Tag Archives: chirality

Fischer-Rosanoff convention

Martin André Rosanoff the Fischer-Rosanoff ConventionIn 1906, the Russian-American chemist Martin André Rosanoff, working at that time at New York University, chose glyceraldehyde, a monosaccharide, as the standards for denoting the stereochemistry of carbohydrates and other chiral molecules, a nomenclature system called the Fischer-Rosanoff convention, or Rosanoff convention, or D-L system.
Because Rosanoff didn’t know the absolute configuration of glyceraldehyde, he assigned in a completely arbitrary manner:

  • the D prefix, from the Latin dexter, meaning “right”, to (+)-glyceraldehyde, the dextrorotatory enantiomer, thus assuming that the configuration, in Fischer projections, was that with the hydroxyl group (–OH)  attached to the chiral center on the right side of the molecule;
  • the L prefix, from the Latin laevus, meaning “left”, to (-)-glyceraldehyde, the levorotatory enantiomer, thus assuming that the configuration, in Fischer projections, was that with the hydroxyl group attached to the chiral center on the left  side of the molecule.
    Fischer-Rosanoff convention: D-glyceraldehyde and L-glyceraldehyde as standard for the stereochemistry of chiral molecules

Although Fischer rejected this nomenclature system, it was universally accepted and used to obtain the relative configurations of the chiral molecules. How? The configuration about a chiral center is related to that of glyceraldehyde by converting its groups to those of the monosaccharide through reactions that occur with retention of configuration, namely, reactions that do not break any of the bonds to the chiral center. This means that the spatial arrangement of the groups around the chiral center in the reagents and products is same. The Fischer convention allows to divide the chiral molecules, such as amino acids and monosaccharides, into two classes, known as the D series and the L series, depending on whether the configuration of the groups around the chiral center is related to that of D-glyceraldehyde or L-glyceraldehyde.

Note: there is no correlation between retention of configuration and sign of the rotatory power: the D-L system does not specify the sign of the rotation of plane-polarized light caused by the chiral molecule, but simply correlates the configuration of the molecule with that of the glyceraldehyde.

CONTENTS

Fischer-Rosanoff convention and carbohydrates

Monosaccharides can be aldoses or ketoses. Aldoses, and ketoses with more than three carbon atoms have at least one chiral center, and, by convention, they belong to the D series or to the L series if the configuration of the chiral carbon farthest from the carbonyl carbon, the carbon with the highest oxidation state, is same as that of D-glyceraldehyde or L-glyceraldehyde, respectively.
In Fischer projections the longest chain of carbon atoms is oriented vertically, and the atoms are numbered so that the carbonyl carbon has the lowest possible number, then, C-1 in aldoses and C-2 in ketoses.
Aldoses, ketoses, carbonyl carbon, and asymmetric center taken as the reference centerNote: in Nature, D-sugars are much more abundant than L-sugars.

If the sign of the rotation of plane-polarized light must be specified in the name, the prefixes (+) or (-) can be employed in addition to the D and L prefixes. For example, fructose, which is levorotatory, can be named D-(-)-fructose, whereas glucose, which is dextrorotatory, can be named D-(+)-glucose.

Fischer-Rosanoff convention and α-amino acids

Amino acids, depending on the position of the amino group (–NH2) with respect to the carboxyl group (–COOH) can be classified as:

  • α-amino acids, in which the amino group is attached to the α-carbon;
  • β-amino acids, in which the amino group is attached to the β-carbon;
  • γ-amino acids, in which the amino group is attached to the γ-carbon;
  • δ -amino acids, in which the amino group is attached to the δ-carbon.

α-Amino acids belong to the D series or to the L series if the configuration of the –NH2, –COOH, –R, and H groups attached to the α-carbon, the chiral center, is the same of the hydroxyl, aldehyde (–CHO), and hydroxymethyl (–CH2OH), and H groups of D-glyceraldehyde or L-glyceraldehyde, respectively.
In Fischer projections the molecules are arranged so that the carboxylic group, namely, the carbon with the highest oxidation state, is at the top, and the R group at the bottom.
Fischer-Rosanoff convention and alpha-amino acids of the D-series and L-series Among α-amino acids, proteinogenic amino acids, with the exception of glycine whose α-carbon is not chiral, have the L configuration, hence, they are L-α-amino acids.

Note: in Nature, L-α-amino acids are much more abundant than all the other amino acids, which do not participate in protein synthesis.

Relative and absolute configurations

When Rosanoff arbitrarily assigned the D prefix to (+)-glyceraldehyde and the L prefix to (-)-glyceraldehyde, he had 50/50 chance of being correct.
In the early 1950s, a new technique, the x-ray diffraction analysis, made possible to establish the absolute configuration of chiral molecules.Johannes Martin Bijvoet and the absolute configurations of chiral molecules In 1951 a Dutch chemist, Johannes Martin Bijvoet established the absolute configuration of sodium rubidium (+)‐tartrate tetrahydrate and, comparing it with glyceraldehyde, demonstrated that Rosanoff’s guess was right. Consequently, the configurations of the chiral compounds obtained by relating them to that of glyceraldehyde were the same as their absolute configurations: hence, the relative configurations became absolute configurations.

Ambiguities of the Fischer-Rosanoff convention

The Fischer-Rosanoff convention gives rise to uncertainties with molecules with more than one chiral center. For example, considering D-(+)-glucose, the D-L system gives information about the configuration of C-2, but no information about the other asymmetric centers, namely, C-3, C-4, and C-5.
Asymmetric centers of D-(+)-GlucoseIn these cases, the RS system, developed in 1956 by Robert Sidney Cahn, Christopher Ingold, and Vladimir Prelog, labeling each chiral center, allows to describe accurately the stereochemistry of the molecule. In the case of D-(+)-glucose, the molecule has the (2R,3S,4R,5R)-configuration.
It should also be noted that depending on the chiral center taken as the reference center, the same molecule can belong to both the D and L series.

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

Mason S.F. Molecular optical activity and the chiral discriminations. Cambridge University Press, 2009 [Google eBooks]

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

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

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, carbohydrates, 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: the priority rules

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 chirality 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

Isomerism

The phenomenon that two or more different chemical compounds have the same molecular formula is called isomerism, from the Greek isos meaning “equal”, and meros meaning “part”, a concept and term introduced by the Swedish scientist Jacob Berzelius in 1830.
Isomerism is a consequence of the fact that the atoms of a molecular formula can be arranged in different ways to give compounds, called isomers, that differ in physical and chemical properties.
There are two types of isomerism: structural isomerism and stereoisomerism, which can be divided into further subtypes.

Tree Diagram for Types of Isomerism

CONTENTS

Structural isomerism

In structural isomerism, also called constitutional isomerism, isomers differ from each other in that the constituent atoms are linked in different ways and sequences.
There are several subtypes of structural isomerism: positional, functional group and chain isomerism.

Positional isomers

In positional isomerism, also called position isomerism, isomers have the same functional groups but in different positions on the same carbon chain.
An example is the compound with molecular formula C6H4Br2, of which there are three isomers: 1,2-dibromobenzene, 1,3-dibromobenzene and 1,4-dibromobenzene. These isomers differ in the position of the bromine atoms on the cyclic structure.

Positional Isomerism

Another example is the compound with molecular formula C3H8O, of which there are two isomers: 1-propanol or n-propyl alcohol, and 2-propanol or isopropyl alcohol. These isomers differ in the position of the hydroxyl group on the carbon chain.

Position Isomers

Functional group isomers

Functional group isomerism, also called functional isomerism, occurs when the atoms form different functional groups.
An example the compound with molecular formula C2H6O, of which there are two isomers: dimethyl ether and ethanol or ethyl alcohol, that have different functional groups, an ether group, –O–, and a hydroxyl group, –OH, respectively.

Functional Group Isomerism

Chain isomers

In chain isomerism, isomers differ in the arrangement of the carbon chains, that may be branched or straight.
An example is the compound with the molecular formula C5H12, of which there are three isomers: n-pentane, 2-methylbutane or isopentane and 2,2-dimethylpropane or neopentane.

Chain Isomers

Stereoisomerism

In stereoisomerism, isomers have the same number and kind of atoms and bonds, but differ in the orientation of the atoms in space. Such isomers are called stereoisomers, from the Greek stereos, meaning “solid”.
There are two subtypes of stereoisomerism, conformational isomerism and configurational isomerism; the latter can be further subdivided into optical isomerism and geometrical isomerism.

Conformational isomerism

In conformational isomerism, the stereoisomers can be interconverted by rotation around one or more single bonds, the σ bonds. These rotations produce different arrangements of atoms in space that are non-superimposable. And the number of possible conformations a molecule can adopted is theoretically unlimited, ranging from the lowest energy structure, the most stable, to the highest energy structure, the less stable. Such isomers are called conformer.
For example, if we consider ethane, C2H4, looking at the molecule from one end down the carbon-carbon bond, using the Newman projection, hydrogen atoms of a methyl group can be, with respect to the hydrogen atoms of the other methyl group, in one of the following conformations.

  • The eclipsed conformation, in which hydrogen atoms of a methyl group are hidden behind those of the other methyl group, then, the angle between carbon-hydrogen bonds on the front and rear carbons, called a dihedral angle, could be 0, 120, 240, 360 degrees. This is the highest energy conformation, then is the less stable.
  • The staggered conformation, in which hydrogen atoms of a methyl group are completely offset from those of the other methyl group, namely, dihedral angles could be 60, 180 or 360 degrees. This is the lowest energy conformation, then the most stable.
  • The skew conformation, corresponding to one of the intermediate conformations between the previous ones.

Ethane Conformers: Newman Projections
The stability of ethane conformers is due to how the electron pairs of the carbon-hydrogen bonds of the two methyl groups are overlapped:

  • in the staggered conformations they are as far away from each other as possible;
  • in the eclipsed conformations they are as close as possible to each other.

The potential energy barrier between these two conformations is small, about 2.8 kcal/mole (11.7 kJ/mole). At room temperature, the kinetic energy of the molecules is 15-20 kcal/mole (62.7-83.6 kJ/mole), more than enough to allow free rotation around the carbon-carbon bond. As a consequence, it is not possible to isolate any particular conformation of ethane.
Note: the potential energy barrier to rotation around double carbon-carbon bonds is about 63 kcal/mole (264 kJ/mole), corresponding to the energy required to break the π bond. (See geometric isomerism). This value is about three times the kinetic energy of the molecules at room temperature at which, then, free rotation is precluded. Only at temperatures above 300 °C molecules acquire enough thermal energy to break the π bond, allowing free rotation around the remaining σ bond. This allows the trans-isomer to be rearranged to the cis-isomer or vice versa.

Configurational isomerism

In configurational isomerism, the interconversion between the stereoisomers does not occur as a result of rotations around single bonds but involves bond breaking and new bond forming, then it doesn’t occur spontaneously at room temperature.
There are two subtypes of configurational isomerism: optical isomerism and geometrical isomerism.

Optical isomers

Optical isomerism occurs in molecules that have one or more chirality centers or chiral centers, namely, tetrahedral atoms that bear four different ligands. The chiral center can be a carbon, phosphorus, sulfur or nitrogen atom.

Chiral Center or Chirality Center
Note: the word chirality derives from the Greek cheiros, meaning “hand”.
Optical isomers lack of a center of symmetry or a plane of symmetry, are mirror image of each other, and cannot be superimposed on one another. Such stereoisomers are called enantiomers, from the Greek enántios, meaning “opposite”, and meros, meaning “part”.
Unlike the other isomers, two enantiomers have identical physical and chemical properties with two exceptions.

  • The direction of rotation of the plane of polarized light, hence the name of optical isomerism.
    If a solution of one enantiomer rotates the plane of polarized light in a clockwise direction, the enantiomer is labeled (+). Conversely, a solution of the other enantiomer rotates the plane of polarized light in a counterclockwise direction by the same angle, and the enantiomer is labeled (-).
  • Although indistinguishable by most techniques, two enantiomers can be distinguished in a chiral environment like the active site of chiral enzymes.

Note: for a molecule with n chiral centers, the maximum number of stereoisomers is equal to 2n.

Geometric isomers

Geometric isomerism, also called cis-trans isomerism, occurs when atoms cannot freely rotate due to a rigid structure such as in:

  • compounds with carbon-carbon, carbon-nitrogen or nitrogen-nitrogen double bonds, where the rigidity is due to the double bond;
  • cyclic compounds, where the rigidity is due to the ring structure.

An example of geometrical isomerism due to the presence of a carbon-carbon double bond is stilbene, C14H12, of which there are two isomers. In one isomer, called cis isomer, the same groups are on the same side of the double bond, whereas in the other, called trans isomer, the same groups are on opposite sides.

Geometric Isomerism

Note: the terms trans and cis are from the Latin trans, meaning “across”, and cis, meaning “on this side of”.
Among the cyclic compounds of carbon, cis-trans isomerism not complicated by the presence of chiral centers occurs in structures with an even number of carbon atoms and substituted in opposite positions, namely, para-substituted. An example is 1,4-dimethylcyclohexane, a cycloalkane, compounds of general formula CnH2n, of which there are two stereoisomers, cis-1,4-dimethylcyclohexane and trans-1,4- dimethylcyclohexane.

cis-trans Isomers

This kind of stereoisomerism cannot exist if one of the atoms that cannot freely rotate carries two groups the same. Why? For the switching between the trans and cis isomers the groups attached to atoms that cannot freely rotate have to be swapped. If there are two groups the same, the switch leads to the formation of the same molecule.
Note: geometric isomers are a special case of diastereomers or diastereoisomers, that, in turn, are stereoisomers that are not mirror image of each other. The other diastereomers are the meso compounds and non-enantiomeric optical isomers.

References

Graham Solomons, T. W., Fryhle C.B.,  Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017

Morris D.G. Stereochemistry. Royal Society of Chemistry, 2001 [GoogleBook]

North M. Principles and applications of stereochemistry. 1th Edition. CRC Press, 1998

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