'' or Δ for clockwise and ''M'' or Λ for counterclockwise. Alternately, all four groups can be ranked by Cahn–Ingold–Prelog priority rules, with overall priority given to the groups on the "front" atom of the Newman projection. The two configurations are termed ''R''a and ''S''a in analogy to the traditional ''R''/''S'' for a traditional tetrahedral stereocenter.


Synthesis

Axially chiral biaryl compounds are prepared by coupling reactions, e.g., Ullmann coupling, Suzuki–Miyaura reaction, or palladium-catalyzed arylation of arenes. Subsequent to the synthesis, the racemic biaryl is resolved by classical methods. Diastereoselective coupling can be achieved through the use of a chiral bridge that links the two aryl groups or through the use of a chiral auxiliary at one of the positions proximal to axial bridge. Enantioselective coupling can be achieved through the use of a chiral leaving group on one of the biaryls or under oxidative conditions that utilize chiral amines to set the axial configuration. Individual atropisomers can be isolated by seed-directed crystallization of racemates. Thus, 1,1'-Binaphthyl crystallizes from the melt as individual enantiomers.


Scope

In one application the asymmetry in an atropisomer is transferred in a chemical reaction to a new stereocenter. The atropisomer is an iodoaryl compound synthesised starting from (S)-
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
and exists as the (M,S) isomer and the (P,S) isomer. The interconversion barrier between the two is 24.3 kcal/ mol (101.7 kJ/mol). The (M,S) isomer can be obtained exclusively from this mixture by recrystallisation from
hexane Hexane () is an organic compound, a straight-chain alkane with six carbon atoms and has the molecular formula C6H14. It is a colorless liquid, odorless when pure, and with boiling points approximately . It is widely used as a cheap, relative ...
s. The iodine group is homolytically removed to form an aryl radical by a tributyltin hydride/triethylboron/oxygen mixture as in the Barton–McCombie reaction. Although the hindered rotation is now removed in the aryl radical, the intramolecular reaction with the
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic ...
is so much faster than is rotation of the carbon–nitrogen bond that the stereochemistry is preserved. In this way the (M,S) isomer yields the (S,S) ''dihydroindolone''. The most important class of atropisomers are biaryls such as ''diphenic acid'', which is a derivative of biphenyl with a complete set of ortho substituents. Heteroaromatic analogues of the biphenyl compounds also exist, where hindered rotation occurs about a carbon-nitrogen or a nitrogen-nitrogen bond. Others are dimers of
naphthalene Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08  ppm by mass. As an aromat ...
derivatives such as 1,1'-bi-2-naphthol. In a similar way, aliphatic ring systems like
cyclohexane Cyclohexane is a cycloalkane with the molecular formula . Cyclohexane is non-polar. Cyclohexane is a colorless, flammable liquid with a distinctive detergent-like odor, reminiscent of cleaning products (in which it is sometimes used). Cyclohe ...
s linked through a single bond may display atropisomerism provided that bulky
substituent A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as '' side ...
s are present. The use of axially chiral biaryl compounds such as BINAP, QUINAP and BINOL, have been found to be useful in the area of asymmetric catalysis as chiral ligands. Their ability to provide stereoinduction has led to use in metal catalyzed hydrogenation, epoxidation, addition, and allylic alkylation reactions. Other reactions that can be catalyzed by the use of chiral biaryl compounds are the Grignard reaction, Ullmann reaction, and the Suzuki reaction. A recent example in the area of chiral biaryl asymmetric catalysis employs a five-membered
imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...
as part of the atropisomer scaffold. This specific phosphorus, nitrogen-ligand has been shown to perform enantioselective A3-coupling.


Natural products, drug design

Many atropisomers occur in nature, and some have applications to drug design. The natural product Mastigophorene A has been found to aid in nerve growth. Other examples of naturally occurring atropisomers include
vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infection ...
isolated from an Actinobacterium, and knipholone, which is found in the roots of ''
Kniphofia ''Kniphofia'' is a genus of perennial flowering plants in the family Asphodelaceae, first described as a genus in 1794. Species are native to Africa. Common names include tritoma, red hot poker, torch lily and poker plant. Description Herbaceou ...
foliosa'' of the family Asphodelaceae. The structure complexity in vancomycin is significant because it can bind with peptides due to the complexity of its stereochemistry, which includes multiple stereocenters, two chiral planes in its stereogenic biaryl axis. Knipholone, with its axial chirality, occurs in nature and has been shown to offer good antimalarial and antitumor activities particularly in the M form. The use of atropisomeric drugs provides an additional way for drugs to have stereochemical variations and specificity in design. One example is , a drug that was discovered to aid in chemotherapy cancer treatment. Telenzepine is atropisomeric in the conformation of its central thienobenzodiazepine ring. The two enantiomers have been resolved, and it was found that the (+)-isomer which is about 500-fold more active than the (–)-isomer at muscarinic receptors in rat cerebral cortex. However, drug design is not always aided by atropisomerism. In some cases, making drugs from atropisomers is challenging because isomers may interconvert faster than expected. Atropisomers also might interact differently in the body, and as with other types of stereoisomers, it is important to examine these properties before administering drugs to patients.


See also

* Dihedral angle


References


Further reading

* {{cite web , url = http://stoltz.caltech.edu/seminars/2005_Allan.pdf , title = Atropisomerism: Axial Chirality in Nature and Synthesis , author = Allen K , date = November 14, 2005 , work = Literature Seminar, Stoltz Research Group , publisher = California Institute of Technology , url-status = dead , archive-url = https://web.archive.org/web/20160303225424/http://stoltz.caltech.edu/seminars/2005_Allan.pdf , archive-date = March 3, 2016 Stereochemistry