Stereochemistry

Stereochemistry, a subdiscipline of chemistry, studies the spatial arrangement of atoms that forms the structure of molecules and their manipulation.^[1] 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 the geometric positioning of the atoms in space. For this reason, it is also known as 3D chemistry—the prefix "stereo-" means "three-dimensionality".^[2]

Stereochemistry 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).

It was not until after the observations of certain molecular phenomena that stereochemical principles were developed. In 1815, Jean-Baptiste Biot's observation of optical activity marked the beginning of organic stereochemistry history. He observed that organic molecules were able to rotate the plane of polarized light in a solution or in the gaseous phase.^[3] Despite Biot's discoveries, Louis Pasteur is commonly described as the first stereochemist, having observed in 1842 that salts of tartaric acid collected from wine production vessels could rotate the plane of polarized light, but that salts from other sources did not. This was the only physical property that differed between the two types of tartrate salts, which is due to optical isomerism. In 1874, Jacobus Henricus van 't Hoff and Joseph Le Bel explained optical activity in terms of the tetrahedral arrangement of the atoms bound to carbon. Kekulé used tetrahedral models earlier in 1862 but never published these; Emanuele Paternò probably knew of these but was the first to draw and discuss three dimensional structures, such as of 1,2-dibromoethane in the Giornale di Scienze Naturali ed Economiche in 1869.^[4] The term "chiral" was introduced by Lord Kelvin in 1904. Arthur Robertson Cushny, Scottish Pharmacologist, in 1908, first offered a definite example of a bioactivity difference between enantiomers of a chiral molecule viz. (-)-Adrenaline is two times more potent than the (±)- form as a vasoconstrictor and in 1926 laid the foundation for chiral pharmacology/stereo-pharmacology^[5][6] (biological relations of optically isomeric substances). Later in 1966, the Cahn-Ingold-Prelog nomenclature or Sequence rule was devised to assign absolute configuration to stereogenic/chiral center (R- and S- notation) ^[7] and extended to be applied across olefinic bonds (E- and Z- notation).

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.

Stereochemistry has important applications in the field of medicine, particularly pharmaceuticals. 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 teratogenicity involve a different biological function for the (R)- and the (S)-thalidomide enantiomers.^[8] 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.^[9] Accordingly, it is incorrect to state that one stereoisomer is safe while the other is teratogenic.^[10] Thalidomide is currently used for the treatment of other diseases, notably cancer and leprosy. Strict regulations and controls have been implemented 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.

In yet another example, the drug ibuprofen can exist as (R)- and (S)-isomers. Only the (S)-ibuprofen is active in reducing inflammation and pain.^{[citation needed]}

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^[11]
• 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)^[12]
• 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.

Atropisomerism is an energetic form of axial chirality. This form of chirality derives from the inability to rotate about a bond, such as due to steric hindrance between functional groups on two sp²-hybridized carbon atoms.

Cis-Trans isomers are often associated alkene double bonds.

cis-pent-2-ene		trans-pent-2-ene

The more general E/Z nomenclature refers to the concept of cis/trans isomerism, and is especially useful for more complex compounds.

(Z)-1-Bromo-1,2-dichloroethene		(E)-1-Bromo-1,2-dichloroethene

Conformational isomers, are also calles conformers, rotational isomers, and rotamers. Conformational isomerism is produced by rotation about the single bond. Conformers can easily interconvert due to a low energy barrier separating them. If the energy barrier were high enough to prevent interconversion, the distinct geometric forms would be considered atropisomers.

Diastereomers are non-superposable, non-identical stereoisomers. A common example of diastereomerism is when two compounds differ from each other by the (R)/(S) absolute configuration at some, but not all corresponding stereocenters. Epimers are diastereomers that differ at exactly one such position. cis/trans isomerism is another type of diastereomeric relationship.

• Example: The below pair can also be classified as epimers.

Enantiomers are pairs of non-superposable mirror images. Each member of the pair has a distinct R).

Epimers are a subcategory of diastereomers that differ in absolute configuration configurations at only one corresponding stereocenter. They are commonly found in sugar chemistry, where two sugars can differ by the configuration of a single carbon atom.

• Example: D-glucose and D-galactose are epimers, differing only at the C-4 position in their structure. (see sugar numbering)

• Alkane stereochemistry
• Chiral resolution, which often involves crystallization
• Chirality (chemistry) (R/S, d/l)
• Chiral switch
• Skeletal formula#Stereochemistry which describes how stereochemistry is denoted in skeletal formulae.
• Solid-state chemistry
• VSEPR theory
• Nuclear Overhauser effect, a method in nuclear magnetic resonance spectroscopy (NMR) employed to elucidate the stereochemistry of organic molecules