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.^[1]
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.^[2]
Carbanions are extremely reactive. Therefore, they must be stabilized in order to allow their attack to the electrophilic centers.^[3] Stabilization may occur by inductive effect, resonance, and may also depend on the hybridization of the carbon atom carrying the negative charge.^[1][2]
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.^[4]

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] Free radicals, which are electrically neutral, are also very unstable molecules. Note that homolytic cleavage is less common than heterolytic cleavage.^[7]

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.^[1]

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.^[2]

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 percent s character, to sp², with 33% s character, to sp, with 50% s character.^[1]

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.^[3]

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.^[8]

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.^[7]

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.^[9]

References

1. ^ ^{a b c d} Soderberg T. Organic chemistry with a biological emphasis. Volume I. Chemistry Publications. 2019
2. ^ ^{a b c} Solomons T.W.G., Fryhle C.B., Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017
3. ^ ^{a b} Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011
4. ^{^} 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
5. ^{^} Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012
6. ^{^} 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
7. ^ ^{a b} Nelson D.L., Cox M.M. Lehninger. Principles of biochemistry. 6th Edition. H. Freeman and Company, 2012
8. ^{^} Berg J.M., Tymoczko J.L., and Stryer L. Biochemistry. 5th Edition. W. H. Freeman and Company, 2002
9. ^{^} Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010

In 1906, Russian-American chemist Martin André Rosanoff, then working at New York University, selected glyceraldehyde, a simple monosaccharide, as the standard for denoting the stereochemistry of molecules with at least one chiral center, such as carbohydrates. This nomenclature system became known as the Fischer-Rosanoff convention (or simply the D-L system).^[1]

Contents

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

Fischer-Rosanoff convention: origin and application

Since the absolute configuration of glyceraldehyde was unknown at the time, Rosanoff assigned the stereochemistry in an entirely arbitrary way:

• The D prefix (from the Latin dexter, meaning “right”) was assigned to (+)-glyceraldehyde, the dextrorotatory enantiomer, assuming that its Fischer projection had the hydroxyl group (–OH) on the right side of the chiral center.
• The L prefix (from the Latin laevus, meaning “left”) was assigned to (−)-glyceraldehyde, the levorotatory enantiomer, assuming the hydroxyl group was on the left side of the chiral center.^[2]

Although Emil Fischer himself rejected this system, it was widely adopted for determining the relative configurations of chiral molecules. How? By chemically converting a molecule into a derivative of glyceraldehyde using reactions that retain the configuration, meaning no bonds to the chiral center are broken, the spatial arrangement around the chiral center is preserved.^[3]

The Fischer-Rosanoff convention allows chemists to classify chiral molecules, such as amino acids and monosaccharides, into two categories: the D series and the L series, depending on whether their configuration corresponds to that of D- or L-glyceraldehyde.

Note: there is no direct correlation between configuration (D or L) and the direction of optical rotation. The D–L system does not indicate whether a molecule is dextrorotatory or levorotatory; it only relates molecular configuration to that of glyceraldehyde.^[4]

Fischer-Rosanoff convention: carbohydrates

Monosaccharides can be classified as either aldoses or ketoses. Aldoses, and ketoses with more than three carbon atoms, have at least one chiral center. By convention, they are assigned to the D or L series depending on the configuration of the chiral carbon farthest from the carbonyl group, which is the carbon with the highest oxidation state. If this configuration matches that of D-glyceraldehyde or L-glyceraldehyde, the molecule is placed in the corresponding D or L series.

In Fischer projections, the longest carbon chain is drawn vertically, and the carbon atoms are numbered so that the carbonyl carbon receives the lowest possible number: C-1 in aldoses and C-2 in ketoses.^[5]
Note: in nature, D-sugars are far more common than L-sugars.

When it is necessary to specify the optical rotation of a monosaccharide, the prefixes (+) or (–) can be added to the D or L designation. For example, fructose, which is levorotatory, can be written as D-(–)-fructose, whereas glucose, which is dextrorotatory, can be written as D-(+)-glucose.

Fischer-Rosanoff convention: alpha-amino acids

Amino acids can be classified based on the position of the amino group (–NH₂) relative to the carboxyl group (–COOH):

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

α-Amino acids are assigned to the D or L series based on the configuration of the four groups attached to the α-carbon, the chiral center: –NH₂, –COOH, –R, and –H. If their spatial arrangement matches that of the hydroxyl, aldehyde (–CHO), hydroxymethyl (–CH₂OH), and hydrogen atoms in D- or L-glyceraldehyde, the amino acid belongs to the corresponding series.^[4]

In Fischer projections, amino acids are represented with the carboxyl group, the carbon with the highest oxidation state, at the top, and the R group at the bottom.

Among α-amino acids, the proteinogenic amino acids (those involved in protein synthesis), with the exception of glycine, whose α-carbon is not chiral, all exhibit the L configuration, and are thus known as L-α-amino acids.

Note: in nature, L-α-amino acids are significantly more abundant than other types of amino acids, which do not participate in protein synthesis.^[5]

Relative and absolute configurations

When Rosanoff arbitrarily assigned the D prefix to (+)-glyceraldehyde and the L prefix to (–)-glyceraldehyde, he had a 50/50 chance of being correct.^[6]

In the early 1950s, the development of X-ray diffraction analysis made it possible to determine the absolute configuration of chiral molecules. In 1951, Dutch chemist Johannes Martin Bijvoet established the absolute configuration of sodium rubidium (+)-tartrate tetrahydrate. By comparing it with glyceraldehyde, he demonstrated that Rosanoff’s assumption was correct.^[7]

As a result, the configurations of chiral compounds previously assigned relative to glyceraldehyde turned out to match their true absolute configurations, meaning that the relative configurations became absolute configurations.

Ambiguities of the Fischer-Rosanoff convention

The Fischer-Rosanoff convention can lead to ambiguities when applied to molecules with more than one chiral center. For example, in D-(+)-glucose, the D–L system provides information only about the configuration at C-2, but gives no indication regarding the other chiral centers, namely C-3, C-4, and C-5.^[3]

In such cases, the RS system, developed in 1956 by Robert Sidney Cahn, Christopher Ingold, and Vladimir Prelog, offers a more precise description by assigning a configuration to each chiral center individually. For instance, D-(+)-glucose has the configuration (2R,3S,4R,5R).^[5][8]

It should also be noted that the D or L designation depends on which chiral center is chosen as the reference point. Consequently, the same molecule can sometimes be classified as either D or L, depending on the structural context.

References

1. ^{^} Rosanoff M.A. On Fischer’s classification of stereo-isomers. J Am Chem Soc 1906:28(1);114-121. doi:10.1021/ja01967a014
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. ^ ^{a b} Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010.
4. ^ ^{a b} Nelson D.L., Cox M.M. Lehninger. Principles of biochemistry. 6th Edition. W.H. Freeman and Company, 2012.
5. ^ ^{a b c} Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011.
6. ^{^} Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012.
7. ^{^} 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
8. ^{^} Cahn R.S., Ingold C., Prelog V. Specification of molecular chirality. Angew Chem 1966:5(4); 385-415. doi:10.1002/anie.196603851

In 1891, Hermann Emil Fischer, a German chemist and Nobel Laureate in Chemistry (1902), developed a systematic method for the two-dimensional representation of molecules with chiral centers (also known as chirality centers): the so-called Fischer projections, or Fischer projection formulas.^[1]
Although they are two-dimensional representations, Fischer projections preserve important information about the stereochemistry of molecules.^[2] While they do not reflect the actual three-dimensional shape of molecules in solution, they are still widely used by biochemists to define the stereochemistry of amino acids, carbohydrates, nucleic acids, terpenes, steroids, and other biologically relevant molecules.^[3]

Contents

• How to draw Fischer projections
• How to manipulate Fischer projection formulas
• References

How to draw Fischer projections

To draw a Fischer projection of a molecule with a single chiral center (e.g., a carbon atom), the tetrahedral structure is rotated so that two groups point downward and two groups point upward. Next, draw a cross, place the chiral carbon at the intersection, and arrange the molecule so that the groups pointing downward (i.e., behind the plane of the paper) are attached to the ends of the vertical line, while the groups pointing upward (i.e., projecting out of the plane of the paper) are attached to the ends of the horizontal line.^[4]

For compounds with more than one chiral center, the same procedure is applied to each asymmetric center.

A Fischer projection can also be converted into a three-dimensional representation, such as a wedge-and-dash (perspective) formula, in which the two horizontal bonds are shown as solid wedges, and the vertical bonds as dashed lines.^[5]

How to manipulate Fischer projection formulas?

Since Fischer projections represent three-dimensional molecules on a two-dimensional plane, certain rules must be followed to preserve the correct configuration.^[2]

• The projection must not be lifted out of the plane of the paper, as doing so would convert one enantiomer into its mirror image (the other enantiomer).
• If you rotate the projection within the plane of the paper, the configuration remains unchanged only when rotated by 180° in either direction. This is because the vertical bonds are oriented behind the plane of the paper, while the horizontal bonds project out of the plane. Conversely, a rotation of 90° or 270° in either direction inverts the configuration and converts the enantiomer into its mirror image.
• Finally, performing an odd number of exchanges between any two groups around the chiral center also results in the conversion of one enantiomer into the other.^[5]

References

1. ^{^} Emil Fischer – Biographical. NobelPrize.org. Nobel Prize Outreach 2025. Sat. 31 May 2025. https://www.nobelprize.org/prizes/chemistry/1902/fischer/biographical/
2. ^ ^{a b} Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012.
3. ^{^} Berg J.M., Tymoczko J.L., and Stryer L. Biochemistry. 5th Edition. W. H. Freeman and Company, 2002.
4. ^{^} Nelson D.L., Cox M.M. Lehninger. Principles of biochemistry. 6th Edition. W.H. Freeman and Company, 2012.
5. ^ ^{a b} Solomons T.W.G., Fryhle C.B., Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017.

In 1956, Robert Sidney Cahn, Christopher Ingold, and Vladimir Prelog developed a nomenclature system which, based on a few simple rules, allows the assignment of the absolute configuration to each chiral center in a molecule.^[1][2]
This nomenclature system, called the RS system or the Cahn-Ingold-Prelog (CIP) system, when combined with the IUPAC system of nomenclature, makes it possible to name chiral molecules accurately and unambiguously, even when there is more than one asymmetric center.^[3]

In most cases, chiral molecules are able to rotate plane-polarized light when it 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 about the RS configuration of its chiral centers.

The Fischer-Rosanoff convention is another way to describe the configuration of chiral molecules.^[4] However, compared to the RS system, it labels the whole molecule rather than each individual chiral center, and it is often ambiguous for molecules with two or more chiral centers.^[5]

Contents

• Priority rules of the RS system
  • First rule
  • Second rule
  • Third rule
• The RS system and molecules with multiple chiral centers
  • Amino acids and glyceraldehyde
• References

Priority rules of the RS system

The RS system assigns a priority sequence to the groups attached to a chiral center. By tracing a curved arrow from the highest-priority group to the lowest (excluding the group positioned away from the observer), each chiral center is labeled as either R or S.^[6][7]

First rule

A priority sequence is assigned to the groups based on the atomic number of the atoms directly bonded to the chiral center.
The atom with the highest atomic number is given the highest priority, while the atom with the lowest atomic number is given 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 priority order is:

Br > Cl > O > C.

For isotopes, the atom with the higher atomic mass is assigned the higher priority.^[8]

Second rule

When different groups are attached to a chiral center through identical atoms, the priority sequence is determined by examining the atomic numbers of the next set of atoms bonded, moving outward from the chiral center until the first point of difference is found.
For example, consider the following groups attached to a chiral center: –CH₃, –CH₂CH₃ and –CH₂OH. These all have a carbon atom directly bonded to the chiral center. To determine priority, we analyze the atoms bonded to each of these carbons:

• methyl group (–CH₃): H, H, H
• ethyl group (–CH₂CH₃): H, H, C
• hydroxymethyl group (–CH₂OH): H, H, O

Since oxygen has a higher atomic number than carbon, and carbon has a higher atomic number than hydrogen, the order of priority is:–CH₂OH > –CH₂CH₃ > –CH₃
A typical priority order for common substituents is:

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

Note: ²H > –¹H refer to the isotopes deuterium and protium, respectively.

It is important to note that the groups attached to a chiral center must not have identical priority, as this would mean the center is not chiral.

Once the priority sequence has been determined, orient the molecule in space so that the group with the lowest priority is pointing away from the observer, i.e., behind the chiral center. Then, trace a circular arrow from the highest-priority group to the next in sequence.

• If the arrow moves in a clockwise direction, the configuration is R (from Latin rectus, meaning “right”).
• If the arrow moves in a counterclockwise direction, the configuration is S (from Latin sinister, meaning “left”).^[8]
  

Third rule

The third rule of the RS system is used to determine the configuration of a chiral center when one or more of the attached groups contain double or triple bonds.
To assign priorities correctly in such cases, atoms involved in double or triple bonds are treated as if they were duplicated or triplicated, respectively.

In the case of a C=Y double bond, the carbon is considered to be bonded to two Y atoms, and the Y atom is considered to be bonded to two carbon atoms.
In the case of a C≡Y triple bond, the carbon is treated as bonded to three Y atoms, and the Y atom as bonded to three carbon atoms. ^[8]

The RS system and molecules with multiple chiral centers

When two or more chiral centers are present in a molecule, each center is analyzed independently using the rules previously described.

Consider 2,3-butanediol. This molecule contains two chiral centers, carbon 2 and carbon 3, and exists as three stereoisomers: two enantiomers and one meso compound. What is the RS configuration of the chiral centers in the enantiomer shown in the figure?

Let’s analyze carbon 2. The order of priority of the attached groups is:

–OH > –CH(OH)CH₃ > –CH₃ > –H

(Here, CH(OH)CH₃ represents the portion of the molecule extending toward carbon 3.)
Rotate the molecule so that the hydrogen, the group with the lowest priority, is pointing away from the viewer (behind the plane). Then trace a path from –OH (highest priority) to –CH₃. This path moves in a clockwise direction, so the configuration at carbon 2 is R.
Applying the same procedure to carbon 3, we also find its configuration to be R.
Therefore, the enantiomer shown in the figure is (2R,3R)-2,3-butanediol.

Amino acids and glyceraldehyde

In the Fischer-Rosanoff convention, all proteinogenic amino acids are classified as L-amino acids. In the RS system, with the exception of glycine, which is not chiral, and cysteine, which, due to the presence of a thiol group, is classified as (R)-cysteine, all other proteinogenic amino acids are (S)-amino acids.

Threonine and isoleucine each have two chiral centers: the α-carbon and an additional carbon atom in the side chain. Both exist as three stereoisomers: two enantiomers and one meso compound.
The naturally occurring forms found in proteins are:

• (2S,3R)-threonine
• (2S,3S)-isoleucine

These correspond, in the Fischer-Rosanoff convention, to L-threonine and L-isoleucine, respectively.

In the RS system, L-glyceraldehyde is classified as (S)-glyceraldehyde, and, accordingly, D-glyceraldehyde is (R)-glyceraldehyde.^[9]

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. ^{^} 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
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. ^{^} Rosanoff M.A. On Fischer’s classification of stereo-isomers. J Am Chem Soc 1906:28(1);114-121. doi:10.1021/ja01967a014
5. ^{^} Voet D. and Voet J.D. Biochemistry. 4th Edition. John Wiley J. & Sons, Inc. 2011.
6. ^{^} Garrett R.H., Grisham C.M. Biochemistry. 4th Edition. Brooks/Cole, Cengage Learning, 2010.
7. ^{^} Moran L.A., Horton H.R., Scrimgeour K.G., Perry M.D. Principles of Biochemistry. 5th Edition. Pearson, 2012.
8. ^ ^{a b c} Graham Solomons T. W., Fryhle C.B., Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017.
9. ^{^} Morris D.G., Drayton C., Hepworth J.D. Stereochemistry. Royal Society of Chemistry. 2001. doi:10.1039/9781847551948

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.^[2]
The term chirality, from the Greek cheir meaning “hand”, was coined by Lord Kelvin, who introduced it during the “Baltimore Lectures”, a series of talks held at Johns Hopkins University in Baltimore, starting on October 1st, 1884, and published twenty years later, in 1904.^[3]

The world is rich in chiral objects: your hands are the prime example, but many others exist, from the shell of a snail to a spiral galaxy. In chemistry, especially in organic chemistry, chirality is a property of primary importance, because molecules such as carbohydrates, many amino acids, and numerous drugs are chiral.^[4]

Chiral molecules can exist in two forms: mirror images of each other that are non-superimposable. In other words, no combination of rotations or translations in the plane of the sheet can align them perfectly. These molecules are called enantiomers, from the Greek enántios, meaning “opposite”, and meros, meaning “part”.^[5]

The most common cause of chirality in a molecule is the presence of a chiral center or chirality center, also called an asymmetric center, an atom bonded to a set of atoms or functional groups arranged in space such that the resulting molecule can exist as two enantiomers.
Enantiomers are a type of stereoisomers, which can be defined as isomers that have the same number and types of atoms and bonds, but differ in the spatial orientation of those atoms.^[2]

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 distinct compounds. But how do they differ?
Each pair of enantiomers has identical physical and chemical properties with respect to achiral characteristics, such as melting point, boiling point, refractive index, infrared spectrum, solubility in the same solvent, and reaction rate with achiral reagents.
The differences emerge when enantiomers interact with chemical or physical phenomena that possess chirality.

• From a chemical point of view, two enantiomers can be distinguished by how they interact with chiral structures, such as the binding site of a chiral receptor or the active site of a chiral enzyme.
• From a physical point of view, they differ in their interaction with plane-polarized light, which exhibits chiral properties, in other words, they display optical activity.^[6]

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.^[7]
Chiral molecules can be classified based on the direction in which plane-polarized light is rotated, from the observer’s point of view, 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 the solution 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-.^[8]

Obviously, if we consider a pair of enantiomers, one is dextrorotatory and the other levorotatory.

Currently, it is not possible to reliably predict the magnitude, direction, or sign of the optical rotation caused by an enantiomer. Conversely, the optical activity of a molecule provides no information about the spatial arrangement of the chemical groups attached to its chirality center.

Note: a system containing molecules that all have the same chirality (i.e., the same “handedness”) is called enantiomerically pure or enantiopure.^[9]

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 observe that, following the recrystallization of a concentrated aqueous solution of sodium ammonium tartrate (which was optically inactive), two types of crystals precipitated that were non-superimposable mirror images of each other.^[10]

After separating them with tweezers, Pasteur discovered that the solutions obtained by dissolving equimolar amounts of the two types of crystals were optically active. Interestingly, the rotation angle of plane-polarized light was equal in magnitude but opposite in direction.
Since the differences in optical activity were due to the dissolved sodium ammonium tartrate crystals, Pasteur hypothesized that the molecules themselves must also be non-superimposable mirror images of each other, just like the crystals. These were what we now call enantiomers.^[11]

It was Pasteur who first used the term asymmetry to describe this property, which would later be termed chirality by Lord Kelvin.^[12]

Racemic mixtures

A solution containing equal amounts of each member of a pair of enantiomers is called a racemic mixture or racemate. These solutions are optically inactive: there is no net rotation of plane-polarized light, since the quantities of dextrorotatory and levorotatory molecules are exactly the same.

Unlike what occurs in biochemical processes, the chemical synthesis of chiral molecules that does not involve chiral reactants, or is not followed by enantiomer separation methods, inevitably leads to the production of a racemic mixture.^[9]
Pharmaceutical chemistry is among the fields most affected by this. As previously mentioned, two enantiomers are distinct compounds. Many chiral drugs are synthesized as racemic mixtures; however, the desired pharmacological activity often resides in only one enantiomer, called the eutomer, while the other, known as the distomer, is less active or inactive.^[14]

An example is ibuprofen, an arylpropionic acid derivative and anti-inflammatory drug: only the S-enantiomer, named according to the nomenclature system called RS system, exhibits pharmacological activity.

Arylpropionic acid derivatives are commonly sold as racemic mixtures. A racemase enzyme in the liver converts the distomer into the eutomer.^[15]

However, in some cases, the distomer may cause harmful effects and must therefore be removed 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 also taken during pregnancy.

The distomer, the S-enantiomer, was found to cause serious birth defects, particularly phocomelia (malformation of limbs). This remains one of the most striking examples of the importance of the chiral properties of molecules, and it prompted health organizations to encourage the pharmaceutical industry to develop drugs, thalidomide included, containing only a single enantiomer.^[16]

Chirality centers

Any tetrahedral atom bearing four different substituents can function as a chirality center.
The classic example is the carbon atom, but other group IVA elements in the periodic table, such as the semimetals silicon and germanium, also adopt tetrahedral geometry and can serve as chiral centers.^[2]

Another notable example is the phosphorus atom in organic phosphate esters: when it adopts a tetrahedral arrangement and is bonded to four different substituents, it too becomes a chirality center.^[4]

The nitrogen atom in a tertiary amine, an amine in which nitrogen is bonded to three different groups, can also be a chiral center. In such compounds, nitrogen occupies the center of a tetrahedron, with its four sp³ hybrid orbitals directed toward the vertices: three are occupied by substituents, while the fourth contains a nonbonding electron pair.

At room temperature, however, nitrogen undergoes rapid inversion of configuration. This process, known as nitrogen inversion, involves a fast oscillation in which the nitrogen atom passes through a planar, sp² hybridized transition state. As a result, if the nitrogen atom is the only chirality center in a molecule, the compound exhibits no optical activity, because it effectively exists as a racemic mixture.Nitrogen inversion does not occur only in specific cases, such as when nitrogen is part of a cyclic structure that prevents this motion. Therefore, the mere presence of a chirality center may not always be sufficient to allow for the isolation or resolution of enantiomers.^[4]

Note: in 1874, Jacobus Henricus van ‘t Hoff and Joseph Achille Le Bel, building on Pasteur’s work, were the first to propose the theory of the tetrahedral carbon atom. For this pioneering contribution, van ‘t Hoff was awarded the first Nobel Prize in Chemistry in 1901.^[17]

Chirality in the absence of a chiral center

Chirality can also arise in the absence of a traditional chiral center, often due to the restricted rotation around certain bonds, typically a double bond or a hindered single bond.^[18] This phenomenon is observed in cases such as:

• allene derivatives: organic compounds containing two cumulated double bonds, i.e., two double bonds located on the same carbon atom;^[19]
• biphenyl derivatives: compounds consisting of two aromatic rings connected by a single bond that cannot freely rotate due to steric hindrance from substituents.^[20]

In such cases, chirality results from the presence of an axis of chirality rather than a center. This form of chirality is known as axial chirality.

Meso compounds

Meso compounds are stereoisomers that contain two or more chiral centers but are superimposable on their mirror image. As such, they are achiral and therefore optically inactive. A defining feature of meso compounds is the presence of an internal mirror plane that bisects the molecule, with each half being the mirror image of the other.^[8]

Meso compounds are classified as diastereomers, meaning stereoisomers that are not enantiomers.
For a molecule with n chirality centers, the maximum number of possible stereoisomers is 2ⁿ.^[2]
Consider 2,3-butanediol, which contains two chirality centers, specifically at carbon atoms 2 and 3. According to the formula, there are 2² = 4 possible stereoisomers, whose structures are depicted in the accompanying figure as Fischer projections, labeled A, B, C, and D.

• Structures A and B are non-superimposable mirror images of each other, and thus constitute a pair of enantiomers.
• Structures C and D are also mirror images of each other, but they are superimposable. In fact, if either structure is rotated by 180 degrees, it aligns perfectly with the other. Therefore, C and D are not enantiomers; they are the same compound in different orientations.

Furthermore, these structures possess an internal mirror plane that divides the molecule into two symmetric halves, each a mirror image of the other. Structure C (or D) is therefore a meso compound: it contains chiral centers, is superimposable on its mirror image, and has an internal plane of symmetry that results in two mirror-image halves.^[2]

References

1. ^{^} Chirality, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. doi:10.1351/goldbook.C01058
2. ^ ^{a b c d e} Solomons T.W.G., Fryhle C.B., Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017.
3. ^{^} Kelvin W.T. Baltimore lectures on molecular dynamics and the wave theory of light. Clay C. J., London: 1904:619. https://archive.org/details/baltimorelecture00kelviala/mode/2
4. ^ ^{a b c} Morsch L., Farmer S., Cunningham K., Sharrett Z., Shea K.M. Organic Chemistry II. Open Educational Resources: Textbooks, Smith College, Northampton, MA, 2023. https://scholarworks.smith.edu/textbooks/6
5. ^{^} Enantiomer, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. doi:10.1351/goldbook.E02069
6. ^{^} Gogoi A., Konwer S., Zhuo G.Y. Polarimetric measurements of surface chirality based on linear and nonlinear light scattering. Front Chem 2021;8:611833. doi:10.3389/fchem.2020.611833
7. ^{^} Flack H.D. Louis Pasteur’s discovery of molecular chirality and spontaneous resolution in 1848, together with a complete review of his crystallographic and chemical work. Acta Crystallogr A 2009;65(Pt 5):371-89. doi:10.1107/S0108767309024088
8. ^ ^{a b} Soderberg T. Organic chemistry with a biological emphasis. Volume I. Chemistry Publications. 2019. https://digitalcommons.morris.umn.edu/chem_facpubs/1
9. ^ ^{a b} Ariëns E.J. Stereochemistry: a source of problems in medicinal chemistry. Med Res Rev 1986;6(4):451-66. doi:10.1002/med.2610060404
10. ^{^} Vantomme G., Crassous J. Pasteur and chirality: a story of how serendipity favors the prepared minds. Chirality 2021;33(10):597-601. doi:10.1002/chir.23349
11. ^{^} Geison G.L. The private science of Louis Pasteur. Princeton University Press, 2014.
12. ^{^} Pasteur L. Memoires sur la relation qui peut exister entre la forme crystalline et al composition chimique, et sur la cause de la polarization rotatoire. C R Acad Sci 1848;26:535‐538.
13. ^{^} Racemate, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. 10.1351/goldbook.R05025
14. ^{^} Tamatam R., Shin D. Asymmetric synthesis of US-FDA approved drugs over five years (2016-2020): a recapitulation of chirality. Pharmaceuticals (Basel) 2023;16(3):339. doi:10.3390/ph16030339
15. ^{^} Evans A.M., Nation R.L., Sansom L.N., Bochner F., Somogyi A.A. The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans. Biopharm Drug Dispos 1990;11(6):507-18. doi:10.1002/bdd.2510110605
16. ^{^} Tokunaga E., Yamamoto T., Ito E., Shibata N. Understanding the thalidomide chirality in biological processes by the self-disproportionation of enantiomers. Sci Rep 2018;8(1):17131. doi:10.1038/s41598-018-35457-6
17. ^{^} Jacobus H. van ‘t Hoff – Facts. NobelPrize.org. Nobel Prize Outreach 2025. Sun. 1 Jun 2025. https://www.nobelprize.org/prizes/chemistry/1901/hoff/facts/
18. ^{^} Capozziello S., Lattanzi A. Geometrical approach to central molecular chirality: a chirality selection rule. Chirality 2003;15:227-230. doi:10.1002/chir.10191
19. ^{^} Ōki M. The chemistry of rotational isomers. New York: Springer; 1993.
20. ^{^} Runge W. The chemistry of the allenes. Vol. 2, Landor S R: Academic Press; 1982.
21. ^{^} Axial chirality, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. doi:10.1351/goldbook.A00547

The phenomenon whereby two or more different chemical compounds share the same molecular formula is called isomerism, from the Greek isos meaning “equal” and meros meaning “part.” The concept and term were introduced by the Swedish scientist Jacob Berzelius in 1830.^[1]
Isomerism arises from the fact that the atoms within a molecular formula can be arranged in different ways to form compounds, called isomers, that differ in their physical and chemical properties.
There are two main types of isomerism: structural isomerism and stereoisomerism, each of which can be further divided into subtypes.^[2]

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 known as constitutional isomerism, isomers differ in the way the constituent atoms are connected to each other, both in bonding sequences and atom arrangement.^[3]
Several subtypes of structural isomerism exist: positional isomerism, functional group isomerism, and chain isomerism.

Positional isomers

In positional isomerism, also called position isomerism, isomers contain the same functional groups but located at different positions along the same carbon chain.^[2]
An example is the compound with molecular formula C₆H₄Br₂, which has three isomers: 1,2-dibromobenzene, 1,3-dibromobenzene, and 1,4-dibromobenzene. These isomers differ in the position of the bromine atoms on the aromatic ring.

Another example is the compound with molecular formula C₃H₈O, which has two isomers: 1-propanol (also known as n-propyl alcohol) and 2-propanol (isopropyl alcohol). These differ in the position of the hydroxyl group (–OH) on the carbon chain.

Functional group isomers

Functional group isomerism, also known as functional isomerism, occurs when compounds with the same molecular formula contain different functional groups.^[2]
An example is the compound with molecular formula C₂H₆O, which has two isomers: dimethyl ether and ethanol (also called ethyl alcohol). These isomers differ in their functional groups: an ether group (–O–) in dimethyl ether, and a hydroxyl group (–OH) in ethanol.

Chain isomers

In chain isomerism, isomers differ in the arrangement of the carbon skeleton, which may be either straight or branched.^[2]
An example is the compound with the molecular formula C₅H₁₂, which has three isomers: n-pentane, 2-methylbutane (also known as isopentane), and 2,2-dimethylpropane (neopentane)

Chain isomerism also occurs in lipids. For instance, among short-chain fatty acids, butyric acid and isobutyric acid (C₄H₈O₂) are chain isomers, as are valeric acid, isovaleric acid, and 2-methylbutyric acid, which share the molecular formula C₅H₁₀O₂.

Stereoisomerism

In stereoisomerism, isomers have the same number and types of atoms and the same bonding sequence, but differ in the spatial orientation of their atoms. Such compounds are called stereoisomers, from the Greek stereos, meaning “solid”.^[4]
There are two subtypes of stereoisomerism: conformational isomerism and configurational isomerism. The latter can be further subdivided into optical isomerism and geometrical isomerism.^[5]

Conformational isomerism

In conformational isomerism, stereoisomers can be interconverted by rotation around one or more single bonds (σ bonds). These rotations generate different spatial arrangements of atoms that are non-superimposable.^[6] The number of possible conformations a molecule can adopt is theoretically unlimited, ranging from the lowest-energy conformation (most stable) to the highest-energy conformation (least stable). Such isomers are called conformer.^[7]
For example, consider ethane C₂H₆. When viewed along the carbon-carbon bond using a Newman projection, the hydrogen atoms of one methyl group can adopt different orientations relative to those of the other methyl group.

• Eclipsed conformation: the hydrogen atoms of one methyl group are aligned directly behind those of the other, resulting in dihedral angles of 0°, 120°, 240°, or 360°. This is the highest-energy (and thus least stable) conformation due to increased electron repulsion.
• Staggered conformation: the hydrogen atoms of one methyl group are positioned between those of the other, giving dihedral angles of 60°, 180°, or 300°. This is the lowest-energy (most stable) conformation, as repulsions are minimized.
• Skew conformation: any intermediate orientation between eclipsed and staggered conformations.

The relative stability of ethane conformers depends on the degree of overlap between the electron pairs in the C–H bonds of the two methyl groups:

• in staggered conformations, these electron pairs are as far apart as possible, minimizing repulsion;
• in eclipsed conformations, they are as close as possible, leading to increased repulsion.

The potential energy barrier between these conformations is relatively low, about 2.8 kcal/mol (11.7 kJ/mol). At room temperature, molecular kinetic energy ranges from 15 to 20 kcal/mol (62.7–83.6 kJ/mol), which is more than sufficient to overcome this barrier. As a result, free rotation occurs around the C–C bond, and individual conformers cannot be isolated.

Note: the potential energy barrier to rotation around carbon-carbon double bonds is approximately 63 kcal/mol (264 kJ/mol), corresponding to the energy required to break the π bond. This value is about three times higher than the average kinetic energy at room temperature, making free rotation impossible under normal conditions. Only at temperatures above 300 °C do molecules acquire sufficient thermal energy to break the π bond, allowing rotation around the remaining σ bond. This permits interconversion between the trans and cis isomers (see geometric isomerism).^[2]

Configurational isomerism

In configurational isomerism, the interconversion between stereoisomers cannot occur through rotation around single (σ) bonds, but instead requires breaking and reforming of covalent bonds. As a result, such interconversion does not occur spontaneously at room temperature.^[7]
There are two subtypes of configurational isomerism: optical isomerism and geometrical isomerism.

Optical isomers

Optical isomerism occurs in molecules that contain one or more chiral centers, which are typically tetrahedral atoms bonded to four different substituents. The chiral center is most commonly a carbon atom, but it can also be phosphorus, sulfur, or nitrogen.^[6]

Optical isomers lack both a center and a plane of symmetry, are non-superimposable mirror images of each other, and are called enantiomers, from the Greek enántios (opposite) and meros (part). Unlike other isomers, enantiomers have identical physical and chemical properties, with two important exceptions.^[8]

• Rotation of plane-polarized light.
  One enantiomer rotates the plane of polarized light in a clockwise direction and is labeled (+), while its mirror image rotates the plane in a counterclockwise direction by the same angle and is labeled (–). This property gives rise to the term optical isomerism.
• Behavior in chiral environments.
  Although enantiomers are indistinguishable by most standard analytical techniques, they behave differently in chiral environments, such as the active sites of enzymes, which are themselves chiral.^[9]

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

Geometric isomers

Geometric isomerism, also known as cis-trans isomerism, occurs when atoms cannot freely rotate due to the presence of a rigid structure, such as:

• double bonds between atoms (e.g., C=C, C=N, or N=N), where rigidity arises from the π bond;
• cyclic structures, where the ring prevents free rotation.^[10]

A classic example of geometric isomerism involving a carbon–carbon double bond is stilbene (C₁₄H₁₂), which exists in two isomeric forms. In the cis isomer, the identical groups are on the same side of the double bond; in the trans isomer, the same groups are on opposite sides.

Note: the terms cis and trans derive from Latin: cis meaning “on this side of” and trans meaning “across”.

Geometric isomerism also occurs in cyclic compounds, especially when the ring contains an even number of carbon atoms and substituents are positioned opposite each other (i.e., para-substituted).^[5] For example, 1,4-dimethylcyclohexane, a cycloalkane (general formula C_nH_2n), exists as two stereoisomers: cis-1,4-dimethylcyclohexane and trans-1,4-dimethylcyclohexane.

This type of stereoisomerism cannot occur if either atom involved in the restricted rotation carries two identical substituents. Why? Because converting between the cis and trans forms requires switching the positions of the groups across the rigid structure. If two groups are the same, the resulting molecule after the “switch” is identical to the original, thus, no distinct isomer is formed.^[7]

Note: geometric isomers are a subclass of diastereomers, which are stereoisomers that are not mirror images of each other. Other types of diastereomers include meso compounds and non-enantiomeric optical isomers.^[11]

References

1. ^{^} Melhado E.M. Jöns Jacob Berzelius. Encyclopedia Britannica, 16 Aug. 2024. https://www.britannica.com/biography/Jons-Jacob-Berzelius. Accessed 3 June 2025.
2. ^ ^{a b c d e} Solomons T.W.G., Fryhle C.B., Snyder S.A. Solomons’ organic chemistry. 12th Edition. John Wiley & Sons Incorporated, 2017.
3. ^{^} Constitutional isomerism, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. doi:10.1351/goldbook.C01285
4. ^{^} Stereoisomerism, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. doi:10.1351/goldbook.S05983
5. ^ ^{a b} North M. Principles and applications of stereochemistry. 1th Edition. CRC Press, 1998.
6. ^ ^{a b} Morsch L., Farmer S., Cunningham K., Sharrett Z., Shea K.M. Organic Chemistry II. Open Educational Resources: Textbooks, Smith College, Northampton, MA, 2023. https://scholarworks.smith.edu/textbooks/6
7. ^ ^{a b c} Morris D.G. Stereochemistry. Royal Society of Chemistry, 2001. doi:10.1039/9781847551948
8. ^{^} Enantiomer, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. doi:10.1351/goldbook.E02069
9. ^{^} Gogoi A., Konwer S., Zhuo G.Y. Polarimetric measurements of surface chirality based on linear and nonlinear light scattering. Front Chem 2021;8:611833. doi:10.3389/fchem.2020.611833
10. ^{^} Hunt I. Stereochemistry. University of Calgary. Retrieved 3 November 2023.
11. ^{^} Diastereoisomerism, in IUPAC Compendium of Chemical Terminology, 5th ed. International Union of Pure and Applied Chemistry; 2025. Online version 5.0.0, 2025. doi:10.1351/goldbook.D01679