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 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 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).

An important branch of stereochemistry is the study of chiral molecules, which are molecules that lack a plane of symmetry and are, therefore, not superimposable on their mirror images.[8] The term chiral stems from the Greek word "cheir," meaning handedness and describes objects that have a "left-handed" and "right-handed" form.[9]

Molecules are considered to be chiral if they contain an asymmetric carbon atom, which is attached to four different substituents that form a tetrahedron. The idea of chirality is essential for explaining the concept of stereoisomerism. Compounds that have the same molecular formula, but differ in the spatial arrangement of their atoms are stereoisomers. Based on arrangement, these compounds can be categorized as either enantiomers or diastereomers. Enantiomers are pairs of stereoisomers that are non superimposable mirror images of each other. Comparably, diasteriomers are stereoisomers which are superimposable on each other and are not mirror images.

Stereoisomers that do not involve chirality are geometrical isomers, also known as cis-trans isomers, which exist as a result of restricted rotation around a double bond within a molecule. When two of the same atoms are attached to the same side of the molecule, a cis isomer is present. Conversely, when two of the same atoms are attached to opposing sides of the molecule, a trans isomer is present.

Another type of stereoisomerism is conformational stereoisomerism. These isomers exist as a result of rotation around the central carbon-carbon bond within a molecule and are constantly being interconverted into its different isomers at room temperature. The possible conformational isomers are gauche (60°), anti (180°), and eclipsed (0°).[10]

Wedge and dash diagrams are used to represent 3-dimensional molecules on paper and are often used to depict the stereochemistry of chiral molecules. Dashed wedges are used to show bonds that project behind the plane of the paper and dark and shaded wedges are used to show bonds that project out of the plan of the paper. The ordinary lines are used to show bonds that are in the plane of the paper.[3]

Fischer projections are a simplified way to represent 3-dimensional stereochemical molecules in 2-dimensional layout. All of the bonds are drawn as ordinary lines that intersect at 90°.[3] The top and bottom lines represent the front and back of the molecule, respectively. One side line represents a dashed wedge and the other represents a dark wedge.

Sawhorse projections are used to view molecules from an angled perspective instead of a side view. The parallel bonds represent eclipsed conformations and all anti parallel bonds can represent either gauche or anti conformations.[10]

Newman projections are used to visualize molecules from front to back along a carbon-carbon bond. The carbon closest to the viewer is the front carbon and the one furthest away is the back carbon. The three atoms attached to the front carbon are depicted as being attached to the center of a circle and the atoms attached to the back carbon are shown as coming from behind the circle. Newman projections are often used as a simplified version of sawhorse projections.[10]

Methane molecule represented by wedge and dash diagram.	Methane molecule represented by Fischer projection.	Butane molecule represented by sawhorse projection.	Ethane molecule represented by eclipsed (left) and gauche (right) Newman projections.

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

Thalidomide structures

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.[11] 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.[12] Accordingly, it is incorrect to state that one stereoisomer is safe while the other is teratogenic.[13] 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.

Polysaccharide example

The application of stereochemistry to biological macromolecules has allowed for the study of the structure and properties of polymers of biological origin. In regards to the degradation of starch and cellulose, D-glucose is produced by different intermediates which are stereoisomers of each other.[14]  When starch and cellulose undergo strong hydrolysis “by means of particular enzymes or through the action of acids” and the carbon chain is broken, the reaction will procure D-glucose.[14]  This D-glucose molecule is the basic unit of the macromolecular structure. Starch and cellulose are both polysaccharides, or polymers, of glucose.

Degradation of diastereomers, α-glucose and β-glucose, yields the near identical product through differing intermediates.

Despite having similar molecular structures, starch and cellulose have many differing properties. Starch is easily digested by humans whereas cellulose is indigestible. When hydrolyzed β-glucose yields cellobiose from cellulose and α-glucose yields maltose from starch.[14] β- and α-glucose are diastereomers. In these pairs of polymers, the chemical structure of the monomeric units is the same. The difference of the polymers lies within the substituents on the molecules, whether they are “cis of trans in the hydrocarbon polymers, and equatorial or axial in cellulose and starch.” [14]

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[15]
• 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)[16]
• 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
  An energetic form of axial chirality. This form of chirality derives from differential substitution about a bond, commonly between two sp²-hydridized atoms.[17]
• Cis–trans isomerism
  Also referred to as geometric isomers, these compounds have different configurations due to the inflexible structure of the molecule. Two requirements must be met for a molecule to present cis-trans isomerism:[18]
  1. Rotation within the molecule must be restricted.
  2. Two nonidentical groups must be on each doubly bonded carbon atom.
• Conformational isomerism
  This form of isomerism is also referred to as conformers, rotational isomers, and rotamers. Conformational isomerism is produced by rotation about the Single bond.
• Diastereomers
  These stereoisomers are non-image, non-identical. Diastereomers occur when the stereoisomers of a compound have differing configurations at corresponding stereocenters.[19]
• Enantiomers
  Stereoisomers which are nonsuperimposable, mirror images.[20]

Wikiquote has quotations related to Stereochemistry.

• Enantiomer
• Diastereomer
• 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