Chapter-1 Stereochemistry
Chapter-1 Stereochemistry
Chapter-1 Stereochemistry
• Isomers, which have same molecular formula, but different structural formula are called structural
isomers.
• Different Structural formula means:
• Different bond pattern or
• Different arrangement of s bonds or
• Different connectivity of atoms.
1. Chain Isomers: Isomers which have same functional groups but different arrangement of carbon
skeleton in principal chain or side chains are chain isomers.
▸ Examples are: n-butane and iso-butane
Structural Isomerism
2. Positional Isomers: Isomers which have same functional groups, same arrangement of carbon
skeleton but different position of functional groups or substituents.
▸ Examples are-
3. Functional isomers: Functional isomers have same molecular formula but differ in functional
groups.
▸ For example: Ethyl alcohol and Dimethyl ether
Structural Isomerism
4. Ring-Chain Isomers: The same molecular formula represents two or more compounds.
• It differs in the mode of linkage of carbon atoms.
• The isomers have either open chain or closed chain.
• Example, Propene and cyclopropane are ring chain isomers.
Structural Isomerism
5. Metamers: This type of isomerism is due to unequal distribution of carbon atoms on either side of
the functional group
• Such compounds are members of homologous series
• Example: Diethyl ether and Methyl propyl ether
Structural Isomerism
6. Tautomers: A type of functional Isomers which exist in rapid equilibrium in solution are called
Tautomers.
• Tautomers are interconvertable in solution
• Tautomers usually differs in position of H atom at a carbon.
• Interconversion of tautomers can be catalysed.
• Tautomers can’t be seperated in solution at normal temperature.
• The more stable form dominates in equillibrium.
• Examples are:
Stereochemistry
Definition:
▸ Mathematically, α=[α]Dlc
▸ Where, [α]D = Specific Rotation
Specific rotation
▸ The specific rotation of plane polarization is measured in degrees and is known as
observed optical rotation (α).
▸ Specific rotation is the number of degrees of rotation observed if a 1-decimeter tube is
used, and the compound being examined is present to the extent of 1g cc.
▸ This is usually calculated from observations with tubes of other lengths and at different
concentrations by means of equation.
▸ Where d represents density of pure liquid or concentrations.
Optical Purity
▸ Whether a particular sample consists of a single enantiomer or a mixture of
enantiomers can be determined by its observed specific rotation.
▸ From the observed specific rotation, we can calculate the optical purity of
the mixture.
Plane of symmetry
Center of symmetry
1. Plane of symmetry:
plane of symmetry (internal mirror plane ) is a mirror plane that cuts the
molecule into two halves, so that one half of the molecule is a reflection
of the other half.
The plane may pass through atoms, between atoms, or both
Plane of Symmetry
Example
(a)2-Chloropropane has a plane of symmetry and is achiral.
(b)2-Chlorobutane does not possess a plane of symmetry and is chiral.
The compound have plane of symmetry is: Optically inactive and called Meso
compound
Plane of Symmetry
cis-1,2-dimethylcyclohexane
This molecule has a plane of symmetry cutting the molecule in half.
Everything on the left side of the plane is mirrored by everything on the
right side. Classify each of the following
pairs as chiral or achiral
It is the point in the center of molecule to which a line can be drawn from any
atom such that when extended an equal distance past the center, the line
meets another atom of the same kind
Center of symmetry
▸ So, for any compound to be optically active it must not possess any
element of symmetry.
Chiral and Achiral Molecules
Chiral compounds:
• Has chiral center
• Has no element of symmetry
• The compound and its mirror image are Non superimposable.
• N.B. The compound and its mirror image called Enantiomers
Chiral and Achiral Molecules
Chiral compounds:
Chiral and Achiral Molecules
Achiral compounds:
• Has No chiral center
• May contain chiral center but the compound and its mirror image are
Superimposable
• Has element of symmetry (Plane of symmetry or center of symmetry)
• N.B: Achiral compound is optically inactive
1 2 3 4
Chiral and Achiral Molecules
Step 2: Push the two bonds coming out of the plane of the paper onto the
plane of the paper.
Fischer Projection
Step 3: Pull the two bonds going into the plane of the paper onto the plane of
the paper.
Fischer Projection
The system that is used to designate the configurations of chiral carbons of naturally
occurring compounds is called the D and L convention or system.
This descriptor (D and L) represent an older system for distinguishing enantiomers of
Carbohydrates and Amino acids.
The arrangement of atoms in an optically active molecule, based on chemical
interconversion from or to a known compound, is a Relative configuration.
D- & L - Glyceraldehyde are used as standard references for D-L system of
configuration of carbohydrates.
D- & L - Alanine are used as standard reference for alpha amino acid with D-L system
of configuration.
D-L system is also called as Fischer-Rosanoff convention.
DL system of nomenclature
Fischer projections were originally proposed for the depiction of carbohydrates and used by
chemists, particularly inorganic chemistry and biochemistry.
The L and D forms of the sugar depends on the orientation of the -H and -OH groups around
the carbon atom adjacent to the terminal primary alcohol carbon (carbon 5 in glucose)
determines whether the sugar belongs to the D or L series.
Most of the monosaccharide occurring in mammals is D sugars, and the enzymes responsible
for their metabolism are specific for this configuration. In solution, glucose is dextrorotatory-
hence the alternative name dextrose.
The direction of rotation is independent of the stereochemistry of the sugar, so it may be
designated D (-), D (+), L (-), or L (+). For example, the naturally occurring form of fructose is the
D (-) isomer.
DL system of nomenclature
Step 1: Make sure the acyclic form of the molecule is drawn as a Fischer projection. If the
monosaccharide is an aldose, the aldehyde group must be on top; if it is a ketose, the carbonyl
carbon must be the second carbon from the top.
DL system of nomenclature
Step 3: Locate the carbon atom that bears the second highest number, which is known
as the penultimate carbon. If the hydroxy group on the penultimate carbon is on the
right of the carbon chain, assign the label D to the compound; if it is on the left of the
carbon chain, assign the label L.
DL system of nomenclature
The enantiomer of a given chiral monosaccharide, simply draw its mirror image.
DL system of nomenclature
The D- & L- system has the disadvantage of specifying configuration of only one stereocenter.
DL system of nomenclature
Step 1: Make sure that the molecule is drawn as the Fischer projection in
which the carboxylic acid group is on top and the side chain on bottom.
DL system of nomenclature
Step 2: If the amine group is on the right of the carbon chain, assign the label
D to the compound; if it is on the left of the carbon chain, assign the label L.
DL system of nomenclature
Threo and Erythro system of nomenclature
Rule I: first we assign the priority numbers to the four atoms/groups attached to chiral
center according to CIP rules. For example in the case of CHClBrI, the four atoms
attached to the chiral center are all different and priority will be given based on atomic
weight, thus the priority follows as I, Br, Cl, H.
RS system of nomenclature
Rule I: If two atoms are isotopes of same element, the atom of higher mass number
has the higher priority.
RS system of nomenclature
Rule 2: If two or more of the atoms that are bonded directly to the chiral center are the
same, then prioritize these groups based on the next set of atoms (i.e., atoms adjacent
to the directly bonded atoms). Continue until priorities can be assigned. Priority is
assigned at the first point of difference.
RS system of nomenclature
Rule 2:
If two atoms have substituents of the same priority, higher priority is assigned to the atom
with more of these substituents.
A larger group (i.e., more atoms) may not necessarily have a higher priority over another
(smaller) group.
RS system of nomenclature
Rule 4: In Fischer projection representations orient the molecule so that the least priority
group must be on lower end of vertical line. If the lower priority group on horizontal line or
upper side on vertical line, then to bring the group on to vertical line do two mutual
exchanges of groups so that the least priority group come to lower end of vertical line.
RS system of nomenclature
Rule 4: In Fischer projection representations orient the molecule so that the least priority
group must be on lower end of vertical line. If the lower priority group on horizontal line or
upper side on vertical line, then to bring the group on to vertical line do two mutual
exchanges of groups so that the least priority group come to lower end of vertical line.
RS system of nomenclature
Rule 5: After giving priority order for the groups at asymmetric center, if priority direction
is clockwise the configuration is specified ‘R’ (Latin: rectus, right); if anticlockwise the
configuration is specified ‘S’ (Latin: sinister, left).
RS system of nomenclature
To assign R and S configuration to the chiral molecule, the least priority group should be
vertically downward in the Fischer projection.
If it is not so, then interchanges in the positions are carried out to bring it to that position
but care needs to be taken so that the interchanges do not change the actual
configuration of the molecule.
This is done by following two rules which state—
1. The interchange is to be carried out only between adjacent positions in the Fischer
projection.
RS system of nomenclature
2. An even number of interchanges must be carried out, as it does not change the actual
configuration of the molecule. It is to be noted that an odd number of interchanges cause a
change in the configuration of the molecule.
RS system of nomenclature
RS system of nomenclature
Rule 6: Orient the molecule in space so that the lowest priority group (#4) is directed
away from you. The three remaining groups then project toward you.
RS system of nomenclature
a) The conversion of an achiral molecule into a chiral molecule, with the generation
of a chiral center
One of the products of chlorination of n-butane is the chiral compound, sec-butyl
chloride.
Reaction of Chiral Molecules
and that a reaction that does not involve the breaking of a bond to a chiral
The mixture may have different boiling point (b. p.) and melting point (m. p.)
from the enantiomers!
If optically inactive reagents combine to form a chiral molecule, a racemic
mixture is formed.
Racemic modification
Racemic modification
Conglomerate
If the molecules of the substance have a greater affinity for the same enantiomer
than for the opposite one, a mechanical mixture of enantiomerically pure crystals will
result.
The melting point of the racemic conglomerate is always lower than that of the pure
enantiomer. Addition of a small amount of one enantiomer to the conglomerate
increases the melting point.
Racemic modification
1. By Mixing:
Racemic modification is by intimate mixing of exactly equal amounts of
dextorotatory (+) and levorotatory (-) isomers. This process is associated
with an entropy mixing, since the racemic modification represents a more
random state of affairs than the separate enantiomers.
Formation of Racemic modification
2. By synthesis:
Any synthesis of dissymmetric molecules, starting from either symmetric
molecules or a racemic modification and using active reagent or
catalysts and no asymmetric physical influence always produces a
racemic modification.
The first method is exemplified by the bromination of propionic acid to
alpha bromopropionic ace by the Hell- Volhard-Zelinsky (H-V-Z) Method.
two alpha hydrogen bears the same relationship to the other and to the rest
of the molecule each is replaced at the only chiral centre.
Formation of Racemic modification
2. By synthesis:
Rate as the other and equal numbers of (+) and (-) molecule of alpha
bromopropionic acid result.
Bromination of propionic acid
Formation of Racemic modification
Epimers
- Those stereoisomers which are differing in its configuration at only one chiral
carbon atom are called as Epimers.
- Epimers are diastereomers that contain more than one chiral center but differ
from each other in the absolute configuration at only one chiral center.
Formation of Racemic modification
Formation of Racemic modification
a) Enolate Mechanism:
Formation of Racemic modification
a) Enediol Mechanism:
Formation of Racemic modification
Physical properties
Racemate may have different physical properties from either of the pure
enantiomers because of the differential intermolecular interactions . The
change from a pure enantiomer to a racemate can change its density,
melting point, solubility, heat of fusion, refractive index, and its various
spectra. Crystallization of a racemate can result in separate (+) and (−)
forms, or a single racemic compound.
Properties of Racemic modification
1. Mechanical Method:
It was the first method used by Pasteur (1884) for the resolution
of sodium ammonium tartarate which crystallizes out in the form
of racemic mixtures below 270C.
Since the crystals too are nonsuperimposable, their appearance
is not identical. They can be separated with the help of
magnifying lens and a pair of tweezers. This method is
laborious and is applicable to only those isomers having different
crystal.
Resolution of Racemic Mixture
3. Biochemical Separation
It was introduced by PASTEUR in 1858.
Biological molecules may react at different rates with the two enantiomers.
For example, a certain bacterium may digest one enantiomer, but not the other.
This method is based on the fact that when certain micro- organisms (e.g. bacteria
yeast, mould, fungi) are grown in dilute solution of racemic modification they
assimilate on one enantiomers rapidly than the others.
Resolution of Racemic Mixture
3. Biochemical Separation
e.g. The mould penicillin glaucum preferentially destroys the (+) isomers of racemic
ammonium tartarate and thus leaves the (-) ammonium tartarate in solution.
This method is limited, since it is necessary to find the proper organism and since
one of the enantiomers is destroyed in the process.
This process has been called chemoenzymatic dynamic kinetic resolution.
Reduction of ethyl acetoacetate with Baker’s yeast
O O baker's yeast
H OH O HO H O
Et +
Et Et
Me O H 2O, sucrose Me O Me O
Ethyl acetoacetate
(S)-(+)-Ethyl (R)-(-)-Ethyl
3-hydroxybutanoate 3-hydroxybutanoate
>90 % < 10%
Resolution of Racemic Mixture
4. By Diastereomers
This method converting the eanantiomers of a racemic modification to
diastereomers with the aid of a pure enantiomers of other compound.
Diastereomers are non- identical, they have different physical properties and hence
easily separated by crystallization and chromatography techniques.
Since the base used is, say, the (S) form, there will be a mixture of two salts
produced having the configurations (S,S) and (R,S).
Example: Resolution of lactic acid using brucine
Resolution of Racemic Mixture
4. By Diastereomers
Example: Resolution of lactic acid using brucine
COOH COO- COOH
+
H3C H H Brucine-H H
OH H3C OH H3C OH
(S)-(+)-form (SS)-form (S)-(+)-form
HCl
+ (S)-Brucine
COOH COOH
COO-
H3C OH + OH
H OH Brucine-H H3C H
H3C H
(R)-(-)-form (R)-(-)-form
(SR)-form
Other examples:
•Resolution of ibuprofen using a-phenethylamine
•Resolution of Duloxetine (=Cymbalta) using mandelic acid
Resolution of Racemic Mixture
4. By Diastereomers
Commonly used resolution reagents are:
Compound Resolution agent
Carboxylic acids brucine, strychnine, ephedrine, cinchonine
Amines camphor-10-sulfonic acid, tartaric acid, mandelic acid
5. By Precipitation
This method is based on
formation of precipitate by
reaction between any reagent
and racemic mixture.
Example: (+) & (-) narcotine
when dissolved in HCL
,precipitates (+) narcotine.
Resolution of Racemic Mixture
6. Chromatographic Separation
When a racemic mixture is placed on a chromatographic column, if the
column consists of chiral substances, then in principle the enantiomers
should move along the column at different rates and should be separable
without having to be converted to diastereomers.
This has been successfully accomplished with paper, column, thin-layer and
gas and liquid chromatography.
Columns packed with chiral materials are now commercially available and
are capable of separating the enantiomers of certain types of compounds.
Resolution of Racemic Mixture
6. Chromatographic Separation
These columns are typically silica gel with bonded optically active functionalities, such as
(either d or l) phenyl urea, naphthyl urea, phenyl glycine or leucine.
cyclodextrins bonded to silica gel also permit the separation of optical isomers, via the
formation of inclusion complexes within the cyclodextrin cavity.
Resolution of Racemic Mixture
7. Kinetic Separation
Since enantiomers react with chiral
compounds at different rates, it is
sometimes possible to effect a partial
separation by stopping the reaction before
completion.
A method has been developed to evaluate
the enantiomeric ratio of kinetic resolution
using only the extent of substrate
conversion.
Asymmetric Synthesis
Asymmetric
Induction
Active substrate.
• If a new stereogenic center is created in a molecule that is already optically active, the
product will generate diastereomers and the two diastereomers may not (except
fortuitously) be formed in equal amounts.
• certain additions to the carbon–oxygen double bond of ketones containing an
asymmetric α carbon, Cram’s rule predicts which of two diastereomers will
predominate.
Asymmetric Synthesis
Active substrate.
• If 45 is observed along its axis, it may be
represented as in 48, where S, M, and L
stand for small, medium, and large,
respectively. The oxygen of the carbonyl
orients itself between the small- and the
medium-sized groups.
• The rule requires that the incoming group
preferentially attacks on the side of the
plane containing the small group. By this
rule, it can be predicted that 47 will be
formed in larger amounts than 46.
Asymmetric Synthesis
Chiral Auxillary
possible to convert an achiral
compound to a chiral compound by:
(i) addition of a chiral group;
(ii) Running an asymmetric synthesis,
and
(iii) cleavage of the original chiral group.
Chiral Auxillary
possible to convert an achiral
compound to a chiral compound by:
(i) addition of a chiral group;
(ii) Running an asymmetric synthesis,
and
(iii) cleavage of the original chiral group.
Active reagent.
• A pair of enantiomers can be separated by an active reagent that reacts faster with
one of them than it does with the other.(Kinetic Resolution).
• If the absolute configuration of the reagent is known, the configuration of the
enantiomers can often be determined by a knowledge of the mechanism and by
determining which diastereomer is preferentially formed.
• Creation of a new stereogenic center in an inactive molecule can also be
accomplished with an optically active reagent, although it is rare for 100%
selectivity to be observed.
Asymmetric Synthesis
Active reagent.
Reduction of methyl benzoylformate with optically active Nbenzyl- 3-
(hydroxymethyl)-4-methyl-1,4-dihydropyridine (55) to produce mandelic acid (after
hydrolysis) that contained ~97.5% of the (S)-(+) isomer and 2.5% of the (R)-(−)
isomer (for another example, see 15-11). Note that the other product, 56, is not
chiral. Reactions like this, in which one reagent (in this case 56) gives up its
chirality to another, are called self-immolative.
Asymmetric Synthesis
Active reagent.
Asymmetric Synthesis