Stereochemistry

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The different types of isomers. Stereochemistry focuses on stereoisomers. Isomerism.svg
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]

Contents

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 diasteriomers. Enantiomers are pairs of stereoisomers that are non superimposable mirror images of each other. Comparably, diasteriomers are stereoisomers that 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.png
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, a-glucose and b-glucose, yields the near identical product through differing intermediates. A-d-glucose and b-d-glucose acid-catalyzed mechanism.png
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

syn/anti peri/clinal Synantipericlinal.svg
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

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.

Monosaccharides, also called simple sugars, are the simplest forms of sugar and the most basic units (monomers) from which all carbohydrates are built.

<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">Enantiomer</span> Stereoisomers which are non-superposable mirror images of each other

In chemistry, an enantiomer – also called optical isomer, antipode, or optical antipode – 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. No amount of reorientation will allow the four unique groups on the chiral carbon to line up exactly. The number of stereoisomers a molecules has can be determined by the number of chiral carbons it has. Stereoisomers include both enantiomers and diastereomers.

<span class="mw-page-title-main">Structural formula</span> Graphic representation of a molecular structure

The structural formula of a chemical compound is a graphic representation of the molecular structure, showing how the atoms are possibly arranged in the real three-dimensional space. The chemical bonding within the molecule is also shown, either explicitly or implicitly. Unlike other chemical formula types, which have a limited number of symbols and are capable of only limited descriptive power, structural formulas provide a more complete geometric representation of the molecular structure. For example, many chemical compounds exist in different isomeric forms, which have different enantiomeric structures but the same molecular formula. There are multiple types of ways to draw these structural formulas such as: Lewis Structures, condensed formulas, skeletal formulas, Newman projections, Cyclohexane conformations, Haworth projections, and Fischer projections.

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">Fischer projection</span> Method of representing 3D organic molecules as a 2D image

In chemistry, the Fischer projection, devised by Emil Fischer in 1891, is a two-dimensional representation of a three-dimensional organic molecule by projection. Fischer projections were originally proposed for the depiction of carbohydrates and used by chemists, particularly in organic chemistry and biochemistry. The use of Fischer projections in non-carbohydrates is discouraged, as such drawings are ambiguous and easily confused with other types of drawing. The main purpose of Fischer projections is to show the chirality of a molecule and to distinguish between a pair of enantiomers. Some notable uses include drawing sugars and depicting isomers.

<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 stereogenic centers, the molecule is not chiral. A meso compound is "superposable" on its mirror image. Two objects can be superposed 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">Skeletal formula</span> Representation method in chemistry

The skeletal formula, or line-angle formula or shorthand formula, of an organic compound is a type of molecular structural formula that serves as a shorthand representation of a molecule's bonding and some details of its molecular geometry. A skeletal formula shows the skeletal structure or skeleton of a molecule, which is composed of the skeletal atoms that make up the molecule. It is represented in two dimensions, as on a piece of paper. It employs certain conventions to represent carbon and hydrogen atoms, which are the most common in organic chemistry.

<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">Conformational isomerism</span> Different molecular structures formed only by rotation about single bonds

In chemistry, conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted just by rotations about formally single bonds. While any two arrangements of atoms in a molecule that differ by rotation about single bonds can be referred to as different conformations, conformations that correspond to local minima on the potential energy surface are specifically called conformational isomers or conformers. Conformations that correspond to local maxima on the energy surface are the transition states between the local-minimum conformational isomers. Rotations about single bonds involve overcoming a rotational energy barrier to interconvert one conformer to another. If the energy barrier is low, there is free rotation and a sample of the compound exists as a rapidly equilibrating mixture of multiple conformers; if the energy barrier is high enough then there is restricted rotation, a molecule may exist for a relatively long time period as a stable rotational isomer or rotamer. When the time scale for interconversion is long enough for isolation of individual rotamers, the isomers are termed atropisomers. The ring-flip of substituted cyclohexanes constitutes another common form of conformational isomerism.

<span class="mw-page-title-main">Eclipsed conformation</span> Molecular form in which substituents on two adjacent atoms are closest together

In chemistry an eclipsed conformation is a conformation in which two substituents X and Y on adjacent atoms A, B are in closest proximity, implying that the torsion angle X–A–B–Y is 0°. Such a conformation can exist in any open chain, single chemical bond connecting two sp3-hybridised atoms, and it is normally a conformational energy maximum. This maximum is often explained by steric hindrance, but its origins sometimes actually lie in hyperconjugation.

<span class="mw-page-title-main">Ring strain</span> Instability in molecules with bonds at unnatural angles

In organic chemistry, ring strain is a type of instability that exists when bonds in a molecule form angles that are abnormal. Strain is most commonly discussed for small rings such as cyclopropanes and cyclobutanes, whose internal angles are substantially smaller than the idealized value of approximately 109°. Because of their high strain, the heat of combustion for these small rings is elevated.

<span class="mw-page-title-main">Octahedral molecular geometry</span> Molecular geometry

In chemistry, octahedral molecular geometry, also called square bipyramidal, describes the shape of compounds with six atoms or groups of atoms or ligands symmetrically arranged around a central atom, defining the vertices of an octahedron. The octahedron has eight faces, hence the prefix octa. The octahedron is one of the Platonic solids, although octahedral molecules typically have an atom in their centre and no bonds between the ligand atoms. A perfect octahedron belongs to the point group Oh. Examples of octahedral compounds are sulfur hexafluoride SF6 and molybdenum hexacarbonyl Mo(CO)6. The term "octahedral" is used somewhat loosely by chemists, focusing on the geometry of the bonds to the central atom and not considering differences among the ligands themselves. For example, [Co(NH3)6]3+, which is not octahedral in the mathematical sense due to the orientation of the N−H bonds, is referred to as octahedral.

<span class="mw-page-title-main">Ring flip</span> Process in organic chemistry

In organic chemistry, a ring flip is the interconversion of cyclic conformers that have equivalent ring shapes that results in the exchange of nonequivalent substituent positions. The overall process generally takes place over several steps, involving coupled rotations about several of the molecule's single bonds, in conjunction with minor deformations of bond angles. Most commonly, the term is used to refer to the interconversion of the two chair conformers of cyclohexane derivatives, which is specifically referred to as a chair flip, although other cycloalkanes and inorganic rings undergo similar processes.

<span class="mw-page-title-main">Asymmetric induction</span> Preferential formation of one chiral isomer over another in a chemical reaction

In stereochemistry, asymmetric induction describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis.

<span class="mw-page-title-main">Isomer</span> Chemical compounds with the same molecular formula but different atomic arrangements

In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.

In stereochemistry, the Klyne–Prelog system for describing conformations about a single bond offers a more systematic means to unambiguously name complex structures, where the torsional or dihedral angles are not found to occur in 60° increments. Klyne notation views the placement of the substituent on the front atom as being in regions of space called anti/syn and clinal/periplanar relative to a reference group on the rear atom. A plus (+) or minus (–) sign is placed at the front to indicate the sign of the dihedral angle. Anti or syn indicates the substituents are on opposite sides or the same side, respectively. Clinal substituents are found within 30° of either side of a dihedral angle of 60°, 120° (90°–150°), 240° (210°–270°), or 300° (270°–330°). Periplanar substituents are found within 30° of either 0° (330°–30°) or 180° (150°–210°). Juxtaposing the designations produces the following terms for the conformers of butane : gauche butane is syn-clinal, anti butane is anti-periplanar, and eclipsed butane is syn-periplanar.

References

  1. Ernest Eliel Basic Organic Stereochemistry ,2001 ISBN   0471374997; Bernard Testa and John Caldwell Organic Stereochemistry: Guiding Principles and Biomedicinal Relevance2014 ISBN   3906390691; Hua-Jie Zhu Organic Stereochemistry: Experimental and Computational Methods2015 ISBN   3527338225; László Poppe, Mihály Nógrádi, József Nagy, Gábor Hornyánszky, Zoltán Boros Stereochemistry and Stereoselective Synthesis: An Introduction2016 ISBN   3527339019
  2. "the definition of stereo-". Dictionary.com. Archived from the original on 2010-06-09.
  3. 1 2 3 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. 1 2 3 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. 1 2 3 4 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.