STEREOISOMERISM
Unit I
Prof. Neelaveni Thangavel
PHARMACEUTICAL ORGANIC CHEMISTRY III THEORY, BP401T
B.Pharm, IV semester
Prepared on 10.09.2024
Introduction
• Stereochemistry deals with the spatial arrangements
of atoms or groups in a molecule.
• Stereoisomerism is exhibited by isomers having the
same structure but different spatial arrangements
(Configuration) eg., Glyceraldehyde, Glucose
• Different configurations are possible because carbon
forms directional covalent bonds (explain)
• Two types of stereoisomerism: Optical isomerism and
Geometrical isomerism (cis-trans isomerism)
OPTICAL ISOMERISM
• Exhibited by compounds having the same molecular structure but
different configuration
• Asymmetric
• Exhibited by crystalline or molecular structures which are NOT
SUPERIMPOSABLE MIRROR IMAGES
• Optically active
• Optical activity is the rotation of the plane of polarization of plane-
polarized light to right or left
OPTICAL ACTIVITY
• May be due to crystalline structure
• These are active in solid state only.eg., Quartz, benzil, sodium chlorate
• Exist in 2 crystalline forms..enantiomorphs..one is dextro rotatory and
the other is levo rotatory
• Crystals are mirror images but non-superimposable
• When fused optical activity is lost. Fusion, vaporization, or solution in
a solvent causes loss in optical activity
OPTICAL ACTIVITY
• May be due to asymmetry in the molecular structure
• Optically active in fused, vaporized, or dissolved state
• Eg..glucose, tartaric acid
• Enantiomorphs, optical antipodes, or optical isomers
Properties of enantiomorphs:
They rotate the plane polarized light in an equal and opposite manner
Exhibit CIRCULAR DICHROISM or COTTON EFFECT: absorption coefficients
for right and left circularly polarised lights are different. This character is
applied in spectroscopy to study the structure of biological molecules and
drugs, their properties, and their interactions.
TETRAHEDRAL CARBON ATOM
• Optical isomerism is due to the asymmetry (essential requirement) of
the molecule, which is due to the tetrahedral arrangement of a
carbon atom and its valence bonds.
• In practice, Ca2b2 or Ca2bd type of molecules, only one form exists
and that coincides with the tetrahedral arrangement.
• In practice compounds with four different valencies, Cabde, exist in a
pair of enantiomorphs which coincides with the tetrahedral
arrangement
• Conversion of D- lactic acid and L- lactic acid forms the same
compound, Propionic acid which is optically inactive, this proves that
C exists in tetrahedral configuration
TETRAHEDRAL CARBON ATOM
• Interchanging any two groups will form the enantiomorph, this proves
the C is tetrahedral.
• X-ray crystallography, dipole moments, absorption spectra, and
electron diffraction studies prove that C is tetrahedral.
• Two postulates underlying tetrahedral theory:
• Principle of constancy of the valency angle: Quantum mechanics
reveal that the four bonds of carbon are directed towards regular
tetrahedron and the bond angles are equivalent 109◦.28. Any
deviation from this value will cause loss of stability.
TETRAHEDRAL CARBON ATOM
• Principle of free rotation around single bond
• Ethane’s Newmann projection formula-restricted rotation due to
steric repulsion CONFORMATIONS OF ETHANE
TETRAHEDRAL CABON ATOM
CONFORMATIONAL ANALYSIS OF DICHLOROETHANE
TETRAHEDRAL CARBON ATOM
• There is no free rotation around a single bond
• Simple molecules may exhibit free rotation if the potential energy
barrier does not exceed 10 Kcal/mole between the different forms
• Organic molecules have restricted rotation because of larger groups
attached to carbon that hinder the free rotation
CONFORMATIONAL ANALYSIS
• Molecules which can form isomers by rotation around single bond are
called FLEXIBLE MOLECULES..and the different forms taken are called
conformational isomers.
• When the stability of a molecule is decreased by interaction between
atoms it is under STERIC STRAIN
• Steric strain is due to repulsion between non-bonded atoms, dipole
interactions, and distortion of bond angles
• Study of preferred conformation and relating physical and chemical
properties to preferred conformation is called conformational analysis
CONFORMATIONAL ANALYSIS
• The conformation having less potential energy will be more stable.
• Staggered is more stable than Gauche conformation
• Gauche is stable than eclipsed conformation
• Methods to perform conformational analysis., or to determine the
existing conformation in a molecule are thermodynamic calculations,
electron and X-ray diffraction, NMR, IR and Raman spectra, dipole
moments, rotatory dispersion, and chemical methods
CONVENTIONS USED IN STEREOCHEMISTRY
DL NOMENCULATURE/RELATIVE CONFIGURATION
• Fischer plane projection formula used to represent asymmetric
molecules and stereoisomers.
• Glyceraldehyde is used as the arbitrary standard to determine the
configuration of all other organic molecules.
• Any compound prepared from or converted to D-glyceraldehyde will
be named the D-isomer
• Configuration is denoted by D and L
• Direction of rotation is denoted by (+) or (-) otherwise dextro or levo
CONVENTIONS USED IN
STEREOCHEMISTRY
D(+)-glyceraldehyde L(-)-glyceraldehyde
Full horizontal lines are above the plane of paper and
broken lines are lying below the plane of the paper
CONVENTIONS USED IN
STEREOCHEMISTRY
• Asymmetric carbon atom or chiral carbon atom means a carbon
having four different groups satisfying its valencies.
• When a molecule has more than one asymmetric carbon, the
asymmetric carbon of glyceraldehyde is drawn at the bottom and
then the molecule is built up. Deriving the configuration of a molecule
with reference to (relative) glyceraldehyde is called RELATIVE
CONFIGURATION
RS NOMENCULATURE/ABSOLUTE CONFIGURATION
• Cahn, Ingold, and Prelog established this.
• To name as R or S, for a MOLECULAE CONTAINING ONE ASYMMETRIC
CARBON ATOM,
• To a molecular model, Apply the sequence rule, and arrange the atoms
or groups attached to the asymmetric carbon according to the
decreased atomic number
• Apply the conversion rule and describe the spatial arrangement
(viewed from the side remote to the group having the lowest atomic
number) as a right or left-handed arrangement
• If it is right-handed, it is named R—rectus, right; S—sinister, left.
Absolute configuration of Glyceraldehyde/RS nomenclature
of Glyceraldehyde- D(+)-glyceraldehyde is R-glyceraldehyde
RS Nomenclature
• When a molecule contains two or more asymmetric carbon atoms
each asymmetric carbon atom is assigned an absolute configuration
according to sequence and conversion rule.
ELEMENTS OF SYMMETRY
• Plane of symmetry
• Center of symmetry
• Alternating axis of symmetry
If the molecule contains at least one of these elements of symmetry, it
is a symmetric molecule. If no element of symmetry is present the
molecule is called an asymmetric molecule.
Plane of symmetry divides the molecule such that functional groups on
one side form the mirror image of the groups on the other side.
Elements of symmetry
Centre of symmetry is a point from which lines when drawn and
extended to an equal distance on the other side of the molecule, meet
similar groups.
2,4-dimethylcyclobutane
-1,3-dicarboxylic acid
Elements of symmetry
Alternating axis of symmetry: A molecule possesses n-fold alternating
axis of symmetry, if rotated though 360/n about the axis and reflected
to a plane perpendicular it produces the same molecule.
1,2,3,4-tetramethylcyclobutane has 4-fold alternating axis of symmetry
NUMBER OF STEREOISOMERS
• A compound containing one asymmetric carbon atom exists in 3 forms: (+),
(-), and (±) ie., one pair of enantiomers and an equimolecular mixture of
pair of enantiomers.
• Equimolecular mixture of a pair of enantiomers is called Racemic
modification/racemic compound/racemic mixture which is OPTICALLY
INACTIVE by external compensation. Eg., DL or (±)-lactic acid
• Compounds having more than 1 asymmetric carbon can form
diastereoisomers/diastereomers.
• Stereoisomers that are not mirror images of each other, but are also non-
superimposable, optically active are called Diastereomers. There is a change
in configuration only for one carbon atom. They have different physical
properties, such as melting, boiling, and densities. Their specific rotations
can be the same sign or opposite signs.
Diastereomers example
Compounds that differ in
configuration on
only one asymmetric
carbon atom
are also called EPIMERS.
L-threose is an epimer
of L-erythrose
Meso form
• Meso form or compounds (i-form) are diastereomers but optically
inactive due to the plane of symmetry and internal compensation of
optical activity.
RACEMISATION
• Racemisation is a chemical process that converts an optically active
compound into an optically inactive racemic mixture, which is a
mixture of equal amounts of two enantiomers.
• Racemisation occurs in the presence of heat, light, or chemical
reagents. Eg: racemization of d-lactic acid in the presence of NaOH
through keto-enol tautomer form.
PROPERTIES OF RACEMIC
MODIFICATION
• Racemic mixture or (±)-conglomerate is a mechanical
mixture of (+) and (-) forms. 2 phases are present.
• Racemic compound is a molecular compound
containing a pair of enantiomers. Only 1 phase is
present.
• Racemic solid solution is a pseudo-racemic compound
and is a solid solution containing single phase in which
the pair of enantiomers have crystallized together.
FREEZING POINT CURVES FOR DETERMINING THE TYPE
OF RACEMIC MODIFICATION
The melting point is determined for the racemic modification and
then the enantiomers are added in different quantities to obtain the
freezing point curves.
a) Racemic mixture b) and C) racemic compound
Freezing point curves for racemic
solid solutions
RESOLUTION
• The process of separating a racemic mixture into its individual
enantiomers is called resolution.
1) Mechanical separation or spontaneous resolution: Crystallization of
2 forms separately and removed by hand. Sodium ammonium
racemate at 28◦ C.
2) Preferential crystallization by inoculation: A supersaturated solution
is treated with one form of the enantiomer and that gets
precipitated. Eg.DL-aspartic acid resolution
3) Biochemical separation: Penicillium glaucum when grown in a dilute
solution of ammonium racemate attacks the D-form and leaves the
L-form.
Resolution
4) Conversion to diastereomers: Optically active compounds are used
to convert the racemic compound into diastereomers and then they are
fractionally crystallized followed by hydrolysis.
Optically active alkaloids like quinine, and brucine; and acids like
tartaric acid are used in the resolution of racemic acids and bases.
Resolution of racemic modification by salt formation results in
Asymmetric transformation. If Dacid is more optically stable than Lacid
then the diastereomer formed will be in high quantity.
WALDEN INVERSION
• Conversion of one enantiomeric form to the other enantiomeric form
ie., (+) to (-) or (-) to (+) form. There is a configuration change.
• The INVERSION may be quantitative which means the product form is
optically pure..100% conversion.
• If the conversion is incomplete then the reaction may result in
RETENTION i.e, a racemic mixture is formed.
MECHANISM OF WALDEN INVERSION
• May be SN1 or SN2
• The mechanism determines whether complete inversion or retention
occurs.
• If Walden inversion takes place by SN2 then complete inversion occurs.
MECHANISM OF WALDEN INVERSION
• SN1
• If Walden inversion takes place by SN1 then inversion and retention
(racemisation) occur.
• If the carbonium ion is stable then retention occurs, because the ion
is flat and it is attacked by the –OH on both sides.
• The leaving group X can have a shielding effect on R, resulting in an
attack on only one side causing inversion in configuration.
ASYMMETRIC SYNTHESIS
• Is the synthesis of optically active compounds from optically inactive
compounds.
• Two types: Partial asymmetric synthesis and Absolute asymmetric
synthesis
PARTIAL ASYMMETRIC SYNTHESIS
Preparing optically active compounds from symmetrical compounds by
intermediate use of an optically active compound.
Partial asymmetric synthesis
Ethylmethyl malonic acid
(-) Valeric acid
ABSOLUTE ASYMMETRIC SYNTHESIS
• Preparing optically active compounds from inactive compounds
without intermediate use of optically active compounds
• The addition of bromine to 2,4,6-trinitro stilbene in a beam of right
circularly polarised light yields a (+) product
