Enantiomer

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(S)-(+)-lactic acid (left) and (R)-(-)-lactic acid (right) are nonsuperposable mirror images of each other. Milchsaure Enantiomerenpaar.svg
(S)-(+)-lactic acid (left) and (R)-(–)-lactic acid (right) are nonsuperposable mirror images of each other.

In chemistry, an enantiomer (/ɪˈnænti.əmər, ɛ-, -oʊ-/ [1] ih-NAN-tee-ə-mər; from Ancient Greek ἐνάντιος (enántios) 'opposite', and μέρος (méros) 'part') – also called optical isomer, [2] antipode, [3] or optical antipode [4] – is one of two stereoisomers that are non-superposable onto their own mirror image. Enantiomers are much like one's right and left hands, when looking at the same face, they cannot be superposed onto each other. [5] No amount of reorientation in three spatial dimensions will allow the four unique groups on the chiral carbon (see Chirality (chemistry)) to line up exactly. The number of stereoisomers a molecule has can be determined by the number of chiral carbons it has. Stereoisomers include both enantiomers and diastereomers.

Contents

Diastereomers, like enantiomers, share the same molecular formula and are non-superposable onto each other however, they are not mirror images of each other. [6]

A molecule with chirality rotates plane-polarized light. [7] A mixture of equal amounts of each enantiomer, a racemic mixture or a racemate, does not rotate light. [8] [9] [10]

Naming conventions

There are three common naming conventions for specifying one of the two enantiomers (the absolute configuration) of a given chiral molecule: the R/S system is based on the geometry of the molecule; the (+)- and (−)- system (also written using the obsolete equivalents d- and l-) is based on its optical rotation properties; and the D/L system is based on the molecule's relationship to enantiomers of glyceraldehyde.

The R/S system is based on the molecule's geometry with respect to a chiral center. [11] The R/S system is assigned to a molecule based on the priority rules assigned by Cahn–Ingold–Prelog priority rules, in which the group or atom with the largest atomic number is assigned the highest priority and the group or atom with the smallest atomic number is assigned the lowest priority.

The (+)- and (−)- is used to specify a molecule's optical rotation — the direction that the molecule in rotates polarized light. [12] When a molecule is denoted dextrorotatory it is rotating the plane of polarized light clockwise and can also be denoted as (+). [11] When it is denoted as levorotatory it is rotating the plane of polarized light counterclockwise and can also be denoted as (−). [11]

The Latin words for left are laevus and sinister, and the word for right is dexter (or rectus in the sense of correct or virtuous). The English word right is a cognate of rectus. This is the origin of the L/D and S/R notations, and the employment of prefixes levo- and dextro- in common names.

The prefix ar-, from the Latin recto (right), is applied to the right-handed version; es-, from the Latin sinister (left), to the left-handed molecule.[ citation needed ] Example: ketamine, arketamine, esketamine.

Chirality centers

Fischer projection of meso-tartaric acid Meso-Weinsaure Spiegel.svg
Fischer projection of meso-tartaric acid

The asymmetric atom is called a chirality center, [13] [14] a type of stereocenter. A chirality center is also called a chiral center [15] [16] [17] or an asymmetric center. [18] Some sources use the terms stereocenter, stereogenic center, stereogenic atom or stereogen to refer exclusively to a chirality center, [15] [17] [19] while others use the terms more broadly to refer also to centers that result in diastereomers (stereoisomers that are not enantiomers). [14] [20] [21]

Compounds that contain exactly one (or any odd number) of asymmetric atoms are always chiral. However, compounds that contain an even number of asymmetric atoms sometimes lack chirality because they are arranged in mirror-symmetric pairs, and are known as meso compounds. For instance, meso tartaric acid (shown on the right) has two asymmetric carbon atoms, but it does not exhibit enantiomerism because there is a mirror symmetry plane. Conversely, there exist forms of chirality that do not require asymmetric atoms, such as axial, planar, and helical chirality. [15] :pg. 3

Even though a chiral molecule lacks reflection (Cs) and rotoreflection symmetries (S2n), it can have other molecular symmetries, and its symmetry is described by one of the chiral point groups: Cn, Dn, T, O, or I. For example, hydrogen peroxide is chiral and has C2 (two-fold rotational) symmetry. A common chiral case is the point group C1, meaning no symmetries, which is the case for lactic acid.

Examples

Structures of the two enantiomeric forms (S left, R right) of mecoprop (+-)-Mecoprop Enantiomers Formulae.png
Structures of the two enantiomeric forms (S left, R right) of mecoprop
Enantiomers of citalopram. The top is (R)-citalopram and the bottom is (S)-citalopram. Citalopram Structural Formulae.png
Enantiomers of citalopram. The top is (R)-citalopram and the bottom is (S)-citalopram.

An example of such an enantiomer is the sedative thalidomide, which was sold in a number of countries around the world from 1957 until 1961. It was withdrawn from the market when it was found to cause birth defects. One enantiomer caused the desirable sedative effects, while the other, unavoidably [22] present in equal quantities, caused birth defects. [23]

The herbicide mecoprop is a racemic mixture, with the (R)-(+)-enantiomer ("Mecoprop-P", "Duplosan KV") possessing the herbicidal activity. [24]

Another example is the antidepressant drugs escitalopram and citalopram. Citalopram is a racemate [1:1 mixture of (S)-citalopram and (R)-citalopram]; escitalopram [(S)-citalopram] is a pure enantiomer. The dosages for escitalopram are typically 1/2 of those for citalopram. Here, (S)-citalopram is called a chiral switch of Citalopram.

Chiral drugs

Enantiomers display distinct biological effects. [25]

Enantiopure medications

Advances in industrial chemical processes have made it economic for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers. This strategy of marketing of a chiral specific drug from an already approved and existing racemic drug is normally done for better therapeutic efficacy. This kind of switching from a racemic drug to an enantiopure drug is called a chiral switch and the process is called chiral switching. In some cases, the enantiomers have genuinely different effects. An interesting case is that of Propoxyphene. The enantiomeric pair of propoxyphene is separately sold by Eli Lilly and company. One of the partner is dextropropoxyphene, an analgesic agent (Darvon) and the other is called levopropoxyphene, an effective antitussive (Novrad). [26] [27]  It is interesting to note that the trade names of the drugs, DARVON and NOVRAD, also reflect the chemical mirror-image relationship. In other cases, there may be no clinical benefit to the patient. In some jurisdictions, single-enantiomer drugs are separately patentable from the racemic mixture. [28] It is possible that only one of the enantiomers is active. Or, it may be that both are active, in which case separating the mixture has no objective benefits, but extends the drug's patentability. [29]

Enantioselective preparations

In the absence of an effective enantiomeric environment (precursor, chiral catalyst, or kinetic resolution), separation of a racemic mixture into its enantiomeric components is impossible, although certain racemic mixtures spontaneously crystallize in the form of a racemic conglomerate, in which crystals of the enantiomers are physically segregated and may be separated mechanically. However, most racemates will crystallize in crystals containing both enantiomers in a 1:1 ratio, arranged in a regular lattice.

In his pioneering work, Louis Pasteur was able to isolate the isomers of tartaric acid because they crystallize from solution as crystals each with a different symmetry and separate them with tweezers. This is known as chiral resolution and its one of the two main strategies for the preparation of enantiopure compounds. A less common method is by enantiomer self-disproportionation.

The second strategy is asymmetric synthesis: the use of various techniques to prepare the desired compound in high enantiomeric excess. Techniques encompassed include the use of chiral starting materials (chiral pool synthesis), the use of chiral auxiliaries and chiral catalysts, and the application of asymmetric induction. The use of enzymes (biocatalysis) may also produce the desired compound.

A third strategy is Enantioconvergent synthesis, the synthesis of one enantiomer from a racemic precursor, utilizing both enantiomers. By making use of a chiral catalyist, both enantiomers of the reactant result in a single enantiomer of product. [30]

Enantiomers may not be isolable if there is an accessible pathway for racemization (interconversion between enantiomorphs to yield a racemic mixture) at a given temperature and timescale. For example, amines with three distinct substituents are chiral, but with few exceptions (e.g. substituted N-chloroaziridines), they rapidly undergo "umbrella inversion" at room temperature, leading to racemization. If the racemization is fast enough, the molecule can often be treated as an achiral, averaged structure.

Parity violation

For all intents and purposes, each enantiomer in a pair has the same energy. However, theoretical physics predicts that due to parity violation of the weak nuclear force (the only force in nature that can "tell left from right"), there is actually a minute difference in energy between enantiomers (on the order of 10−12 eV or 10−10 kJ/mol or less) due to the weak neutral current mechanism. This difference in energy is far smaller than energy changes caused by even small changes in molecular conformation, and far too small to measure by current technology, and is therefore chemically inconsequential. [16] [31] [32] In the sense used by particle physicists, the "true" enantiomer of a molecule, which has exactly the same mass-energy content as the original molecule, is a mirror-image that is also built from antimatter (antiprotons, antineutrons, and positrons). [16] Throughout this article, "enantiomer" is used only in the chemical sense of compounds of ordinary matter that are not superposable on their mirror image.

Quasi-enantiomers

Quasi-enantiomers are molecular species that are not strictly enantiomers, but behave as if they are. In quasi-enantiomers majority of the molecule is reflected; however, an atom or group within the molecule is changed to a similar atom or group. [33] Quasi-enantiomers can also be defined as molecules that have the potential to become enantiomers if an atom or group in the molecule is replaced. [34] An example of quasi-enantiomers would (S)-bromobutane and (R)-iodobutane. Under normal conditions the enantiomers for (S)-bromobutane and (R)-iodobutane would (R)-bromobutane and (S)-iodobutane respectively. Quasi-enantiomers would also produce quasi-racemates, which are similar to normal racemates (see Racemic mixture) in that they form an equal mixture of quasi-enantiomers. [33]

Though not considered actual enantiomers, the naming convention for quasi-enantiomers also follows the same trend as enantiomers when looking at (R) and (S) configurations - which are considered from a geometrical basis (see Cahn–Ingold–Prelog priority rules).

Quasi-enantiomers have applications in parallel kinetic resolution. [35]

See also

Related Research Articles

<span class="mw-page-title-main">Cahn–Ingold–Prelog priority rules</span> Naming convention for stereoisomers of molecules

In organic chemistry, the Cahn–Ingold–Prelog (CIP) sequence rules are a standard process to completely and unequivocally name a stereoisomer of a molecule. The purpose of the CIP system is to assign an R or S descriptor to each stereocenter and an E or Z descriptor to each double bond so that the configuration of the entire molecule can be specified uniquely by including the descriptors in its systematic name. A molecule may contain any number of stereocenters and any number of double bonds, and each usually gives rise to two possible isomers. A molecule with an integer n describing the number of stereocenters will usually have 2n stereoisomers, and 2n−1 diastereomers each having an associated pair of enantiomers. The CIP sequence rules contribute to the precise naming of every stereoisomer of every organic molecule with all atoms of ligancy of fewer than 4.

<span class="mw-page-title-main">Stereoisomerism</span> When molecules have the same atoms and bond structure but differ in 3D orientation

In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but the bond connections or their order differs. By definition, molecules that are stereoisomers of each other represent the same structural isomer.

<span class="mw-page-title-main">Stereochemistry</span> Subdiscipline of chemistry

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 stereoisomers, which by definition have the same molecular formula and sequence of bonded atoms (constitution), but differ in structural formula. For this reason, it is also known as 3D chemistry—the prefix "stereo-" means "three-dimensionality".

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.

In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic form. This creates a 1:1 molar ratio of enantiomers and is referred too as a racemic mixture. Plus and minus forms are called Dextrorotation and levorotation. The D and L enantiomers are present in equal quantities, the resulting sample is described as a racemic mixture or a racemate. Racemization can proceed through a number of different mechanisms, and it has particular significance in pharmacology as different enantiomers may have different pharmaceutical effects.

<span class="mw-page-title-main">Stereocenter</span> Atom which is the focus of stereoisomerism in a molecule

In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups creates a new stereoisomer. Stereocenters are also referred to as stereogenic centers.

<span class="mw-page-title-main">Diastereomer</span> Molecules which are non-mirror image, non-identical stereoisomers

In stereochemistry, diastereomers are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have different configurations at one or more of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereoisomers differ from each other at only one stereocenter, they are epimers. Each stereocenter gives rise to two different configurations and thus typically increases the number of stereoisomers by a factor of two.

<span class="mw-page-title-main">Meso compound</span>

A meso compound or meso isomer is a non-optically active member of a set of stereoisomers, at least two of which are optically active. This means that despite containing two or more stereocenters, the molecule is not chiral. A meso compound is "superimposable" on its mirror image. Two objects can be superimposed if all aspects of the objects coincide and it does not produce a "(+)" or "(-)" reading when analyzed with a polarimeter. The name is derived from the Greek mésos meaning “middle”.

<span class="mw-page-title-main">Chirality (chemistry)</span> Geometric property of some molecules and ions

In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality. The terms are derived from Ancient Greek χείρ (cheir) 'hand'; which is the canonical example of an object with this property.

<span class="mw-page-title-main">Enantioselective synthesis</span> Chemical reaction(s) which favor one chiral isomer over another

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric products in unequal amounts."

In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of a pre-existing one. The selectivity arises from differences in steric and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since the activation energy difference between the two pathways is finite. Both products are at least possible and merely differ in amount. However, in favorable cases, the minor stereoisomer may not be detectable by the analytic methods used.

In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%. A sample with 70% of one enantiomer and 30% of the other has an ee of 40%.

<span class="mw-page-title-main">Axial chirality</span> Type of symmetry in molecules

In chemistry, axial chirality is a special case of chirality in which a molecule contains two pairs of chemical groups in a non-planar arrangement about an axis of chirality so that the molecule is not superposable on its mirror image. The axis of chirality is usually determined by a chemical bond that is constrained against free rotation either by steric hindrance of the groups, as in substituted biaryl compounds such as BINAP, or by torsional stiffness of the bonds, as in the C=C double bonds in allenes such as glutinic acid. Axial chirality is most commonly observed in substituted biaryl compounds wherein the rotation about the aryl–aryl bond is restricted so it results in chiral atropisomers, as in various ortho-substituted biphenyls, and in binaphthyls such as BINAP.

Homochirality is a uniformity of chirality, or handedness. Objects are chiral when they cannot be superposed on their mirror images. For example, the left and right hands of a human are approximately mirror images of each other but are not their own mirror images, so they are chiral. In biology, 19 of the 20 natural amino acids are homochiral, being L-chiral (left-handed), while sugars are D-chiral (right-handed). Homochirality can also refer to enantiopure substances in which all the constituents are the same enantiomer, but some sources discourage this use of the term.

<span class="mw-page-title-main">Atropisomer</span>

Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy 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 enantiomers (atropoenantiomers), showing axial chirality; otherwise they are diastereomers (atropodiastereomers).

<span class="mw-page-title-main">Chiral derivatizing agent</span> Reagent for converting a chemical compound to a chiral derivative

A chiral derivatizing agent (CDA) also known as a chiral resolving reagent, is a chiral auxiliary used to convert a mixture of enantiomers into diastereomers in order to analyze the quantities of each enantiomer present within the mix. Analysis can be conducted by spectroscopy or by chromatography. The use of chiral derivatizing agents has declined with the popularization of chiral HPLC. Besides analysis, chiral derivatization is also used for chiral resolution, the actual physical separation of the enantiomers.

Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term with the same meaning is optical resolution.

<span class="mw-page-title-main">Diastereomeric recrystallization</span>

Diastereomeric recrystallisation is a method of chiral resolution of enantiomers from a racemic mixture. It differs from asymmetric synthesis, which aims to produce a single enantiomer from the beginning, in that diastereomeric recrystallisation separates two enantiomers that have already mixed into a single solution. The strategy of diastereomeric recrystallisation involves two steps. The first step is to convert the enantiomers into diastereomers by way of a chemical reaction. A mixture of enantiomers may contain two isomers of a molecule with one chiral center. After adding a second chiral center in a determined location, the two isomers are still different, but they are no longer mirror images of each other; rather, they become diastereomers.

The eudysmic ratio represents the difference in pharmacologic activity between the two enantiomers of a drug. In most cases where a chiral compound is biologically active, one enantiomer is more active than the other. The eudysmic ratio is the ratio of activity between the two. A eudysmic ratio significantly differing from 1 means that they are statistically different in activity. Eudisimic ratio (ER) reflects the degree of enantioselectivity of the biological systems. For example, (S)-propranolol meaning that (S)-propranolol is 130 times more active as its (R)-enantiomer.

Chemical compounds that come as mirror-image pairs are referred to by chemists as chiral or handed molecules. Each twin is called an enantiomer. Drugs that exhibit handedness are referred to as chiral drugs. Chiral drugs that are equimolar (1:1) mixture of enantiomers are called racemic drugs and these are obviously devoid of optical rotation. The most commonly encountered stereogenic unit, that confers chirality to drug molecules are stereogenic center. Stereogenic center can be due to the presence of tetrahedral tetra coordinate atoms (C,N,P) and pyramidal tricoordinate atoms (N,S). The word chiral describes the three-dimensional architecture of the molecule and does not reveal the stereochemical composition. Hence "chiral drug" does not say whether the drug is racemic, single enantiomer or some other combination of stereoisomers. To resolve this issue Joseph Gal introduced a new term called unichiral. Unichiral indicates that the stereochemical composition of a chiral drug is homogenous consisting of a single enantiomer.

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