Stereochemistry

The different types of isomers. Stereochemistry focuses on stereoisomers

Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. An important branch of stereochemistry is the study of chiral molecules.

Stereochemistry is also known as 3D chemistry because the prefix "stereo-" means "three- dimensionality".

The study of stereochemistry focuses on stereoisomers and spans the entire spectrum of organic, inorganic, biological, physical and especially supramolecular chemistry. Stereochemistry includes methods for determining and describing these relationships; the effect on the physical or biological properties these relationships impart upon the molecules in question, and the manner in which these relationships influence the reactivity of the molecules in question (dynamic stereochemistry).

History

Louis Pasteur could rightly be described as the first stereochemist, having observed in 1849 that salts of tartaric acid collected from wine production vessels could rotate plane polarized light, but that salts from other sources did not. This property, the only physical property in which the two types of tartrate salts differed, is due to optical isomerism. In 1874, Jacobus Henricus van 't Hoff and Joseph Le Belexplained optical activity in terms of the tetrahedral arrangement of the atoms bound to carbon.

Significance

Cahn–Ingold–Prelog priority rules are part of a system for describing a molecule's stereochemistry. They rank the atoms around a stereocenter in a standard way, allowing the relative position of these atoms in the molecule to be described unambiguously. A Fischer projection is a simplified way to depict the stereochemistry around a stereocenter.

Thalidomide example

An often cited example of the importance of stereochemistry relates to the thalidomide disaster. Thalidomide is a pharmaceutical drug, first prepared in 1957 in Germany, prescribed for treating morning sickness in pregnant women. The drug was discovered to be teratogenic, causing serious genetic damage to early embryonic growth and development, leading to limb deformation in babies. Some of the several proposed mechanisms of teratogenecity involve a different biological function for the (R)- and the (S)-thalidomide enantiomers.[3] In the human body however, thalidomide undergoes racemization: even if only one of the two enantiomers is administered as a drug, the other enantiomer is produced as a result of metabolism.[4] Accordingly, it is incorrect to state that one of the stereoisomer is safe while the other is teratogenic.[5] Thalidomide is currently used for the treatment of other diseases, notably cancer and leprosy. Strict regulations and controls have been enabled to avoid its use by pregnant women and prevent developmental deformations. This disaster was a driving force behind requiring strict testing of drugs before making them available to the public.

Definitions syn/anti peri/clinal

Many definitions that describe a specific conformer (IUPAC Gold Book) exist, developed by William Klyne and Vladimir Prelog, constituting their Klyne–Prelog system of nomenclature:

 a torsion angle of ±60° is called gauche [6]  a torsion angle between 0° and ± 90° is called syn (s)  a torsion angle between ± 90° and 180° is called anti (a)  a torsion angle between 30° and 150° or between –30° and –150° is called clinal  a torsion angle between 0° and 30° or 150° and 180° is called periplanar (p)  a torsion angle between 0° to 30° is called synperiplanar or syn- or cis- conformation (sp)  a torsion angle between 30° to 90° and –30° to –90° is called synclinal or gauche or skew (sc)[7]  a torsion angle between 90° to 150°, and –90° to –150° is called anticlinal (ac)  a torsion angle between ± 150° to 180° is called antiperiplanar or anti or trans (ap).

Torsional strain results from resistance to twisting about a bond.

Types

 Atropisomerism  Cis-trans isomerism  Conformational isomerism  Diastereomers  Enantiomers  Rotamers

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. The word atropisomer(Gr., , atropos, 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 substitutedbiphenyl, a diacid, 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 of at least 1000 seconds at a given temperature, corresponding to an energy barrier of 93 kJ mol−1 (22 kcal mol −1) at 300 K (27 °C). Three basic factors contribute to the stability of individual atropisomers: the repulsive interactions (e.g., steric bulk) of substituents near the axis of rotation, the length and rigidity of the single bond, a largely sp3-sp3 type of bond joining the aryl rings, and whether there are photochemical or other mechanisms to induce rotation in addition to thermal pathways. A variety of methods are employed to study atropisomers, including (from more general to more specific/structural),dipolemetry, titrimetry, electronic and infrared spectroscopy, and X- ray crystallography and nuclear magnetic resonancespectroscopy, the last two being primary means of structure characterization of organic systems, and the last being an ideal means of studying dynamics when the system is amenable to it; inferences from theory and results of reaction outcomes and yields also contribute. The importance of atropisomers arises to significant degree because with sufficient stability of a conformer, they can displayaxial chirality (planar chirality). Atropisomers that display axial chirality often have substituents ortho to the bond joining the aryl rings, substituents that cause significant steric repulsion that hinders rotation about the bond. The degree of hindrance correlates with the van der Waals radii of the particular substituents, and other properties that contribute to their repulsive potentials. As the Ōki refinement of the atropisomer definition suggests, atropisomers are involved in a chemical equilibrium that, for a given structure, is thermally controlled; they differ in this way from most other types of chiral structures, where interconversion involves a chemical isomerization (i.e., with breaking and reforming of covalent bonds).

Atropisomers of 6,6'-dinitro-2,2'-diphenic acid, first experimentally described case, by Christie and Kenner (1922).

Cis/trans isomerism (geometric isomerism, configurational isomerism) is a term used in organic chemistry to refer to the stereoisomerism engendered in the relativeorientation of functional groups within a molecule. It is not to be confused with E/Zisomerism, which is an absolute stereochemical description, and only to be used with alkenes. In general, such isomers contain double bonds that cannot rotate, or they may contain ring structures, where the rotation of bonds is restricted or eliminated. Cis and trans isomers occur both in organic molecules and in inorganic coordination complexes. Cis and trans descriptors are not used for cases ofconformational isomerism where the two geometric forms easily interconvert, such as most open-chain single-bonded structures; instead, the terms “syn” and “anti” would be used. The terms “cis” and “trans” are from Latin, in which cis means "on this side" andtrans means "on the other side" or "across". The term "geometric isomerism" is considered an obsolete synonym of "cis/trans isomerism" by IUPAC.

cis-but-2-ene trans-but-2-ene

In chemistry, conformational isomerism is a form of stereoisomerismin which the isomers can be interconverted exclusively by rotations about formally single bonds (refer to figure on single bond rotation). Such isomers are generally referred to as conformational isomers orconformers and, specifically, as rotamers. Rotations about single bonds are restricted by a rotational energy barrier which must be overcome to interconvert one conformer to another. Conformational isomerism arises when the rotation about a single bond is relatively unhindered. That is, the energy barrier must be small enough for the interconversion to occur. Conformational isomers are thus distinct from the other classes ofstereoisomers (i. e. configurational isomers) where interconversion necessarily involves breaking and reforming of chemical bonds. For example, L- & D and R- & S- configurations of organic molecules have different handedness and optical activities, and can only be interconverted by breaking one or more bonds connected to the chiral atom and reforming a similar bond in a different direction or spatial orientation. The study of the energetics between different rotamers is referred to as conformational analysis. It is useful for understanding the stability of different isomers, for example, by taking into account the spatial orientation and through-space interactions of substituents. In addition, conformational analysis can be used to predict and explain product(s) selectivity, mechanisms, and rates of reactions.

Rotation about single bond of butane to interconvert one conformer to another. Above: Newman projection; below: depiction of spatial orientation.

Diastereomers (sometimes called diastereoisomers) are a type of a stereoisomer. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more (but not all) 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 increases the number of stereoisomers by a factor of two. Diastereomers differ from enantiomers in that the latter are pairs of stereoisomers that differ in all stereocenters and are therefore mirror images of one another.Enantiomers of a compound with more than one stereocenter are also diastereomers of the other stereoisomers of that compound that are not their mirror image. Diastereomers have different physical properties (unlike enantiomers) and different chemical reactivity. Diastereoselectivity is the preference for the formation of one or more than one diastereomer over the other in an organic reaction.

n chemistry, an enantiomer ( NAN-tee-ə-mər; from Greek (enantíos), meaning "opposite", and (méros), meaning "part") is one of two stereoisomers that are mirror images of each other that are non-superposable (not identical), much as one's left and right hands are the same except for opposite orientation. Organic compounds that contain a chiral carbon usually have two non-superposable structures. These two structures are mirror images of each other and are, thus, commonly called enantiomorphs (enantio = opposite ; morph = form), hence this structural property is now commonly referred to as enantiomerism. Enantiopure compounds refer to samples having, within the limits of detection, molecules of only one chirality. Enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light (+/−) by equal amounts but in opposite directions (although the polarized light can be considered an asymmetric medium). A mixture of equal parts of an optically active isomer and its enantiomer is termedracemic and has zero net rotation of plane-polarized light because the positive rotation of each (+) form is exactly counteracted by the negative rotation of a (−) one. Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many biological molecules are enantiomers themselves, there is sometimes a marked difference in the effects of two enantiomers on biological organisms. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even responsible for adverse effects. Owing to this discovery, drugs composed of only one enantiomer ("enantiopure") can be developed to enhance the pharmacological efficacy and sometimes do away with some side effects. An example of this kind of drug is eszopiclone(Lunesta), which is enantiopure and therefore is given in doses that are exactly 1/2 of the older, racemic mixture calledzopiclone. In the case of eszopiclone, the S enantiomer is responsible for all the desired effects, though the other enantiomer seems to be inactive; while an individual must take 2 mg of zopiclone to get the same therapeutic benefit as they would receive from 1 mg of eszopiclone, that appears to be the only difference between the two drugs.