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Stereochemistry

Definition: “Stereochemistry refers to the 3-dimensional properties and reactions of molecules.” OR “ It is the study of the static and dynamic aspects of the three-dimensional shapes of molecules.”

The field of stereochemistry is one of the central parts of organic chemistry and includes many important topics. It provides a foundation for understanding structure and reactivity.

Contents:

Isomerism
Stereoisomerism
Optical isomerism
Geometrical isomerism
Molecules with more than one chiral center
Resolution of racemic mixture
Stereochemical Descriptors

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Isomerism

Isomerism: “Two or more than two compounds having same molecular formula (due to similar number of atoms of each element in them) but different structures (due to different arrangement of atoms) are known as isomers and the phenomenon of formation or existence of isomers is called isomerism.”

Isomers: Isomers are different compounds with the same molecular formula. "Iso" means "same" & "mers" means "parts".

Note: Isomers differ in physical and chemical properties.

Basic two types of isomerism:

Constitutional or Structural isomerism: “Structural isomerism, or constitutional isomerism (per IUPAC), is a form of isomerism in which molecules with the same molecular formula have a different connectivity or different bonding patterns and atomic organization.”

Stereoisomerism: “Stereoisomerism is a form of isomerism in which each of two or more compounds with the same molecular formula differ only in the configuration i.e. spatial or three-dimensional arrangement of their atoms.”

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Comparison of Constitutional Isomers and Stereoisomers

Constitutional isomers have:

• different IUPAC names;

• the same or different functional groups;

• different physical properties, so they are separable by physical techniques such as distillation; and

• different chemical properties. They behave differently or give different products in chemical reactions.

Stereoisomers differ only in the way atoms are oriented in space.

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[B]. Stereoisomerism

Definition: “Compounds having same molecular formula, same constitution and same sequence of covalent bonds but differ in the three-dimensional orientations i.e. relative positions of their atoms or groups in space are called stereoisomers and the phenomenon of their formation or existence is called as stereoisomerism.”

Sterioisomers have identical IUPAC names except for a prefix like cis or trans, L or D etc. Because they differ only in the three dimensional arrangement of atoms (called a configuration), stereoisomers always have the same functional group(s).

Types of Stereoisomerism:

Stereoisomerism is of two types:

Configurational Isomerism
Conformational Isomerism

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[1]. Configurational Isomerism:

Definition: “Stereoisomers which cannot be interconverted unless a covalent bond is broken are called configurational isomers or simply configurations and the phenomenon of their formation or existence is called as configurational isomerism.”

The configurational isomerism is again of two types:
Geometrical Isomerism
Optical Isomerism or Enantiomerism

[A]. Geometric Isomerism (also known as cis-trans isomerism or E-Z isomerism):

Definition: "Two or more than two compounds having same molecular formula and same structural formula but due to restricted rotation across a double bond or a ring structure have a different spatial geometry (arrangement of its atoms or groups of atoms in space) are known as Geometric or Cis-Trans Isomers and the phenomenon of their formation or existence is known as Geometric or Cis-Trans Isomerism.”

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Geometric Isomerism results most commonly from Carbon-Carbon double bonds i.e. in alkenes mainly.

The important property which introduces the feature is the inability of the carbon atoms to rotate relative to one another about the double bond. Because rotation will break the double bond. This is due specifically to the Pi bond.

Cis isomer is one in which two similar groups are on the same side of a double bond.
Trans isomer is that in which two similar groups are on the opposite side of the double bond.

Trans isomers are more stable than the corresponding cis isomer. This is because in trans bulky groups are on the opposite side, hence less repulsion or steric hindrance. The alkyl group attached with the double bonded carbon atom of an alkene is known as "bulky group".

Geometrical isomers have different physical and chemical properties. These can be separated by conventional techniques like distillation and gas chromatography etc.

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Example: Consider the case of 2-butene. It exists in two special arrangements i.e. Cis 2-butene and Trans 2-butene.

Conversion of such isomers into each other is only possible if heated at high temperature or absorb light. Energy around 62 Kcal/mole is needed.

Geometrical isomerism in cyclic compounds: Geometrical isomerism is possible in cyclic compounds as well. There should be restriction of rotation if two carbons are linked with a cyclic structure. Example No. 1:

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Example No. 2: Cis and trans isomers are also possible for 1,4-dimethylcyclohexane.

Stereocenter/Stereogenic Centre: “It is a tetrahedral atom, most commonly carbon, at which exchange of two groups produces a stereoisomer.” Its new concept.

E.g. 1,2-dimethylcyclopentane has two stereocenters i.e. both carbons 1 and 2. In this molecule, exchange of H and CH₃ groups at either stereocenter converts a trans isomer to a cis isomer, or vice versa.

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Old Concept of Stereogenic Centre: “It is a tetrahedral atom, most commonly carbon, to which four different ligands or groups are attactced.”
Note: Its new name is assymmetric centre or carbon or chiral centre/carbon. E.g.:

Molecules can contain zero, one, or more stereogenic centers.
With no stereogenic centers, a molecule generally is not chiral. H₂O and CH₂BrCl have no stereogenic centers and are achiral molecules.

With one tetrahedral stereogenic center, a molecule is always chiral. CHBrClF is a chiral molecule containing one stereogenic center.

With two or more stereogenic centers, a molecule may or may not be chiral.

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[B]. Optical Isomerism (Enantiomerism): “Optical isomerism is a type of stereoisomerism in which the isomers are identical in molecular weight and most chemical and physical properties but differ in their effect on the rotation of the plane of polarized light.”

In optical isomers, asymmetry of the molecule as a whole or the presence of one or more asymmetrical atoms is responsible for such effects.

These molecules are not necessarily locked into their positions, but cannot be converted into one another, even by a rotation around a single bond. E.g. Molecular formula C₃H₆O₃ represents two enantiomeric lactic acids as shown below:

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Enantiomers and Diastereomers

[1]. Enantiomers: “When two chiral stereoisomers are non-congruent (non-superimposable) mirror images of each other, they are known as enantiomers.”

Enantiomers have identical chemical and physical properties (IR, NMR, mp, mass spectra, etc.), except for their ability to rotate plane polarized light (+/-) by equal amounts but in opposite directions.

Examples:

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[2]. Diastereomers: “Diastereomers are stereoisomers that are not enantiomers i.e. that are not mirror images of eachother.”

Diastereomers can have different physical properties and reactivity. They have different melting points and boiling points and different densities. They have two or more stereocenters.

Notice that a is the mirror image of b, and C is the mirror image of d. Thus, four isomers are two pairs of enantiomers. Now, compare a and c. They are neither super imposable nor are they mirror images they are called as diastereomers. Thus, a and C and b and d etc. are diastereomers. So, stereo isomers, which are not mirror images are called diastereomers.

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[2]. Conformational Isomerism:

Definition: “The stereoisomers which can be interconverted simply by rapid rotation (twisting) about one or more single bonds (σ bonds) at room temperature without breaking the covalent bond are called conformational isomers (or conformers or rotational isomers or rotamers) and the phenomenon of their formation is known as Conformational Isomerism.”

Conformers interconvert rapidly and a structure is an average of conformers.
Because such isomers can be readily interconverted, they cannot be separated under normal conditions.

Conformation: The shapes that a molecule can adopt due to rotation around one or more single bonds are called conformations.

Two types of conformational isomers are:

Conformational isomers resulting from rotation about single bond.

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(a). Conformational Isomers Resulting from Rotation About Single Bond:

Because the single bond in a molecule rotates continuously, the compounds containing single bonds have many inter-convertible conformational isomers .
Example: 'boat' and 'chair' forms of cyclohexane.

Conformational isomers are normally best seen using Newman Projections as shown below:

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Example: Eclipsed, gauche, and anti butane are all conformational isomers of one another.

(Eclipsed means that identical groups are all directly in-line with one another, gauche means that identical groups are 60 degrees apart from one another, and anti means that identical groups are at 180 degrees from one another).

These molecules can be interconverted by rotating around the central carbon single bond. For example, eclipsed butane can be made into gauche butane by rotating 60 degrees and into anti butane by rotating 180 degrees. Similarly, gauche butane can be made into anti butane by rotating 120 degrees. This rotation can be seen below.

Because of this rotational property, eclipsed, gauche, and anti butane are conformational isomers of one another.

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A Review of Isomerism

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Figure: Simple flowchart for classifying various kinds of isomers.

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For Your Concept

Asymmetric Atom or Asymmetric Center: It is an sp³ carbon atom (mostly) with 4 different groups attached. It is also called as chiral center.

Optically active molecules are those that can rotate the plane of polarized light.
Note: The result of interaction of plane-polarized light with a chiral compound is rotation of the plane of polarization.

Chiral Compound: A compound is said to be chiral if it contains a chiral center. Note: Molecules of most chiral compounds contain one or more stereogenic centers.

Note: Optical activity establishes that a sample is chiral, but a lack of optical activity does not prove a lack of chirality.

�Ordinary light: Light oscillating in all planes perpendicular to its direction of propagation.

�Plane-polarized light: Light oscillating only in parallel planes.

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Ordinary and Plane-Polarized Light

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Plane-Polarized Light through a Chiral Compound

Optical isomers rotate the plane of plane polarised light.

Optical rotation is an inherent property of an optically active compound and is used as a physical constant for characterization of the compound.

Optical rotation depends on the arrangement of atoms or groups around the chiral center—the configuration.

Optical activity is measured automatically with an instrument called a polarimeter.

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Plane-Polarized Light through an Achiral Compound

Polarimetry:

It is a sensitive, nondestructive technique for measuring the optical activity exhibited by inorganic and organic compounds.

Historically, the most common technique used to detect chirality and to distinguish enantiomers has been to determine whether a sample rotates plane polarized light.

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A Light source produces light vibrating in all directions

B Polarising filter only allows through light vibrating in one direction

C Plane polarised light passes through sample

D If substance is optically active it rotates the plane polarised light

E Analysing filter is turned so that light reaches a maximum

F Direction of rotation is measured coming towards the observer

Polarimeter: “A device for measuring the extent of rotation of plane-polarized light.” OR “An instrument that measures the optical rotation of the chiral compound.”
Polarimeters can be used to analyse the effect that optical isomers have on plane polarised light.

Polarimeter

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Polarimeter

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Measurement of Optical Rotation: We can measure optical rotation, the direction and the degree (angle) of rotation by using a polarimeter.

1. Ordinary light vectors (lines) oscillate randomly (in all directions); it is symmetrical. When ordinary light is passed through a Nicol prism (polarizer), only the light whose electric and magnetic vectors oscillate in one specific direction (plane) can pass. The light so becomes plane polarized light.

2. When plane polarized light passes through a solution of chiral molecules the plane of polarization is rotated by a certain angle in a certain direction, either clockwise or counter-clockwise (that’s why chiral compounds are said to be optically active).

3. Compounds that rotates light clockwise (towards right) are called dextrorotatory (dexter is Greek word that means “right”); they are designated by a prefix of (+) or D before their names. Compounds that rotate light to the left (anticlockwise) are called levorotatory (Greek for left); they are designated by a (–) or letter L in front of their names.

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Factors Affecting Angle of Rotation

(1). The measured angle of rotation, α, depends on several factors, including the type of molecule and the number of molecules in the light path; this quantity is given by concentration, c, of the chiral substance and

(2). the distance light travels through the solution, the cell length, l.

Other factors include (3). the temperature and (4). wavelength of the polarized light.

We combine these factors in defining the specific rotation, [α], which is the observed rotation of an optically active substance in a solution at a concentration of 1.0 g/mL, and a path length, l = 1.0 dm (10 cm).

OR The number of degrees by which an optically active compound rotates the plane of polarized light is called its specific rotation and is given the symbol [α].

The specific rotation is calculated from the measured rotation, α, as follows:

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The temperature (T) and wavelength (λ) are indicated by superscripts and subscripts, respectively.

It is common practice to report the temperature (in °C) at which the measurement is made. The most common wavelength of light used in polarimetry is the sodium D line, the same wavelength responsible for the yellow color of sodium-vapor lamps.

Absence of Optical Activity:

When we detect optical activity, we can be sure that a chiral compound is present. But, failure to observe optical activity does not mean that no chiral compound is present.

Each compound with an asymmetric C-atom has two enantiomers, each rotating light with the same magnitude of specific rotation, but rotating light in opposite directions, one to the right (+) and one to the left (–).

If we have a 50-50 mixture of the pair of enantiomers, we observe NO rotation at all, because the two rotations, equal in magnitude but opposite in direction, cancel each other.

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Biological Importance of Sterioisomerism

Nature is inherently chiral because the building blocks of life (α-amino acids, nucleotides and sugars) are chiral & appear in nature in enantiomerically pure forms.

[1]. Amino Acids: They are generally homochiral—all amino acids have the same sense of chirality (left Handed or L).

There are twenty common amino acids, and all except one (glycine) are chiral. Amino acids have a central carbon, called an α-carbon, bonded to an NH₂group and a COOH group.
18 of the 19 α-carbons of amino acids have the R configuration, one has the S configuration.

[2]. Sugars: All sugars have the same sense of chirality (Right handed or D). As the receptor sites are chiral, (+)-glucose is metabolized by animals but NOT (-) glucose.

[3]. Enzymes: The chirality of the amino acids leads to chiral enzymes, which in turn produce chiral natural products.

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Any synthetic substance (drug) to interact with or modify nature are interacting with a chiral environment.

This is an important issue for bio-organic chemists, and a practical issue for pharmaceutical chemists.

The Food and Drug Administration (FDA) now requires that drugs be produced in enantiomerically pure forms, or that rigorous tests be performed to ensure that both enantiomers are safe.

Many drugs are optically active, with one enantiomer only having the beneficial effect.

In the case of some drugs, the other enantiomer can even be harmful, e.g. thalidomide.

The conversion of one enantiomer into a racemic mixture is called racemization.

Pharmaceutical Importance of Sterioisomerism

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Example No. 1, Thalidomide: Thalidomide occurs as a racemic mixture.

The S isomer is a sedative and has teratogenic side effects.

The R isomer is also a sedative but has no teratogenic activity. However, the enantiomers are converted into each other in vivo.

Dosing with a single-enantiomer form of the drug will still lead to both the S and R isomers eventually being present in the patient's serum and thus would not prevent adverse effects.

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Example No. 2: Many natural compounds such as enzymes are not symmetrical. Thus individual enantiomers will react with enzymes to give different results. As is the case of epinephrine given below:

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For proper actions, binding of drugs to receptor needs to be properly matched sterio-chemically at receptor sites.

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Example No. 3: One enantiomer of a drug may effectively treat a disease whereas its mirror image may be ineffective or toxic e.g. Naproxen.

Example No. 4: L-dopa is more rapidly absorbed than its enantiomer D-dopa.

Example No. 5: A large number of chiral drugs, however, are sold as racemic mixtures. The popular analgesic ibuprofen is an example.

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Resolution of Racemic Mixture

��Resolution (Optical Resolution): “The resolution of racemates or racemic mixture is the separation of an equimolar mixture of enantiomers (racemate) into its individual component enantiomers by physical, chemical or bio-chemical methods.”

Racemic Mixture OR Racemic Modification, OR Racemate: “A mixture consisting of equal amounts (50:50) of an optically active isomer and its enantiomer is termed as racemic mixture, racemic modification, or racemate.”

Because a racemic mixture contains equal numbers of dextro-rotatory and levo-rotatory molecules, it exhibits no optical activity i.e. its specific rotation is zero and so it does not rotate plane polarized light because the activities of the individual enantiomers are equal and opposite in value, thereby canceling each other out.

Secondly, safety will not be ensured until the elimination of the toxic enantiomer. Thus enantiomers must be separated in order to observe the optical activity and to produce optically pure and safe active drugs.

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Enantiomers have identical physical properties, and consequently cannot be directly separated by conventional methods such as distillation, crystallization, sieving, or chromatography on conventional stationary phases.

Diastereomers have different physical properties like b.p, m.p, density, refractive index, solubility etc., so can be separated through conventional means (distillation, recrystallization, chromatography).

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Resolving Agent:

“A chiral probe or resolving agent is a chiral compound used to reversibly separate components of a racemate (racemic mixture) by making a derivative of each enantiomer that is free of its enantiomer.”
Enantiomers have the same physical properties, but they differ in a chiral sense, so a chiral probe must be used for such a separation.
Any optically pure chiral organic acid or base may be a candidate as resolving agent.

Characteristics of an ideal resolving agent:

It should be a strong acid or base to secure formation of stable salts with weakly basic or acidic racemates, respectively.
The center of chirality should be as close as possible to the functional group involved in salt formation to provide significant differences in the stereostructure of the diastereomeric salts.
Both enantiomers should be available.
It should be chemically stable and should not racemize under the conditions of resolution.
It should be non-toxic, readily recoverable and starting materials for its preparation should be readily available and inexpensive.

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Various methods and techniques for the separation of enantiomers exists, though not all methods are equally applicable for every racemic mixture.

For each method, several advantages and disadvantages prevail, depending upon factors such as time, purity, chemical processing, and inherent side reactions.

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[1]. Chemical Resolution

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[1]. Chemical Resolution:

It is a typical procedure for the resolution of chiral compounds. Here we react the racemic mixture with an enantiomerically pure compound.

This gives rise to a pair of diastereomers – which have different physical properties and therefore can be separated based on their differing solubility or via suitable chemical reaction.
The resolving agent is then cleaved off, leaving pure separated enantiomers.

Example:

Alcohols react with the enantiomerically pure tartaric acid, to give two diastereomeric esters.
These diasteromeric derivatives can be separated by conventional separation methods such as crystallization, or chromatography on silica or other conventional stationary phases.
After separation of the diastereomers, acid hydrolysis cleaves each ester back to an optically active alcohol and carboxylic acid.
The enantiomerically pure resolving agent (tartaric acid) is recovered and often recycled.

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[2]. Chiral Chromatography:

“Chiral Chromatography is a branch of chromatography that is oriented towards the exclusive separation of chiral substances by the use of chiral phases.”

It is a variant of column chromatography in which the stationary phase contains a single enantiomer of a chiral compound rather than being achiral.

The two enantiomers of the same analyte compound differ in affinity to the single-enantiomer stationary phase and therefore they exit the column at different times.

For the smaller scales associated with the research laboratory, it is increasingly becoming the method of choice for analyzing and separating mixtures of enantiomers.

The mobile phase can be a gas or liquid giving rise to chiral gas chromatography and chiral liquid Chromatography.

Chiral selectivity is usually achieved by employing chiral stationary phases, although, in chiral liquid chromatography, chiral mobile phases have been successfully employed.

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Example: The most common method for the enantiomeric resolution of ibuprofen enantiomers and chiral materials in general is high performance liquid chromatography (HPLC). Chromatography is often much faster and more efficient than crystallization.

Two important techniques employed for the direct separation of enantiomers by chromatography on chiral stationary phases (CSP) include:
Construction of a chiral stationary phase or
Prederivatization of the individual enantiomers to produce the diastereisomeric pair.
In most instances ethyl chloroformate is used to couple a chiral ligand to the racemic enantiomers in order to produce the diastereoisomeric pair.
The most successful chiral packing materials comprise the derivatives of cellulose, amylose, cyclodextrins, proteins, and amino acids.

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[3]. Bio-Resolution:

It was introduced by Pasteur in 1858. This method is based on fact that when certain micro organisms like bacteria, fungi, yeast, moulds, etc. are grown in dilute solution of racemic mixture, they eat up one enantiomer rapidly than other.
If the microorganism is wisely chosen, the desired enantiomer is the only thing that remains and can then be separated from the mixture by common separation techniques.

Example No. 1: The mould Penicillium glaucum preferentially destroys the (+) isomer of racemic ammonium tartarate leaving (-) ammonium tartarate in solution.

Example No. 2: Enzymes are chiral catalysts which often exhibit very high selectivity for one enantiomer of a racemic mixture.
A continuous process has been described for the enantiospecific hydrolysis of the ethoxyethyl ester of naproxen using a column packed with Candida cylindracea immobilized on an ion exchange resin.
(S)-naproxen is prepared by enzymatic hydrolysis of these racemic esters.
Though not exclusively, one enantiomer in general "fits" better on the active site and is therefore converted to its corresponding ester at a higher rate.

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The advantage of the enzymatic method is the high enantiomeric excess, resulting from the inherent selectivity of the enzyme. The enzyme is reusable and the products of the reaction are easy to separate.
The disadvantages of this method are related to the number of parameters that must be optimized for the enzyme and the selectivity of the system is limited by the extent of conversion.

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[4]. Physical/Mechanical Separation Methods:

This method was first used successfully by Louis Pasteur for the resolution of sodium ammonium tartarate which crystallise out in the form of racemic mixture below 27 degree.

This involved mechanical separation of the crystals of one enantiomer from the other in racemic mixture based on difference in their shapes. Crystal of the two forms have different shapes separated by magnifying lens and forceps.

In the crystallization process, the enantiomers crystallize separately and form two macroscopically different kinds of crystals with a mirror-image relationship. These crystals can be separated manually with a pair of tweezers.

This methods is time consuming and every compound can not be crystallized at room temperature.

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There are two primary methods of crystallization for enantiomeric resolution.

[A]. Preferential crystallization: This method involve seeding of a saturated solution of the racemic mixture with a pure crystal of one the two enantiomers. The soluition now become supersaturated with respect to the added enantiomers. It begins to crystallize out. This process requires no resolving agent.

[B]. Diastereoisomeric crystallization (most attractive method): Derivatization of racemic compounds is possible with resolving agent (optically pure reagents) forming pairs of diastereoisomers (e.g. salt formation between an amine and a carboxilic acid) which can be separated by conventional techniques in chemistry and finally simple deprotonation affords the pure enantiomer.

Note: Diastereoisomeric crystallization has been the dominant technique among industrial pharmaceutical companies for the resolution of ibuprofen enantiomers. This method is often referred to as classical resolution.

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[5]. Kinetic Resolution of Enantiomers:

This method is based on the fact that one of the enantiomer of racemic mixture reacts faster than other with the resolving agent (optically active enantiopure compound).
Treatment of a racemic mixture with a limited amount of a chiral reagent will convert one of the enantiomers to product in preference to the other. Since this is based on different reaction rates, the separation technique is called kinetic resolution.
If the difference is large enough, the enantiomers can be separated by stereoselectively converting only one of the enantiomers, while the desired enantiomer remains. After workup one enantiomer will be recovered unchanged while the other will have been converted to a new different chiral product.

Example: Menthol reacts faster with (+) mandelic acid than with (-) mandelic acid. Thus with difference in kinetics of reaction, racemic mixture can be seperated.

Important Condition: The efficiency of the kinetic resolution will depend on the relative rates of reaction of the two enantiomers. If rates of reaction (selectivity factor) vary by > 100, then the recovered enantiomer will be >99% optically pure. Lower selectivity factors will lead to less pure enantiomers.

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After separation,

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[6]. Precipitation: This method is based on formation of precipitate by reaction between any reagent and racemic mixture. Example: (+) narcotine & (-) narcotine when dissolved in HCL, precipitates (+) narcotine.

(Narcotine an alkaloid present in opium; used as a nonaddictive antitussive.)

Other Resolution Methods:

Gas chromatography-mass spectrometry (GCMS), electrochromatography, capillary electrophoresis and nuclear magnetic resonance (NMR) have also been utilized as potential analytical techniques in enantiomeric separation of ibuprofen. These methods have proven to be less useful due to their inability to achieve baseline resolutions or their inability to remove the free acid of ibuprofen after separation.

A recent development in the separation of ibuprofen enantiomers has been in supercritical fluid chromatography. The most commonly used supercritical fluid is carbon dioxide, which has chemical inertness and low toxicity.

Supercritical fluid chromatography (SFC) behaves in a way similar to normal phase high pressure liquid chromatography, but can be run three to ten times faster than normal phase HPLC.

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Stereochemical Descriptors

Descriptor: “A descriptor is in chemical nomenclature a prefix placed before the systematic substance name, which describes the configuration or the stereochemistry of the molecule.”

Types of Stereochemical Descriptors:

In stereochemistry, following types of descriptors are usually used:

(R)/(S) Notation (As per Cahn-Ingold-Prelog (CIP) Sequence Rules).
E and Z System.
Cis and Trans System (Already discussed).
D and L System.
Erythro and Threo System.

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[1]. (R)/(S) Notation (As Per Cahn-Ingold-Prelog (CIP) Sequence Rules):

For tetracoordinate carbon and related structures we use the Cahn–Ingold–Prelog system. Cahn, Ingold and Prelog introduced this systematic notation during the period 1951-1956.

This notation allows us to define in an unambiguous manner the absolute configuration of a drawn stereogenic centre by assigning it as either (R) or (S).

In order to use this notation the first thing to do is to assign an order of priority to the atoms of the groups directly attached to a stereogenic centre.

In order to make this easy to remember a set of rules for specifying the configuration about a stereocenter are used.

In this system highest priority group is given number 1, whereas the lowest priority group is given number 4.

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Priority Rules:

Rule 1: Each atom bonded to the chiral center is assigned a priority based on atomic number; the higher the atomic number, the higher the priority. Lone pairs of electrons are assigned the lowest priority.

Rule 2: Molecules where two or more of the atoms directly attached to the stereogenic centre are the same, look to the next set of atoms; priority is assigned at the first point of difference.

Rule 3: If two atoms bonded to the stereogenic center under comparison are isotopes, the one with higher mass is assigned the higher priority. Example: In comparing the three isotopes of hydrogen, the order of priorities is:

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R,S Priorities of Some Common Groups

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Rule 4: Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds.

Rule 5: Having established the priorities, we now view the molecule so that the atom/group with lowset priority is pointing away from us in space.

Finally, we count around the face of the molecule which is pointing towards us the three other groups in order of decreasing priority.

If moving from the highest (#1), to the second (#2), to the third (#3) priority ligand involves a clockwise direction, the center is termed R (for "Rectus" → Latin= "right").

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An anti-clockwise decreasing order defines an (S)-configuration (S for "Sinister" → Latin= "left"). The R or S is then added as a prefix, in parenthesis, to the name of the enantiomer of interest.

Example No.1: In (+)-glyceraldehyde the order of priority of the groups is OH > CHO > CH₂OH > H and the configuration is (R).

Figure: Group 1 is highest priority, group 4 is lowest priority