Carbanions are ions containing a negatively charged carbon atom.
They are formed by the heterolytic cleavage of a covalent bond between a carbon atom and another atom or group.^[7]
Having an unshared electron pair, they are powerful nucleophiles, and strong bases, and attack, in order to form a covalent bond, a proton or an electrophilic center, such as a polarized or positively charged center.^[8]
Carbanions are extremely reactive. Therefore, they must be stabilized in order to allow their attack to the electrophilic centers.^[9] Stabilization may occur by inductive effect, resonance, and may also depend on the hybridization of the carbon atom carrying the negative charge.^[7][8]
They are intermediates in many enzyme-catalyzed reactions.

Contents

• Heterolysis and homolysis
• Stabilization of carbanions
• Carbanions in enzymatic reactions
• References

Heterolysis and homolysis

Considering two atoms or group, indicated as A and B, joined by a covalent bond, there are two ways to break the bond: heterolysis and homolysis.

In heterolysis, the breaking of the covalent bond leads to the formation of two charged atoms, namely two ions, a cation and an anion, as both bonding electrons are taken by only one of the two previously bonded atoms, the more electronegative.

A:B → :A^– + B⁺, if A is more electronegative than B;

A:B → A⁺ + :B^–, if B is more electronegative than A.

In the heterolysis of a covalent bond involving a carbon atom, if both electrons are retained by the carbon atom, it will have a negative charge, therefore it is an anion, and is defined as a carbanion. On the contrary, if the carbon loses both electrons, it will have a positive charge, therefore it is a cation, and is defined as a carbocation.^[5]
In homolysis, the breaking of the covalent bond between A and B leads to the formation of two free radicals, as each atom or group takes one of the two bonding electrons.^[6]

Stabilization of carbanions

Carbanions are extremely reactive chemical species, and, like carbocations and free radicals, they are almost always transient intermediates in organic reactions. In order to allow their attack to the electrophilic centers, they must be stabilized. Their stabilization depends on the dispersion of the negative charge, which may occur by inductive effect, resonance, and may also depend on the s character of the hybrid orbitals of the negatively charged carbon atom.
The inductive effect is due to the presence in the molecule of one or more permanent dipoles in one or more bonds, dipoles which in turn arise from the difference in electronegativity between two groups. This difference leads to a non-uniform distribution of the bonding electrons. The inductive effect can be positive, also known as +I effect, feature of atoms or groups that tend to repel electrons, or negative, also known as –I effect, feature of atoms or groups that tend to attract electrons. The atoms or groups with the +I effect tend to decrease the stability of the carbanions, whereas those with the –I effect, therefore more electronegative, tend to stabilize them.^[7]
The stability of carbanions increases when they are bound to an electrophilic structure where the unshared electron pair can delocalize by resonance, therefore a structure that acts as an electron trap or electron sink. Aromatic structures, such as the phenyl group, are particularly effective.^[8]
Finally, the stability is also a function of the s character of hybrid orbitals of the negatively charged carbon atom, increasing as the percentage s character increases. Therefore it will increase going from sp³ hybridization, which has 25% s character, to sp², with 33% s character, to sp, with 50% s character.^[7]

R-CH₂^– < R₁R₂C=CH^– < RC≡C^–

Carbanions in enzymatic reactions

Examples of enzymatic reactions that proceed with the formation of carbanions are those catalyzed by three multienzyme complexes belonging to the family of 2-oxoacid dehydrogenases or alpha-ketoacid dehydrogenases, which are involved in the oxidative decarboxylation of ketoacids, in particular of alpha-ketoacids, briefly described below.

• The pyruvate dehydrogenase complex, which catalyzes the oxidative decarboxylation of pyruvate, the conjugate base of pyruvic acid, into acetyl-CoA, thus acting as a bridge between glycolysis and the citric acid cycle;
• The oxoglutarate dehydrogenase or alpha-ketoglutarate dehydrogenase complex, which catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA in step 4 of the citric acid cycle;
• The branched-chain alpha-ketoacid dehydrogenase complex, which catalyzes the oxidative decarboxylation of the branched amino acids valine, leucine and isoleucine into acetyl-CoA and succinyl-CoA. The remaining carbon skeleton can then enter the citric acid cycle.^[9]

The three multienzyme complexes have very similar structures and reaction mechanisms, and their E₁ subunits, which are thiamine pyrophosphate dependent enzymes, catalyze a reaction in which a carbanion intermediate is formed, whose formation and stabilization by resonance involves thiamine.^[1]
Transketolase (EC 2.2.1.1) also catalyzes a reactions that involves the formation of a carbanion intermediate. This enzyme, which catalyzes steps 6 and 8 of the pentose phosphate pathway, requires thiamine pyrophosphate as a cofactor, and has a reaction mechanism similar to that of the E₁ subunits of multienzyme complexes seen previously.^[6]
Acetyl-CoA carboxylase (EC 6.4.1.2) is another enzyme that catalyzes a reaction that involve the formation of a carbanion intermediate. The enzyme catalyzes the committed step of de novo synthesis of fatty acids, namely, the carboxylation of acetyl-CoA to malonyl-CoA.^[2]

References

1. ^{^} Berg J.M., Tymoczko J.L., and Stryer L. Biochemistry. 5th Edition. W. H. Freeman and Company, 2002
2. ^{^} Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010
3. ^{^} Heterolysis, in IUPAC Compendium of Chemical Terminology, 3rd ed. International Union of Pure and Applied Chemistry; 2006. Online version 3.0.1, 2019. doi:1351/goldbook.H02809
4. ^{^} Homolysis, in IUPAC Compendium of Chemical Terminology, 3rd ed. International Union of Pure and Applied Chemistry; 2006. Online version 3.0.1, 2019. doi:1351/goldbook.H02851
5. ^{^} Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012
6. ^ ^{a b} Nelson D.L., Cox M.M. Lehninger. Principles of biochemistry. 6th Edition. H. Freeman and Company, 2012
7. ^ ^{a b c d} Soderberg T. Organic chemistry with a biological emphasis. Volume I. Chemistry Publications. 2019
8. ^ ^{a b c} Solomons T. W.G., Fryhle C.B., Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017
9. ^ ^{a b} Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011

In 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 molecules with at least one chirality center, such as carbohydrates. This nomenclature system was called the Fischer-Rosanoff convention, or Rosanoff convention, or D-L system.^[7]
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.^[4]

Although Fischer rejected this nomenclature system, it was universally accepted and used to obtain the relative configurations of the chiral molecules.^[3] 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.^[6]

Contents

• Fischer-Rosanoff convention and carbohydrates
• Fischer-Rosanoff convention and alpha-amino acids
• Relative and absolute configurations
• Ambiguities of the Fischer-Rosanoff convention
• References

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.^[8]
Note: 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 alpha-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.^[6][8]
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.
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 the synthesis of proteins.

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.^[5]
In the early 1950s, a new technique, the x-ray diffraction analysis, made possible to establish the absolute configuration 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.^[1] 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.^[3] 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.

In 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.^[2][8] 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

1. ^{^} Bijvoet J.M., Peerdeman A.F., Van Bommel A.J. Determination of the absolute configuration of optically active compounds by means of X-rays. Nature 1951;168(4268):271. doi:10.1038/168271a0
2. ^{^} Cahn R.S., Ingold C., Prelog V. Specification of molecular chirality. Angew Chem 1966:5(4); 385-415. doi:10.1002/anie.196603851
3. ^ ^{a b} Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010
4. ^{^} 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
5. ^{^} Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012
6. ^ ^{a b} Nelson D.L., Cox M.M. Lehninger. Principles of biochemistry. 6th Edition. W.H. Freeman and Company, 2012
7. ^{^} Rosanoff. On Fischer’s classification of stereo-isomers. J Am Chem Soc 1906:28(1);114-121. doi:10.1021/ja01967a014
8. ^ ^{a b c} Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011

In 1891, Hermann Emil Fischer, a German chemist, Nobel Laureate in chemistry in 1902, developed a systematic method for the two-dimensional representation of molecules with chirality centers, 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
• How to manipulate Fischer projection formulas
• References

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.

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

References

1. Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010
2. 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
3. Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012
4. Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011

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.^[1][5]
This nomenclature system, called the RS system, or the Cahn-Ingold-Prelog (CIP) system, when added to the IUPAC system of nomenclature,^[3] allows 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.^[6] 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.^[7]

Contents

• The priority rules of the RS system
  • First rule
  • Second rule
  • Third rule
• RS system and multiple chiral centers
  • Amino acids and gliceraldeide
• References

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.^[2][4]

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

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”.

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.

In 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?

Consider 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

1. ^{^} Cahn R.S., Ingold C., Prelog V. Specification of molecular chirality. Angew Chem 1966:5(4); 385-415. doi:10.1002/anie.196603851
2. ^{^} Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010
3. ^{^} 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
4. ^{^} Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012
5. ^{^} Prelog V. and Helmchen G. Basic principles of the CIP‐system and proposals for a revision. Angew Chem 1982:21(8);567-583. doi:10.1002/anie.198205671
6. ^{^} Rosanoff M.A. On Fischer’s classification of stereo-isomers. J Am Chem Soc 1906:28(1);114-121. doi:10.1021/ja01967a014
7. ^{^} Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011

Chirality is 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 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“.
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
  • Chirality and optical activity
  • Pasteur and the discovery of enantiomers
  • Racemic mixtures
• Chirality centers
  • Chirality in the absence of a chiral center
• Meso compounds
• References

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, from the observer’s point of view, 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, 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, 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

In 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. However, 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, so named based on the  nomenclature system called the RS system, has the pharmacological activity.

Arylpropionic 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.

The 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 and germanium, 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.

At 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.

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

Meso compounds

Meso compounds 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. Therefore, there are 2² = 4 possible stereoisomers, whose structures are depicted in the figure, in the Fischer projections, indicated as A, B, C, D.

Structures 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

1. 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
2. Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010
3. 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
4. Kelvin WT. Baltimore lectures on molecular dynamics and the wave theory of light. Clay C. J., London: 1904:619. https://archive.org/details/baltimorelecture00kelviala/mode/2
5. Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011

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.^[3][4]
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.^[1]

Contents

• Structural isomerism
  • Positional isomers
  • Functional group isomers
  • Chain isomers
• Stereoisomerism
  • Conformational isomerism
  • Configurational isomerism
    • Optical isomers
    • Geometric isomers
• References

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.

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.

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.

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 isomerism also occurs in lipids. For example, among short-chain fatty acids, butyric acid and isobutyric acid, which have molecular formula C₄H₈O₂, are chain isomers, as well as valeric acid, isovaleric acid and 2-methylbutyric acid, which have the molecular formula C₅H₁₀O₂.

Stereoisomerism

In stereoisomerism, isomers have the same number and kind of atoms and bonds, but differ in the orientation of the atoms in space.^[3][4] 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.

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.^[2] The chiral center can be a carbon, phosphorus, sulfur or nitrogen atom.

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.

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 C_nH_2n, of which there are two stereoisomers, cis-1,4-dimethylcyclohexane and trans-1,4- dimethylcyclohexane.

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

1. ^{^} Graham Solomons T. W., Fryhle C.B., Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017
2. ^{^} Kelvin WT. Baltimore lectures on molecular dynamics and the wave theory of light. Clay C. J., London: 1904:619. https://archive.org/details/baltimorelecture00kelviala/mode/2
3. ^ ^{a b} Morris D.G. Stereochemistry. Royal Society of Chemistry, 2001. doi:10.1039/9781847551948
4. ^ ^{a b} North M. Principles and applications of stereochemistry. 1th Edition. CRC Press, 1998