Chirality (chemistry)

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Two enantiomers of a generic amino acid that are chiral
(S)-Alanine (left) and (R)-alanine (right) in zwitterionic form at neutral pH

In

rotations, translations, and some conformational changes. This geometric property is called chirality (/kaɪˈrælɪti/).[1][2][3][4] The terms are derived from Ancient Greek χείρ
(cheir) 'hand'; which is the canonical example of an object with this property.

A chiral molecule or ion exists in two

optical activities. A homogeneous mixture of the two enantiomers in equal parts is said to be racemic
, and it usually differs chemically and physically from the pure enantiomers.

Chiral molecules will usually have a stereogenic element from which chirality arises. The most common type of stereogenic element is a stereogenic center, or stereocenter. In the case of organic compounds, stereocenters most frequently take the form of a carbon atom with four distinct (different) groups attached to it in a tetrahedral geometry. Less commonly, other atoms like N, P, S, and Si can also serve as stereocenters, provided they have four distinct substituents (including lone pair electrons) attached to them.

A given stereocenter has two possible configurations (R and S), which give rise to stereoisomers (diastereomers and enantiomers) in molecules with one or more stereocenter. For a chiral molecule with one or more stereocenter, the enantiomer corresponds to the stereoisomer in which every stereocenter has the opposite configuration. An organic compound with only one stereogenic carbon is always chiral. On the other hand, an organic compound with multiple stereogenic carbons is typically, but not always, chiral. In particular, if the stereocenters are configured in such a way that the molecule can take a conformation having a plane of symmetry or an inversion point, then the molecule is achiral and is known as a meso compound.

Molecules with chirality arising from one or more stereocenters are classified as possessing central chirality. There are two other types of stereogenic elements that can give rise to chirality, a stereogenic axis (axial chirality) and a stereogenic plane (planar chirality). Finally, the inherent curvature of a molecule can also give rise to chirality (inherent chirality). These types of chirality are far less common than central chirality. BINOL is a typical example of an axially chiral molecule, while trans-cyclooctene is a commonly cited example of a planar chiral molecule. Finally, helicene possesses helical chirality, which is one type of inherent chirality.

Chirality is an important concept for

pharmaceutical usually have vastly different potencies
or effects.

Definition

The chirality of a molecule is based on the molecular symmetry of its conformations. A conformation of a molecule is chiral if and only if it belongs to the Cn, Dn, T, O, I point groups (the chiral point groups). However, whether the molecule itself is considered to be chiral depends on whether its chiral conformations are persistent isomers that could be isolated as separated enantiomers, at least in principle, or the enantiomeric conformers rapidly interconvert at a given temperature and timescale through low-energy conformational changes (rendering the molecule achiral). For example, despite having chiral gauche conformers that belong to the C2 point group, butane is considered achiral at room temperature because rotation about the central C–C bond rapidly interconverts the enantiomers (3.4 kcal/mol barrier). Similarly, cis-1,2-dichlorocyclohexane consists of chair conformers that are nonidentical mirror images, but the two can interconvert via the cyclohexane chair flip (~10 kcal/mol barrier). As another example, amines with three distinct substituents (R1R2R3N:) are also regarded as achiral molecules because their enantiomeric pyramidal conformers rapidly invert and interconvert through a planar transition state (~6 kcal/mol barrier).

However, if the temperature in question is low enough, the process that interconverts the enantiomeric chiral conformations becomes slow compared to a given timescale. The molecule would then be considered to be chiral at that temperature. The relevant timescale is, to some degree, arbitrarily defined: 1000 seconds is sometimes employed, as this is regarded as the lower limit for the amount of time required for chemical or chromatographic separation of enantiomers in a practical sense. Molecules that are chiral at room temperature due to restricted rotation about a single bond (barrier to rotation ≥ ca. 23 kcal/mol) are said to exhibit atropisomerism.

A chiral compound can contain no

improper axis of rotation (Sn), which includes planes of symmetry and inversion center. Chiral molecules are always dissymmetric (lacking Sn) but not always asymmetric (lacking all symmetry elements except the trivial identity). Asymmetric molecules are always chiral.[5]

The following table shows some examples of chiral and achiral molecules, with the Schoenflies notation of the point group of the molecule. In the achiral molecules, X and Y (with no subscript) represent achiral groups, whereas XR and XS or YR and YS represent enantiomers. Note that there is no meaning to the orientation of an S2 axis, which is just an inversion. Any orientation will do, so long as it passes through the center of inversion. Also note that higher symmetries of chiral and achiral molecules also exist, and symmetries that do not include those in the table, such as the chiral C3 or the achiral S4.

Molecular symmetry and chirality
Rotational
axis (Cn)		 Improper rotational elements (Sn)
  Chiral
no Sn		 Achiral
mirror plane
S1 = σ		 Achiral
inversion center
S2 = i
C1
C1
Cs
Ci
C2
C2
(Note: This molecule has only one C2 axis:
perpendicular to line of three C, but not in the plane of the figure.)
C2v
C2h
Note: This also has a mirror plane.

An example of a molecule that does not have a mirror plane or an inversion and yet would be considered achiral is 1,1-difluoro-2,2-dichlorocyclohexane (or 1,1-difluoro-3,3-dichlorocyclohexane). This may exist in many conformers (

conformational isomers), but none of them has a mirror plane. In order to have a mirror plane, the cyclohexane
ring would have to be flat, widening the bond angles and giving the conformation a very high energy. This compound would not be considered chiral because the chiral conformers interconvert easily.

An achiral molecule having chiral conformations could theoretically form a mixture of right-handed and left-handed crystals, as often happens with

racemic mixtures of chiral molecules (see Chiral resolution#Spontaneous resolution and related specialized techniques), or as when achiral liquid silicon dioxide is cooled to the point of becoming chiral quartz
.

Stereogenic centers

Main article:
Stereogenic center
Here, swapping of the two groups a and b leads to a molecule that is a stereoisomer of the original (the enantiomer, assuming there are no other stereogenic elements in the molecule). Hence, the central carbon atom is a stereocenter.

A stereogenic center (or stereocenter) is an atom such that swapping the positions of two ligands (connected groups) on that atom results in a molecule that is stereoisomeric to the original. For example, a common case is a

coordination compounds). However, a stereogenic center can also be a trivalent atom whose bonds are not in the same plane, such as phosphorus in P-chiral phosphines (PRR′R″) and sulfur in S-chiral sulfoxides
(OSRR′), because a lone-pair of electrons is present instead of a fourth bond.

1,1′-Bi-2-naphthol
is an example of a molecule with a stereogenic axis.

Similarly, a stereogenic axis (or plane) is defined as an axis (or plane) in the molecule such that the swapping of any two ligands attached to the axis (or plane) gives rise to a stereoisomer. For instance, the

1,1′-bi-2-naphthol (BINOL) and 1,3-dichloroallene have stereogenic axes and exhibit axial chirality, while (E)-cyclooctene and many ferrocene derivatives bearing two or more substituents have stereogenic planes and exhibit planar chirality
.

Chirality can also arise from isotopic differences between atoms, such as in the deuterated benzyl alcohol PhCHDOH; which is chiral and optically active ([α]D = 0.715°), even though the non-deuterated compound PhCH2OH is not.[6]

If two enantiomers easily interconvert, the pure enantiomers may be practically impossible to separate, and only the racemic mixture is observable. This is the case, for example, of most amines with three different substituents (NRR′R″), because of the low

nitrogen inversion
.

An adamantane derivative that is a chiral molecule but lacking any stereogenic centers.[7] The center of chirality, marked by a black dot, is not at any of the atoms themselves.

It is not necessary for the chiral substance to have a stereogenic element. Examples include certain

fullerenes, which have inherent chirality. Moreover, it is possible for a molecule to have a center of chirality that sits in a position that does not correspond to an atom. Such a molecule may be chiral without having any stereogenic centers. Examples include 1,3,5(,7)-substituted adamantanes such as (1S,3R,5R,7S)-3-methyl-5-phenyladamantane-1-carboxylic acid (pictured).[7][8]

When the optical

rotation for an enantiomer is too low for practical measurement, the species is said to exhibit cryptochirality
.

Chirality is an intrinsic part of the identity of a molecule, so the systematic name includes details of the absolute configuration (R/S, D/L, or other designations).

Manifestations of chirality

In biochemistry

Many biologically active molecules are chiral, including the naturally occurring amino acids (the building blocks of proteins) and sugars.

The origin of this homochirality in biology is the subject of much debate.[14] Most scientists believe that Earth life's "choice" of chirality was purely random, and that if carbon-based life forms exist elsewhere in the universe, their chemistry could theoretically have opposite chirality. However, there is some suggestion that early amino acids could have formed in comet dust. In this case, circularly polarised radiation (which makes up 17% of stellar radiation) could have caused the selective destruction of one chirality of amino acids, leading to a selection bias which ultimately resulted in all life on Earth being homochiral.[15][16]

Enzymes, which are chiral, often distinguish between the two enantiomers of a chiral substrate. One could imagine an enzyme as having a glove-like cavity that binds a substrate. If this glove is right-handed, then one enantiomer will fit inside and be bound, whereas the other enantiomer will have a poor fit and is unlikely to bind.

L-forms of amino acids tend to be tasteless, whereas D-forms tend to taste sweet.

receptors
are chiral.

Chirality is important in context of ordered phases as well, for example the addition of a small amount of an optically active molecule to a nematic phase (a phase that has long range orientational order of molecules) transforms that phase to a chiral nematic phase (or cholesteric phase). Chirality in context of such phases in polymeric fluids has also been studied in this context.[17]

In inorganic chemistry

Delta-ruthenium-tris(bipyridine) cation
Main article:
Complex (chemistry): Isomerism

Chirality is a symmetry property, not a property of any part of the periodic table. Thus many inorganic materials, molecules, and ions are chiral. Quartz is an example from the mineral kingdom. Such noncentric materials are of interest for applications in nonlinear optics.

In the areas of

dextro- and levo- (laevo-)
.

Chiral ligands confer chirality to a metal complex, as illustrated by metal-

asymmetric catalysis.[19]

Methods and practices

The term

dextrorotatory form, of an optical isomer does the opposite. The rotation of light is measured using a polarimeter
and is expressed as the optical rotation.

Enantiomers can be separated by chiral resolution. This often involves forming crystals of a salt composed of one of the enantiomers and an acid or base from the so-called chiral pool of naturally occurring chiral compounds, such as malic acid or the amine brucine. Some racemic mixtures spontaneously crystallize into right-handed and left-handed crystals that can be separated by hand. Louis Pasteur used this method to separate left-handed and right-handed sodium ammonium tartrate crystals in 1849. Sometimes it is possible to seed a racemic solution with a right-handed and a left-handed crystal so that each will grow into a large crystal.

Liquid chromatography (HPLC and TLC) may also be used as an analytical method for the direct separation of

active pharmaceutical ingredients (APIs) which are chiral.[20][21]

Miscellaneous nomenclature

History

The rotation of plane polarized light by chiral substances was first observed by Jean-Baptiste Biot in 1812,[26] and gained considerable importance in the sugar industry, analytical chemistry, and pharmaceuticals. Louis Pasteur deduced in 1848 that this phenomenon has a molecular basis.[27][28] The term chirality itself was coined by Lord Kelvin in 1894.[29] Different enantiomers or diastereomers of a compound were formerly called optical isomers due to their different optical properties.[30] At one time, chirality was thought to be restricted to organic chemistry, but this misconception was overthrown by the resolution of a purely inorganic compound, a cobalt complex called hexol, by Alfred Werner in 1911.[31]

In the early 1970s, various groups established that the

human olfactory organ is capable of distinguishing chiral compounds.[10][32][33]

See also

References

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  2. ^ Organic Chemistry (3rd Edition) Marye Anne Fox, James K. Whitesell Jones & Bartlett Publishers (2004)
    ISBN 0763721972
  3. doi:10.1351/goldbook.C01058
  4. doi:10.1351/goldbook.S06144
  5. ^ Cotton, F. A., "Chemical Applications of Group Theory," John Wiley & Sons: New York, 1990.
  6. doi:10.1016/0040-4020(59)80014-4
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  15. ^ McKee, Maggie (2005-08-24). "Space radiation may select amino acids for life". New Scientist. Retrieved 2016-02-05.
  16. PMID 16035020.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
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  19. ISBN 189138953X
  20. doi:10.1016/j.chroma.2009.12.071
    )
  21. doi:10.1002/tcr.202100295
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  22. doi:10.1002/(sici)1520-636x(1997)9:5/6<428::aid-chir5>3.3.co;2-e. Archived from the original
    on 3 March 2016. Retrieved 5 February 2016.
  23. doi:10.1351/goldbook.E02072
  24. doi:10.1351/goldbook.E02071
  25. doi:10.1351/goldbook.E02070
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  27. ^ Pasteur, L. (1848). Researches on the molecular asymmetry of natural organic products, English translation of French original, published by Alembic Club Reprints (Vol. 14, pp. 1–46) in 1905, facsimile reproduction by SPIE in a 1990 book.
  28. ISBN 978-0471016700
    . Retrieved 2 February 2016.
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  30. doi:10.1351/goldbook.O04308
  31. doi:10.1002/cber.19110440297
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  32. S2CID 25725148
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  33. doi:10.1002/hlca.19800630721
    .

Further reading

External links

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