Stereochemistry

Md. Didarul Islam

 Isomerism> Definition

 Isomerism is the phenomenon in which more than one

compounds have the same chemical formula but different
chemical structures.
 Chemical compounds that have identical chemical formulae
but differ in chemical and physical properties and the
arrangement of atoms in the molecule are called isomers and
the phenomenon is termed Isomerism
 Isomerism> Classification
Isomer

Stereoisomers
Structural
Can the compounds be interconverted
by rotation about single bonds
Chain NO YES

Positional
Configurational Conformational
Functional
YES Is isomerism due to restricted rotation
NO
Metamerism
Geometric Optical
(cis-trans) Are the compounds non-superimposable
Tautomerism mirror images
NO YES
Ring-chain
Diastereomers Enantiomers
 Isomerism> Classification
Isomerism Types
There are two primary types of isomerism, which can be further categorized into different subtypes.
1. Structural Isomerism
2. Stereoisomerism
1. Structural Isomerism
Structural isomerism is commonly referred to as constitutional isomerism. The functional groups and the atoms in the
molecules of these isomers are linked in different ways. Molecules having the same molecular formulas, possessing
different structural formulas are known as structural isomers and the phenomenon is known as structural isomerism.
Chain Isomerism
 It is also known as skeletal isomerism.
 The components of these isomers display differently branched structures.
 Commonly, chain isomers differ in the branching of carbon
 An example of chain isomerism can be observed in the compound C5H12, as illustrated below.
 Isomerism> Classification
Position Isomerism
 The positions of the functional groups or substituent atoms are different in
position isomers.
 Typically, this isomerism involves the attachment of the functional groups to
different carbon atoms in the carbon chain.
 An example of this type of isomerism can be observed in the compounds having
the formula C3H7Cl.

Functional Isomerism
 It is also known as functional group isomerism.
 As the name suggests, it refers to the compounds that have the same chemical
formula but different functional groups attached to them.
 An example of functional isomerism can be observed in the compound C3H6O.
 Isomerism> Classification
Metamerism
 This type of isomerism arises due to the presence of different alkyl chains on each
side of the functional group.
 It is a rare type of isomerism and is generally limited to molecules that contain a
divalent atom (such as sulphur or oxygen), surrounded by alkyl groups.
 Example: C4H10O can be represented as ethoxyethane (C2H5OC2H5) and
methoxy-propane (CH3OC3H7).

Tautomerism
It is a special type of functional isomerism in which the isomers are in dynamic equilibrium with each other.
 A tautomer of a compound refers to the isomer of the compound which only differs in the position of
protons and electrons.
 Typically, the tautomers of a compound exist together in
equilibrium and easily interchange.
 It occurs via an intramolecular proton transfer.
 An important example of this phenomenon is Keto-enol
tautomerism.
 Isomerism> Classification
Ring-Chain Isomerism
 In ring-chain isomerism, one of the isomers has an open-chain structure whereas
the other has a ring structure.
 They generally contain a different number of pi bonds.
 A great example of this type of isomerism can be observed in C3H6. Propene and
cyclopropane are the resulting isomers, as illustrated below.
 Isomerism> Classification
2. Stereoisomerism
This type of isomerism arises in compounds having the same chemical formula but different orientations of the atoms
belonging to the molecule in three-dimensional space. In other words, stereoisomer is exhibited by such compounds
which have the same structural formula but different configuration. The compounds that exhibit stereoisomerism are
often referred to as stereoisomers. This phenomenon can be further categorized into two subtypes. Both these subtypes
are briefly described in this subsection.
Geometric Isomerism
 It is popularly known as cis-trans isomerism
 These isomers have different spatial arrangements of atoms or groups about the three-dimensional space.
 They must have a bond restriction.
 The cis isomer is one in which two similar groups are on the same side of the bond restricting the C-C bond. The
trans isomer is one in which two similar groups are on the opposite side
 Trans isomers are more stable than the corresponding cis isomers.
An illustration describing the geometric isomerism observed in the But-2-ene molecule is provided below.
 Isomerism> Classification

Question:
Is it possible to find out the geometric isomerism of the following compound? If possible then figure out the cis
and trans isomers
a. CH3-CH2-CH=CH-CH2-CH3
b. COOH-CH=CH-COOH
 Isomerism> Classification
Optical Isomerism
 A substance that has the ability to rotate the plane of polarized light is said to be optically active and exhibits
optical isomerism.
 Light from ordinary electric lamp is composed of waves vibrating in many different planes. When it is passes
through Nicol prism (made of CaCO3) or polaroid lense, light is found to vibrate in only one plane, and is said to
be plane-polarized or simply polarized.
 Compounds that exhibit optical isomerism feature similar bonds but different spatial arrangements of atoms
forming non-superimposable mirror images.
 These optical isomers are also known as enantiomers.
 Enantiomers differ from each other in their optical activities.
 Optical activity in a compound is detected and measured by means of a polarimeter.
 Dextrorotatory enantiomers rotate the plane of polarized light to the right (clockwise), whereas Levorotatory
enantiomers rotate it to the left (anti-clockwise).
 All organic compounds containing one asymmetric carbon atom are optically active.

Figure: A simple polarimeter in operation.

 Isomerism> Classification
Specific rotation:
Specific rotation is defined as the rotation produced by a solution of length 10 centimeters and unit concentration
(1g/ml) for the given wavelength of light at the given temperature. The specific rotation of a given substance can be
calculated by using the following expression:

Chiral (or Asymmetric) Carbon Atom:

A Carbon atom which is bonded to four different atom or groups is called a Chiral (or Asymmetric) Carbon
Atom. For example,
 Isomerism> Classification
Optical isomerism of Lactic acid:
Lactic acid (2-hydroxypropanoic acid) is an example of a compound which shows optical isomerism. It contains
one chiral carbon atom.
 Isomerism> Classification
Optical isomerism of Tartaric Acid:
Tartaric acid (2,3-dihydroxybutanedioic acid) is an example of a compound which shows optical isomerism. It
contains two chiral carbon atom.
 Isomerism> Classification
Enantiomer
Enantiomers can be defined as one of two different stereoisomers of a compound which is the mirror
image of the second stereoisomer of that compound. Enantiomers can be classified as specific types of
optical isomers. It is important to note that two enantiomers of a compound must be non-superimposable
on each other. Therefore, enantiomers can be alternately defined as optical isomers that are non-
superimposable mirror images of each other. The presence of a single chiral atom (or a structural feature
in a compound that results in something similar) can result in the compound as a whole having two
different possible structures, each of which are non-superimposable mirror images of each other.
 Isomerism> Classification
Diastereomer
Diastereomers are defined as compounds that have the same molecular formula and are optically active but
not mirror images and are non-superimposable.
Diastereomers have different physical properties. Thus they have different melting points, boiling points,
solubilities in a given solvent, densities and refractive indices.

In the above a and b are optical enantiomers and so are forms c and d. While a and c are not mirror
images and yet they are optically active. Similarly, the other two forms b and d are also optically active
but not mirror images which means those couples are diastereomers.
 Isomerism> Classification
Asymmetric or dissymmetric molecules
A carbon atom is described as being asymmetric when four different atoms or groups are bonded to it. All
asymmetric carbon atom based compounds are optically active. For example, lactic acid, amyl alcohol etc.
Those molecules which have asymmetric molecular structures in tetrahedral perspective are called
asymmetric molecules. The two feature \s of such structures are

1. No Plane of Symmetry. A “plane of symmetry” is a plane which divides an object in such a way that
the part of it on one side is the mirror image of that on the other side of the plane.
Similarly, an organic molecules is asymmetric if it has no plane (or center) of symmetry. For example,
 Isomerism> Classification
2. Nonsuperimposable on its Mirror Image. An asymmetric object can not be superimposed on its
mirror image. Thus the right hand produces a mirror image which is identical with left hand. The two
hands are nonsuperimposable while a symmetric object like a ball can be superimposed on its mirror
which is another similar ball.
 Isomerism> Classification
Meso compounds
A meso compound is a stereoisomer with two or more chiral centers but no optical activity due to an
internal plane of symmetry. Mesomers are compounds with zero net rotation of plane polarized light.
In other words, mesomers are organic molecules that have two chiral carbons that are identical, resulting in
zero net rotation.
 Isomerism> Classification
Number of Optical Isomers
A compounds having two dissimilar carbon atoms can exist in four optically active forms. Reasoning in
the same fashion, we will find that a compound containing three such asymmetric carbon atoms can exist
in eight different configurations which represent optical isomers. Thus in general, the number of
stereoisomers for a compound with n distinct asymmetric carbon atoms is 2n
 Isomerism> Classification
Racemic mixture/racemic modification
Racemic mixture or racemic modification, also called racemate, is a mixture of equal quantities of two
enantiomers, or substances that have dissymmetric molecular structures that are mirror images of one
another. Each enantiomer rotates the plane of polarization of plane-polarized light through a characteristic
angle, but, because the rotatory effect of each component exactly cancels that of the other, the racemic
mixture is optically inactive.
Racemic acid, or, more properly, racemic tartaric acid, is a mixture of equal amounts of dextrorotatory and
levorotatory tartaric acids; it is customarily designated D or L, or (+) or (–), respectively, tartaric acid.
The process by which an optically active substance is transformed into the corresponding racemic
modification is known as racemization; the converse process, by which a racemic modification is
separated into the two enantiomers, is known as resolution.
 Isomerism> Classification
Resolution Of Racemic Mixtures
Synthesis of an optically active compound produces a mixture of both (+) and (-) isomers in equal amounts.
Such a mixture is called a racemic mixture or a racemate. The separation of a racemic mixture into its two
optically active components (+ and - isomers) is known as Resolution. The following methods are used
(1) Mechanical Separation (Pasteur, 1848). This method is applicable only to solid substances which form
well-defined crystals. Frequently the racemic mixtures consist of two types of crystals that have different
shapes, being the mirror images of each other.
The two varieties of crystals can be separated with the aid of a magnifying lens and small forceps. Since the
crystals of one type are all d-isomer and the crystals of the other types are l-isomer, their separation leads to the
resolution of the racemic mixture. This method is too tedious for practical purposes and is now of historical
interest only because it was the first method that Pasteur employed for the separation of tartaric acids.
(2) Biochemical Method (Pasteur, 1858). In this method, the resolution is affected by destroying one form
(d- or l.) by a biochemical process. When certain micro-organisms such as yeast, moulds and bacteria are
allowed to grow in the solution of a racemic mixture, they assimilate one form selectively leaving the other in
the solution. The separation is almost complete so that the form left in the solution can be isolated by fractional
crystallization. For example, if ordinary mould, Pinicillium glaucum, is added to a solution of dl-tartaric acid,
the solution becomes levorotatory due to the destruction of dextro form. The selective consumption of one
isomer is believed to be due to the asymmetry and optical activity of the enzyme present in the micro-organism.
 Isomerism> Classification
(3) Chemical Method (Pasteur, 1858). This is the most general method of resolution. In this method. the dl-
mixture is united with another suitable optically active isomer when the products are no longer mirror image
isomers and may be separated by crystallization.
For example, a solution of racemic lactic acid may be treated with an optically active base such as alkaloid l-
brucine. The resulting product will consist two salts:
(i) d-Acid. l-Base
(ii) l-Acid. t-Base
The relation of the configurations of the two salts may be explained by the following illustration. Suppose the
two enantiomorphic forms of lactic acid are represented by the symbols
Inception of the configurations of the two salts shows
that they are not enantiomorphic. Therefore, they have
different solubility in water and can be separated by
fractional crystallization. The isolated salts are then
treated with dilute sulphuric acid when the optically
active acids are regenerated.
Similarly, a racemic mixture of a base can be resolved,
by combination with an optically active acid such as d-
tartaric acid. A racemic mixture of alcohols may be
resolved by esterification with an optically active acid.
 Isomerism> Classification
(4) Kinetic Method (Markwald, McKenzie, 1899). The fact that enantiomers react with an optically. active
substance at different rates is used for the separation of racemic mixtures: Thus, l menthol (an alcohol) reacts
faster with d-mandelic acid (C6H5CHOHCOOH) than l-mandelic acid to form ester. Therefore; when racemic
mandelic acid is esterified with a limited quantity of l-menthol, the product is richer in dl'-ester than ll'-ester
which upon hydrolysis gives partially resolved mandelic acid.
(5) Selective Adsorption. Sometimes 'resolution' may be achieved by passing a solution of the recemate
over a column of a finely powdered, optically active adsorbent such as starch, sugar or quartz. The surface of
the adsorbent, adsorbs selectively one enantiomer and thus the solution emerging at the bottom is richer in
the other enantiomer. In this way partial resolution is affected
 Isomerism> Classification
The conversion of an optically active compound into a racemic mixture is called racemization. Recall: A
racemic mixture is a mixture containing equal amounts of (+) and (-)-isomers. Thus,

Racemization can be accomplished by means of heat, light, or by conversion of the isomer into an optically
inactive intermediate which reverts to the racemic mixture. The conversion of either of the optically active
lactic acids into a racemic mixture by heating its aqueous solution may proceed through an enol intermediate.

When the proton migrates back to the carbon atom, the process can involve the opening of either of the two
linkages of the double bond and can produce either the original configuration or the opposite of it.
 Isomerism> Classification
Rotational (conformational) isomerism
Some parts of the molecule may rotate compared to other parts of the molecule, around the bonds of the molecule
especially around single bonds.
For example, a methyl group in an ethane molecule may rotate around carbon-carbon bonds. The spatial
structures received by rotation are called conformations, and the molecules are called conformational or
rotational isomers (conformers or rotamers).
 Isomerism> Classification
Optical Activity Without Chiral Carbons
Compounds containing a chiral carbon Can exist in optically active forms. However, compounds that do not possess a chiral
carbon atom can also exist in optically active forms provided that the molecule is dissymmetric. Example are:
(1) Allene Derivatives
Some derivatives of allene (CH2=C=CH2) exhibit optical isomerism. Example is 1,3-diphenyl propadiene.

(2) Biphenyl Derivatives

Substituted biphenyls show optical isomerism when substituents in the 2-positions are large enough to prevent rotation about
the bond joining the two benzene rings. For example, biphenyl 2,2’-disulfonic acid exists in two forms.
 R and S configuration
Assigning R and S Configuration: Steps and Rules
To assign the absolute configuration, we need to first locate the carbon(s) with four different groups (atoms)
connected to it. These are called chirality centers (chiral center).
Step 1:
Give each atom connected to the chiral center a priority based on its atomic number. The higher the atomic
number, the higher the priority.
So, based on this, bromine gets priority one, oxygen gets priority two, methyl carbon is the third and
hydrogen is the lowest priority-four:
Step 2:
Draw an arrow starting from priority one and going to priority two and then to priority 3:
If the arrow goes clockwise, like in this case, the absolute configuration is R.
As opposed to this, if the arrow goes anti-clockwise then the absolute configuration is S.
 R and S configuration
And this is another important thing to remember:
All the chirality centers in enantiomers are inverted (every R is S, and every S is R in the enantiomer).
So, we discussed the roles of priorities 1, 2, and 3 but what about the lowest priority? We did not mention
anything about the arrow going to it. Is it part of the game and how do you use it?
The lowest priority does not affect the direction of the arrow. However, this is very important, and it is a
requirement when assigning the R and S configuration, that;
In other words, the lowest priority must be a dashed line to assign the R and S based on the direction of the
arrow as we just did:
 Examples
Bromine is the priority and the hydrogen is number four. Carbon “a” is connected to one oxygen and two
hydrogens. Carbon “b” is connected to one oxygen and one hydrogen. However, because of the double
bond, carbon “b” is treated as if it is connected to two oxygens. The same rule is applied for any other
double or triple bond. So, when you see a double bond count it as two single bonds when you see a triple
bond cut it as three single bonds.
Examples
Examples
 Isomerism> Classification
Fischer Projections
Fischer projections provide an easy way to draw three-dimensional molecules on paper. All atoms are projected
onto one plane. The Fischer projection of one of the enantiomers of lactic acid is shown below:

The Fischer rules for showing the arrangement around a Chiral carbon are as follows:
1. The carbon chain of the compound is arranged vertically, with the most oxidized carbon at the top. Or, put
the carbon number l (as defined by nomenclature rules) at the top.
2. Represent the chiral carbon (s) at the intersection of crossed lines.
3. Groups attached to the vertical lines are understood to be going back behind the plane of the paper. That is,
the vertical lines represent bonds going away from the observer. The Chiral carbon is in the paper plane.
4. Groups attached to the horizontal lines are understood to be coming forward out of the paper plane. That is,
the horizontal lines represent bonds coming toward the observer.
 Thank you

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