The different types of isomers. Stereochemistry focuses on stereoisomers.
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.[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 structural formula (the three-dimensional orientations of their 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).

History

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).

Stereoisomers

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, diastereomers 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]

Representation of Stereochemical Structures

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-2D.png
Fischer Projection2.png
Sawhorse projection butane -sc.png
Newman projection ethane.png
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.

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

Thalidomide structures
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.
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]

Definitions

Further information: Torsion angle
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:

Torsional strain results from resistance to twisting about a bond.

Types

See also

Wikiquote has quotations related to Stereochemistry.

References

  1. ^ Ernest Eliel Basic Organic Stereochemistry ,2001 ISBN 0471374997; Bernard Testa and John Caldwell Organic Stereochemistry: Guiding Principles and Biomedicinal Relevance 2014 ISBN 3906390691; Hua-Jie Zhu Organic Stereochemistry: Experimental and Computational Methods 2015 ISBN 3527338225; László Poppe, Mihály Nógrádi, József Nagy, Gábor Hornyánszky, Zoltán Boros Stereochemistry and Stereoselective Synthesis: An Introduction 2016 ISBN 3527339019
  2. ^ "the definition of stereo-". Dictionary.com. Archived from the original on 2010-06-09.
  3. ^ a b c Nasipuri, D (2021). Stereochemistry of Organic Compounds Principles and Applications (4th ed.). New Delhi: New Age International. p. 1. ISBN 978-93-89802-47-4.
  4. ^ Paternò, Emanuele (1869). "Intorno all'azione del percloruro di fosforo sul clorale". Giorn. Sci. Nat. Econ. 5: 117–122.
  5. ^ Smith, Silas W. (2009-05-04). "Chiral Toxicology: It's the Same Thing…Only Different". Toxicological Sciences. 110 (1): 4–30. doi:10.1093/toxsci/kfp097. ISSN 1096-6080. PMID 19414517.
  6. ^ Patočka, Jiří; Dvořák, Aleš (2004-07-31). "Biomedical aspects of chiral molecules". Journal of Applied Biomedicine. 2 (2): 95–100. doi:10.32725/jab.2004.011.
  7. ^ Cahn, R. S.; Ingold, Christopher; Prelog, V. (April 1966). "Specification of Molecular Chirality". Angewandte Chemie International Edition in English. 5 (4): 385–415. doi:10.1002/anie.196603851. ISSN 0570-0833.
  8. ^ March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7
  9. ^ Morris, David (2001). Stereochemistry. Vol. 1. Royal Society of Chemistry. pp. 19–24. ISBN 978-0471224778.
  10. ^ a b c Brown, William (2022). Organic Chemistry (9th ed.). Cengage. ISBN 978-0357451861.
  11. ^ Stephens TD, Bunde CJ, Fillmore BJ (June 2000). "Mechanism of action in thalidomide teratogenesis". Biochemical Pharmacology. 59 (12): 1489–99. doi:10.1016/S0006-2952(99)00388-3. PMID 10799645.
  12. ^ Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL (2004). "Clinical pharmacokinetics of thalidomide". Clin. Pharmacokinet. 43 (5): 311–327. doi:10.2165/00003088-200443050-00004. PMID 15080764. S2CID 37728304.
  13. ^ Francl, Michelle (2010). "Urban legends of chemistry". Nature Chemistry. 2 (8): 600–601. Bibcode:2010NatCh...2..600F. doi:10.1038/nchem.750. PMID 20651711.
  14. ^ a b c d Natta, Giulio (1972). Stereochemistry. Mario Farina. [London]: Longmans. ISBN 0-582-44039-4. OCLC 589463.
  15. ^ Anslyn, Eric V. and Dougherty, Dennis A. Modern Physical Organic Chemistry. University Science (2005), 1083 pp. ISBN 1-891389-31-9
  16. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "gauche". doi:10.1351/goldbook.G02593
  17. ^ Toenjes, Sean T; Gustafson, Jeffrey L (February 2018). "Atropisomerism in medicinal chemistry: challenges and opportunities". Future Medicinal Chemistry. 10 (4): 409–422. doi:10.4155/fmc-2017-0152. ISSN 1756-8919. PMC 5967358. PMID 29380622.
  18. ^ "13.2: Cis-Trans Isomers (Geometric Isomers)". Chemistry LibreTexts. 2014-07-17. Retrieved 2022-11-27.
  19. ^ Garrett, Reginald H.; Grisham, Charles M. (2005). Biochemistry (3rd ed.). Belmont, CA: Thomson Brooks/Cole. ISBN 0-534-49033-6. OCLC 56058171.
  20. ^ Caillet, Céline; Chauvelot-Moachon, Laurence; Montastruc, Jean-Louis; Bagheri, Haleh; French Association of Regional Pharmacovigilance Centers (November 2012). "Safety profile of enantiomers vs . racemic mixtures: it's the same?: Short report". British Journal of Clinical Pharmacology. 74 (5): 886–889. doi:10.1111/j.1365-2125.2012.04262.x. PMC 3495153. PMID 22404187.
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