Tag Archives: chiral

Fischer projections

Hermann Emil FischerIn 1891, Hermann Emil Fischer, a German chemist, Nobel Laureate in chemistry in 1902, developed a systematic method for the two-dimensional representation of chiral molecules, the so-called Fischer projections or Fischer projection formulas.
Despite they are two-dimensional structures, Fischer projections  preserve information about the stereochemistry of the molecules and, although not being a representation of how molecules might look in solution, are still widely used by biochemists to define the stereochemistry of amino acids, monosaccharides, nucleic acids, terpenes, steroids, and other molecules of biological interest.

CONTENTS

How to draw Fischer projections

By considering a molecule with a single chiral center, e.g. a carbon atom, for drawing the Fischer projections, the tetrahedral structure is rotated so that two groups point downward, whereas two groups point upwards. Then, you draw a cross, place the chiral center at the center of the cross, and arrange the molecule so that the groups pointing downward, that is, behind the plane of the paper, are attached to the ends of the vertical line, and the groups pointing upwards, that is, out front from the plane of the paper, are attached to the ends of the horizontal line.
How to draw Fischer projections of molecules with one chiral center
For compounds  with more than one chiral center, the same procedure is applied to each asimmetric center.
It is also possible to convert a Fischer projection into a three-dimensional representation, for example using the wedges and dashes of perspective formulas, where the two horizontal bonds are represented by solid wedges, whereas the vertical bonds are represented by dashed lines.

How to manipulate Fischer projection formulas?

  • Since Fischer projections represent three-dimensional molecules on a two-dimensional sheet of paper, some rules must be respected to avoid changing the configuration.
    • The projections must not be lifted out the plane of the paper, because this causes enantiomer is converted into the other enantiomer.
    • If you rotate the projections in the plane of the paper, you obtain the same enantiomer if you rotate the structures by 180° in either direction, because the vertical groups must lie below  the plane of the paper, whereas the horizontal groups above. Conversely, the rotation by 90° or 270° in either direction causes an enantiomer is converted into the other enantiomer.

    Rules for manipulating Fischer projections

  • An odd number of exchanges of two groups leads to the other enantiomer.

References

Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010

IUPAC. Compendium of Chemical Terminology, 2nd ed. (the “Gold Book”). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by S. J. Chalk. ISBN 0-9678550-9-8. doi:10.1351/goldbook

Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012

Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011

RS system

In 1956, Robert Sidney Cahn, Christopher Ingold and Vladimir Prelog developed a nomenclature system that, based on a few simple rules, allows to assign the absolute configuration of each chiral center in a molecule.
This nomenclature system, called the RS system, or the Cahn-Ingold-Prelog (CIP) system, when added to the IUPAC system of nomenclature, allow to name accurately and unambiguously the chiral molecules, even when there is more than one asymmetric center.
Chiral molecules are, in most cases, able to rotate plane-polarized light when light passes through a solution containing them. In this regard, it should be emphasized that the sign of the rotation of plane-polarized light caused by a chiral compound provides no information concerning RS configuration of its chiral centers.
The Fischer-Rosanoff convention is another way to describe the configuration of chiral molecules. However, compared to RS system, it labels the whole molecule and not each chirality center, and is often ambiguous for molecules with two or more chirality centers.

CONTENTS

The priority rules of the RS system

The RS system assigns a priority sequence to the groups attached to the chirality center and, tracing a curved arrow from the highest priority group to the lowest, labels each chiral center R or S.

First rule

A priority sequence is assigned to the groups based on the atomic number of the atoms directly attached to the chiral center.

  • The atom with the highest atomic number is assigned the highest priority.
  • The atom with the lowest atomic number is assigned the lowest priority.

For example, if an oxygen atom, O, atomic number 8, a carbon atom, C, atomic number 6, a chlorine atom, Cl, atomic number 17, and a bromine atom, Br, atomic number 35 are attached to the chiral center, the order of priority is: Br > Cl > O > C.
For isotopes, the atom with the highest atomic mass is assigned the highest priority.

Second rule

When different groups are attached to the chiral center through identical atoms, the priority sequence is assigned based on the atomic number of the next atoms bound, then moving outward from the chirality center until the first point of difference is reached.
If, for example, –CH3, –CH2CH3 and –CH2OH groups are attached to a chiral center, there are three identical atoms directly attached to the chiral center. Analyzing the next atoms bound, we have:

  • for the methyl group –CH3
H, H, H
  • for the ethyl group –CH2CH3
H, H, C
  • for the hydroxymethyl group –CH2OH
H, H, O

RS system priority sequence first rule

Because the atomic number of oxygen is higher than that of carbon, that, in turn, is higher than that of hydrogen, the order of priority is –CH2OH > –CH2CH3 > –CH3
The order of priority of some groups is:

–I > –Br > –Cl > –SH > –OR > –OH > –NHR > –NH2 > –COOR > –COOH > –CHO > –CH2OH > –C6H5 > –CH3 > –2H > –1H

Note that the groups attached to a chirality center must not have identical priority ranking, because, in that case, the center cannot be chiral.

Once the priority sequence has been established, the molecule is oriented in space so that the group with the lowest priority is pointed away from the viewer, then behind the chiral center. Now, trace a curved arrow, a circle, from the highest priority group to the lowest.

  • If you move in a clockwise direction, the configuration of chiral center is R, from the Latin rectus, meaning “right”.
  • If you move in a counterclockwise direction, the configuration of chiral center is S, from the Latin sinister, meaning “left”.

R configuration chiral center

Third rule

This is the third rule of the RS system, by which we can determine the configuration of a chirality center when there are double or triple bonds in the groups attached to the chirality center.
To assign priorities, the atoms engaged in double or triple bonds are considered duplicated and tripled, respectively.
RS system priority sequence third ruleIn the case of a C=Y double bond, one Y atom is attached to the carbon atom, and one carbon atom is attached to the Y atom.
In the case of a C≡Y triple bond, two Y atoms are attached to the carbon atom, and two carbon atoms are attached to the Y atom.

RS system and multiple chiral centers

When two or more chirality centers are present in a molecule, each center is analyzed separately using the rules previously described.
Consider 2,3-butanediol. The molecule has two chiral centers, carbon 2 and carbon 3, and exists as three stereoisomers: two enantiomers and a meso compound. What is the RS configuration of the chiral centers of the enantiomer shown in figure?RS configuration chiral centers (2R,3R)-2,3-ButanediolConsider carbon 2. The order of priority of the groups is –OH > –CH2OHCH3 > –CH3 > –H. Rotate the molecule so that the hydrogen, the lowest priority group, is pointed away from the viewer. Tracing a path from –OH, the highest priority group, to –CH3, the lowest priority group, we move in a clockwise direction: the configuration of the carbon 2 is, therefore, R. Applying the same procedure to carbon 3, its configuration is R. Then, the enantiomer shown in figure is (2R,3R)-2,3-butanediol.

Amino acids and gliceraldeide

In the Fischer-Rosanoff convention, all the proteinogenic amino acids are L-amino acids. In the RS system, with the exception of glycine, that is not chiral, and cysteine ​​that, due to the presence of the thiol group, is (R)-cysteine, all the other proteinogenic amino acids are (S)-amino acids.
Threonine and isoleucine have two chirality centers, the α-carbon and a carbon atom on the side chain, and exist as three stereoisomers: two enantiomers and a meso compound. The forms of the two amino acids isolated from proteins are (2S,3R)-threonine and (2S,3S)-isoleucine, in Fischer-Rosanoff convention, L-threonine and L-isoleucine.
In the RS system, L-glyceraldehyde is (S)-glyceraldehyde, and, obviously, D-glyceraldehyde is (R)-glyceraldehyde.

References

Cahn R.S., Ingold C., Prelog V. Specification of molecular chirality. Angew Chem 1966:5(4); 385-415. doi:10.1002/anie.196603851

Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010

IUPAC. Compendium of Chemical Terminology, 2nd ed. (the “Gold Book”). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by S. J. Chalk. ISBN 0-9678550-9-8. doi:10.1351/goldbook

Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012

Prelog V. and Helmchen G. Basic principles of the CIP‐system and proposals for a revision. Angew Chem 1982:21(8);567-83. doi:10.1002/anie.198205671

Rosanoff M.A. On Fischer’s classification of stereo-isomers. J Am Chem Soc 1906:28(1);114-121. doi:10.1021/ja01967a014

Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011

Chirality

The definition of chirality, from the Greek cheir meaning “hand”, is due to Lord Kelvin who enunciated it during the “Baltimore Lectures”, a series of lectures held at Johns Hopkins University in Baltimore, starting from October 1st 1884, and published twenty years later, in 1904, in which the English scientist, among other things, stated: “I call any geometrical figure, or groups of points, chiral, and say it has chirality, if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself“.
Lord Kelvin and The Definition of ChiralityChirality is, therefore, the geometric property of a group of points or atoms in space, or of a solid object, of not being superimposable on its mirror image. These structures, defined as chiral, have the peculiar property of being devoid of symmetry elements of the second kind, namely, a mirror plane, an center of inversion, or a rotation-reflection.
The environment is rich in chiral objects: your hands are the example par excellence, but there are many others, from the shell of a snail to a spiral galaxy. In chemistry, and especially in organic chemistry, chirality is a property of primary importance, because molecules such as carbohydrates, many amino acids, as well as many drugs, are chiral.
Chiral molecules can exist in two forms, mirror images of each other and non-superimposable, namely, there is no combination of rotations or translations on the plane of the sheet that allows their superposition. Such molecules are called enantiomers, from the Greek enántios, meaning “opposite” and meros,meaning “part”.
The most common cause of chirality in a molecule is the presence of a chirality center or chiral center, also called asymmetric center, namely, an atom that bears a set of atoms or functional groups in a spatial arrangement so that the resulting molecule can exist as two enantiomers.
Enantiomers are a kind of stereoisomers, that, in turn, can be defined as isomers having the same number and kind of atoms and bonds, but differing in the spatial orientation of the atoms.

CONTENTS

Enantiomers

Two enantiomers of a chiral molecule, being non-superimposable, are different compounds. How do they differ?
Each pair of enantiomers has identical physical and chemical properties towards achiral properties, such as melting point, boiling point, refractive index, infrared spectrum, the solubility in the same solvent, or the same reaction rate with achiral reagents.
The differences emerge when they interacts with chemical and physical phenomena that have chiral properties.
From the chemical point of view, two enantiomers can be distinguished by the way they interact with chiral structures, such as the binding site of a chiral receptor or the active site of a chiral enzyme.
From the physical point of view, they differ in their interaction with plane-polarized light, that has chiral properties, namely, they have optical activity.

Chirality and optical activity

The optical activity of materials such as quartz and, more importantly, of organic compounds such as sugars or tartaric acid, was discovered in 1815 by the French scientist Jean-Baptiste Biot.
Chiral molecules can be classified based on the direction in which plane-polarized light is rotated when it passes through a solution containing them.

  • If a solution containing one enantiomer rotates plane-polarized light in a clockwise direction from the observer’s point of view, the molecule is called dextrorotatory or dextrorotary, from the Latin dexter, meaning “right”, and is designated by the prefixes (+)-, or d from dextro-.
  • If a solution containing one enantiomer rotates plane-polarized light in a counterclockwise direction from the observer’s point of view, the molecule is called levorotatory or levorotary, from the Latin laevus, meaning “left”, and is designated by the prefixes (-), or l from laevo-.

Obviously, if we consider a pair of enantiomers, one is dextrorotatory and the other levorotatory.
At present it is not possible to reliably predict the magnitude, direction, or sign of the rotation of plane-polarized light caused by an enantiomer. On the other hand, the optical activity of a molecule provides no information on the spatial arrangement of the chemical groups attached to the chirality center.
Note: a system containing molecules that having the same chirality sense is called enantiomerically pure or enantiopure.

Pasteur and the discovery of enantiomers

Louis Pasteur and the discovery of enantiomersIn 1848, thirty three years after Biot’s work, studies on the optical activity of molecules led Louis Pasteur, who had been a student of Biot, to note that, following the recrystallization of a concentrated aqueous solution of sodium ammonium tartrate, optically inactive, two kinds of crystals precipitated, that were non-superimposable mirror images of each other. After separating them with tweezers, Pasteur discovered that the solutions obtained by dissolving equimolar amounts of the two kind of crystals were optically active and, interestingly, the rotation angle of plane-polarized light was equal in magnitude but opposite in sign. Because the differences in optical activity were due to the dissolved sodium ammonium tartrate crystals, Pasteur hypothesized that the molecules themselves should be non-superimposable mirror images of each other, like their crystals: they were what we now call enantiomers. And it is Pasteur who first used the term asymmetry to describe this property, then called chirality by Lord Kelvin.

Racemic mixtures

A solution containing an equal amount of each member of a pair of enantiomers is called racemic mixture or racemate. These solutions are optically inactive: there is no net rotation of plane-polarized light since the amount of dextrorotatory and levorotatory molecules is exactly the same.
Unlike what happens in biochemical processes, the chemical synthesis of chiral molecules that does not involve chiral reactants, or that is not followed by methods of separation of enantiomers, inevitably leads to the production of a racemic mixture.
The pharmaceutical chemistry is among the sectors most affected by this. As previously mentioned, two enantiomers are different compounds. Many chiral drugs are synthesized as racemic mixtures, but most often the desired pharmacological activity resides in one enantiomer, called eutomer; the other, called distomer, is less active or inactive. An example is ibuprofen, an arylpropionic acid derivative, and anti-inflammatory drug: only the S enantiomer has the pharmacological activity.

Enantiomers of IbuprofenArylpropionic derivatives are sold as racemic mixtures: a racemase converts the distomer to the eutomer in the liver.
However, it is also possible that the distomer causes harmful effects and must be eliminated from the racemic mixture. A tragic example is thalidomide, a sedative and anti-nausea drug sold as a racemic mixture from the 1950s until 1961, and taken also during pregnancy.

Enantiomers of ThalidomideThe distomer, the S enantiomer, could cause serious birth defects, particularly phocomelia. This is probably the most striking example of the importance of the chiral properties of molecules, which prompted health care organizations to promote the synthesis of drugs, including thalidomide, containing a single enantiomer by the pharmaceutical industry.

Chirality centers

Any tetrahedral atom that bears four different substituents can be a chirality center.
Carbon atom is the classic example, but also other atoms from group IVA of the periodic table, such as the semimetals silicon (Si) and germanium (Ge), have a tetrahedral arrangement and can be chiral centers. Another example is the phosphorus atom in organic phosphate esters that has a tetrahedral arrangement, then, when it binds four different substituents it is a chiral center.
The nitrogen atom of a tertiary amine, an amine in which the nitrogen is bounded to three different groups, is a chiral center. In these compounds, nitrogen is located at the center of a tetrahedron and its four sp3 hybrid orbitals point to the vertices, three of which are occupied by the three substituents, whereas the nonbonding electron pair points towards the fourth.
Nitrogen inversion and chiralityAt room temperature, nitrogen rapidly inverts its configuration. The phenomenon is known as nitrogen inversion, namely, a rapid oscillation of the atom and its ligands, during which nitrogen passes through a planar sp2-hybridized transition state. As a consequence, if the nitrogen atom is the only chiral center of the molecule, there is no optical activity because a racemic mixture exists. The inversion of configuration does not occur only in some cases in which nitrogen is part of a cyclic structure that prevents it. Therefore, the presence of a chiral center could be not sufficient to allow the separation of the respective enantiomers.

Note: in 1874, Jacobus Henricus van ‘t Hoff and Joseph Achille Le Bel, based on the work of Pasteur, first formulated the theory of the tetrahedral carbon atom. For this work van ‘t Hoff received the first Nobel Prize in chemistry in 1901.

Chirality in the absence of a chiral center

Chirality can also occur in the absence of a chiral center, due to the lack of free rotation around a double or a single bond, as in the case of:

  • allene derivatives, organic compounds in which there are two cumulative double bonds, namely, two double bonds localized on the same carbon atom;
  • biphenyl derivatives.

Chirality is due to the presence of an axis of chiralityIn this case, chirality is due to the presence of an axis of chirality.

Meso compounds

Meso compounds or meso isomers are stereoisomers with two or more chiral centers that are superimposable on their mirror image, then achiral and, as such, optically inactive. Moreover, they have an internal mirror plane that bisects the molecule, with each half a mirror image of the other. Then, meso compounds can be classified as diastereomers, namely, stereoisomers which are not enantiomers.
For a molecule with n chirality centers, the maximum number of possible stereoisomers is 2n.
Consider 2,3-butanediol. The molecule has two chirality centers, the carbons 2 and 3, so there are 22 = 4 possible stereoisomers, whose structures are depicted in the figure, in the Fischer projections, indicated as A, B, C, D.
Stereoisomers, chirality centers, and meso compoundsStructures A and B are mirror images of each other and non-superimposable, then they are a pair of enantiomers.
Structures C and D are mirror images of each other, but are superimposable. In fact, if we rotate structure C or D of 180 degrees, the two structures are superimposable. Then, they are not a pair of enantiomers: they are the same molecule with opposite orientation. Moreover, they have an internal mirror plane, that bisects the molecule, giving two halves, each a mirror image of the other. Structure C, or D, is therefore a meso compound because it has chiral centers, is superimposable on its mirror image, and has internal mirror plane that divides the molecule into two mirror‐image halves.

References

Capozziello S. and Lattanzi A. Geometrical approach to central molecular chirality: a chirality selection rule. Chirality 2003;15:227-230. doi:10.1002/chir.10191

Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010

IUPAC. Compendium of Chemical Terminology, 2nd ed. (the “Gold Book”). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by S. J. Chalk. ISBN 0-9678550-9-8. doi:10.1351/goldbook

Kelvin WT. Baltimore lectures on molecular dynamics and the wave theory of light. Clay C. J., London: 1904:619. doi:https://archive.org/details/baltimorelecture00kelviala/mode/2

Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011