Inchemistry, a molecule or ion is calledchiral (/ˈkaɪrəl/) if it cannot be superposed on itsmirror image by any combination ofrotations,translations, and someconformational changes. This geometric property is calledchirality (/kaɪˈrælɪti/).[1][2][3][4] The terms are derived fromAncient Greekχείρ (cheir) 'hand'; which is thecanonical example of an object with this property.
A chiral molecule or ion exists in twostereoisomers that are mirror images of each other,[5] calledenantiomers; they are often distinguished as either "right-handed" or "left-handed" by theirabsolute configuration or some other criterion. The two enantiomers have the same chemical properties, except when reacting with other chiral compounds. They also have the samephysical properties, except that they often have oppositeoptical activities. A homogeneous mixture of the two enantiomers in equal parts, aracemic mixture, 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 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 andenantiomers) 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 ameso 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, whiletrans-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 forstereochemistry andbiochemistry. Most substances relevant tobiology are chiral, such ascarbohydrates (sugars,starch, andcellulose), all but one of theamino acids that are the building blocks ofproteins, and thenucleic acids. Naturally occurringtriglycerides are often chiral, but not always. In living organisms, one typically finds only one of the two enantiomers of a chiral compound. For that reason, organisms that consume a chiral compound usually can metabolize only one of its enantiomers. For the same reason, thepotencies or effects of enantiomers of apharmaceutical can differ sharply.
The chirality of a molecule is based on themolecular symmetry of its conformations. A conformation of a molecule is chiral if and only if it belongs to theCn,Dn,T,O, orIpoint 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 theenantiomeric conformers rapidly interconvert at a given temperature and timescale through low-energy conformational changes (rendering the molecule achiral). For example, despite having chiralgauche conformers that belong to theC2 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 ofchair 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 undergopyramidal inversion.
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 exhibitatropisomerism.
A chiral compound can contain noimproper axis of rotation (Sn), which includes planes of symmetry and inversion center. Chiral molecules are always dissymmetric (lackingSn) but not always asymmetric (lacking all symmetry elements except the trivial identity). Asymmetric molecules are always chiral.[6]
The following table shows some examples of chiral and achiral molecules, with theSchoenflies notation of thepoint 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 representenantiomers. Note that there is no meaning to the orientation of anS2 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 chiralC3 or the achiralS4.
| Rotational axis (Cn) | Improper rotational elements (Sn) | ||
|---|---|---|---|
| Chiral noSn | Achiral mirror plane S1 = σ | Achiral inversion center S2 =i | |
| C1 |  C1 |  Cs |  Ci |
| C2 |  C2 (Note: This molecule has only oneC2 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, thecyclohexane 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 withracemic mixtures of chiral molecules (seeChiral resolution#Spontaneous resolution and related specialized techniques), or as when achiral liquidsilicon dioxide is cooled to the point of becoming chiralquartz.
Astereogenic center (orstereocenter) 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 atetrahedral carbon bonded to four distinct groupsa,b,c, andd (Cabcd), where swapping any two groups (e.g., Cbacd) leads to a stereoisomer of the original, so the central C is a stereocenter. Many chiral molecules have point chirality, namely a single chiral stereogenic center that coincides with an atom. This stereogenic center usually has four or more bonds to different groups and may be carbon (as in many biological molecules), phosphorus (as in manyorganophosphates), silicon, or a metal (as in many chiralcoordination compounds). However, a stereogenic center can also be a trivalent atom whose bonds are not in the same plane, such asphosphorus inP-chiral phosphines (PRR′R″) andsulfur inS-chiral sulfoxides (OSRR′), because a lone-pair of electrons is present instead of a fourth bond.
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, theC2-symmetric species1,1′-bi-2-naphthol (BINOL) and 1,3-dichloroallene have stereogenic axes and exhibitaxial chirality, while (E)-cyclooctene and manyferrocene derivatives bearing two or more substituents have stereogenic planes and exhibitplanar chirality.
Chirality can also arise fromisotopic differences between substituents, such as in thedeuteratedbenzyl alcohol PhCHDOH; which is chiral and optically active ([α]D = 0.715°), even though the non-deuterated compound PhCH2OH is not.[7]
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 lowenergy barrier fornitrogen inversion.
When the opticalrotation for an enantiomer is too low for practical measurement, the species is said to exhibitcryptochirality.
Chirality is an intrinsic part of the identity of a molecule, so thesystematic name includes details of theabsolute configuration (R/S,D/L, orother designations).
Many biologically active molecules are chiral, including the naturally occurringamino acids (the building blocks ofproteins) andsugars.
The origin of thishomochirality inbiology is the subject of much debate.[13] 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.[14][15]
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, whereasD-forms tend to taste sweet.[13]Spearmint leaves contain theL-enantiomer of the chemicalcarvone orR-(−)-carvone andcaraway seeds contain theD-enantiomer orS-(+)-carvone.[9] The two smell different to most people because our olfactoryreceptors 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.[16]
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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 innonlinear optics.
In the areas ofcoordination chemistry andorganometallic chemistry, chirality is pervasive and of practical importance. A famous example istris(bipyridine)ruthenium(II) complex in which the three bipyridine ligands adopt a chiral propeller-like arrangement.[17] The two enantiomers of complexes such as [Ru(2,2′-bipyridine)3]2+ may be designated as Λ (capitallambda, the Greek version of "L") for a left-handed twist of the propeller described by the ligands, and Δ (capitaldelta, Greek "D") for a right-handed twist (pictured).dextro- and levo-rotation (the clockwise and counterclockwise optical rotation ofplane-polarized light) uses similar notation, but shouldn't be confused.
Chiral ligands confer chirality to a metal complex, as illustrated by metal-amino acid complexes. If the metal exhibits catalytic properties, its combination with a chiral ligand is the basis ofasymmetric catalysis.[18]
The termoptical activity is derived from the interaction of chiral materials with polarized light. In a solution, the (−)-form, orlevorotatory form, of an optical isomerrotates the plane of a beam oflinearly polarized lightcounterclockwise. The (+)-form, ordextrorotatory form, of an optical isomer does the opposite. The rotation of light is measured using apolarimeter and is expressed as the optical rotation.
Enantiomers can be separated bychiral resolution. This often involves forming crystals of a salt composed of one of the enantiomers and an acid or base from the so-calledchiral pool of naturally occurring chiral compounds, such asmalic acid or the aminebrucine. 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-handedsodium 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 ofenantiomers and the control of enantiomeric purity, e.g.active pharmaceutical ingredients (APIs) which are chiral.[19][20]
The prediction of chiral properties using computational methods has emerged as an important area in modern stereochemistry[25][26], complementing experimental techniques for characterizing and separatingenantiomers. These approaches leverage machine learning algorithms and molecular representations to predict various chiral-specific behaviors, including chromatographic retention, optical rotation, and stereochemical assignments[27].
Computational methods for representing molecular chirality must encode three-dimensional stereochemical information in a format suitable for machine learning algorithms.SMILES (Simplified Molecular Input Line Entry System) notation incorporates stereochemistry through the use of @ and @@ symbols at chiral centers, where @ typically denotes anticlockwise and @@ denotes clockwise configuration when viewing the chiral center along the bond from the center to the first atom in the SMILES string[28][29].
Traditionalmolecular descriptors used incomputational chemistry, such as circular fingerprints (Extended Connectivity Fingerprints or ECFP[30]), can encode structural information including stereochemical features. These descriptors represent molecules as fixed-length binary vectors that capture local atomic environments and connectivity patterns. However, conventional fingerprints may not optimally capture the subtle three-dimensional differences between enantiomers.
Neural network-based molecular representations can be derived fromSMILES strings. Variationalautoencoders and heteroencoders trained on large databases of molecular structures can generate latent space vectors (LSVs) that encode molecular properties in a continuous, lower-dimensional space[31]. These methods calculate difference vectors between the descriptor of a molecule and that of its enantiomer, or between the original descriptor and one derived from a stereochemistry-depleted SMILES string. Such difference descriptors can amplify the stereochemical information relevant to chiral properties while reducing noise from other structural features[32].
Machine learning models trained on these molecular representations have been applied to predict various chirality-related properties. One practical application is forecasting the elution order of enantiomers in chiral chromatography. Models trained on experimental retention data from chiral stationary phases can learn structure-retention relationships[27].Random Forest and other ensemble methods have been applied to predict which enantiomer elutes first on columns such as Chiralpak AD-H using both traditional circular fingerprints andneural network-derived descriptors[32].
Another application is the prediction of optical rotation, a fundamental chiral property. Machine learning models have been developed to predict specific rotation values for chiral molecules based on their structure, with applications to both organic compounds and specialized classes such as chiral fluorinated molecules[25][26]. These predictions can assist in structural characterization and quality control inpharmaceutical development.
While these machine learning approaches show promise, several limitations remain. Model accuracy depends heavily on training data quality and coverage of chemical space. Neural network architectures, particularlyTransformers, face inherent challenges in learning stereochemical features from string-based representations like SMILES[33]. These models tend to recognize partial molecular structures early in training but require significantly longer to accurately distinguish between enantiomers, sometimes exhibiting periods of confusion where @ and @@ tokens are frequently interchanged. The interpretability of neural network-based descriptors is often limited compared to traditional physically-motivated descriptors. Additionally, these methods typically perform best for compounds structurally similar to training data and may not generalize well to novel scaffolds or unusual stereochemical arrangements.
The rotation of plane polarized light by chiral substances was first observed byJean-Baptiste Biot in 1812,[34] and gained considerable importance in thesugar industry, analytical chemistry, and pharmaceuticals.Louis Pasteur deduced in 1848 that this phenomenon has a molecular basis.[35][36] The termchirality itself was coined byLord Kelvin in 1894.[37] Individual enantiomers or diastereomers of a compound were formerly calledoptical isomers due to their distinct optical properties.[38] 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 calledhexol, byAlfred Werner in 1911.[39]
In the early 1970s, various groups established that thehuman olfactory organ is capable of distinguishing chiral compounds.[9][40][41]
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