UNIT 3

STEREOCHEMISTRY
By Ayele W.

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Introduction
• Stereochemistry is a branch of chemistry, which deals about three-
dimensional structures of molecules.
• They contain the same type and number of atoms except the
difference in the manner the groups are oriented in space.
• The first molecule is a naturally existing isomer and biologically
important form of amino acid while the second molecule is not
biologically important.

(+) - alanine (The natural existing isomer) (-) - alanine

• (+)-Alanine and (-)-alanine are related to each other as left hand is
related to right hand. As our hands are not identical, (+)-alanine and
(-)-alanine are not the same.
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 Isomers
• Isomers are different compounds with the same molecular formula,
but different structure and properties.
• Isomerism in organic chemistry is a phenomenon shown by two or
more organic compounds having the same molecular formula but
different properties due to difference in arrangement of atoms along
the carbon skeleton (structural isomerism) or in space (Stereo
isomerism).

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 3.1.2. Structural Isomerism (Constitutional)
1. Chain (Skeleton) Isomerism
• It is an isomer with the same molecular formula, but different
C-C skeletons.
• It occurs when carbon atoms are linked to the main chain in
different ways. For example:

2. Position Isomerism
• They have the same molecular formula, but different
arrangement or position of atoms or functional groups.
• It occurs when functional groups are attached on different
positions on a carbon chain. For example:

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 Cont’d

3. Functional Isomerism
• It is a very interesting form of isomerism where the compounds
are different due to different arrangements of atoms leading to
different functional groups.
• As functional groups are usually the reactive center of a
molecule this leads to entirely different properties. For
example:

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4. Metamerism:
• This type of isomerism is due to unequal distribution of
carbon atoms on either sides of the functional group in the
same molecules.
• Metamers always belong to the same homologous series.
• Compounds like ethers, thioethers ketones, secondary
amines, etc. show metamerism.
• This form of isomerism is rare and is limited tomolecules
having a divalent atom like O or S and alkyl groups around it.
The main examples come from ethers and thioethers

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5. Tautomerism
• This isomerism is due to spontaneous interconversion of
two isomeric forms with different functional groups.
• The prerequisites for this is the presence of the C=O, C=N or
N=O in the usual cases and an alpha H atom.

• In general, the Keto form is more stable.

• Enols can be forms by acid or base catalysis from the ketone
and are extensively used in making C-C single bonds in
organic synthesis.

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6. Ring-Chain isomerism
• Here one isomer is an open chain molecule and the
other a cyclic molecule.

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 3.1.3. Types of Stereoisomers
• Isomers that have the same constitution but differ in the spatial
arrangement of their atoms are called stereoisomers.

I. Geometrical (Configurational isomers)

• These isomers result from restricted rotation.
• Restricted rotation can be caused by either a cyclic structure or a
double bond.
• The isomer that has similar groups on the same side of the double
bond is called cis-isomer and
• the one with similar groups on the opposite side is called trans-
isomers.
• The phenomenon is called cis-trans-isomerism.
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Cont’d
• For example, cis-trans configuration of the following
buthenedioic acid results up on their differences in chemical and
physical properties as well as biological activity since the trans-
isomer of butenedioic acid is an essential metabolic intermediate
in both plant and animals whereas the cis-isomer is toxic and
irritant towards tissues.

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II. Optical isomers have the same chemical and physical properties
except that the show a pronounced difference towards a plane
polarized light.
A. Enantiomers: molecules related to each other as an object related
to its mirror image are called enantiomers.
• They are also non-super impossible mirror images to each other.
Example left hand and right hand.

B. Diastereomers: are stereoisomers whose molecules are not mirror

images of each other.
• All stereoisomers that are not enantiomers are diastereomers.
• Cis -1,2-dichloroethene and trans-1,2-dichloroethene are not mirror
images to each other while they are stereoisomers.

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 C. Conformational isomerism
• Conformations of Alkanes: Rotation about C-C Single
Bonds
• Different spatial arrangements of atoms that result
from rotation about carbon-carbon single bonds are
known as conformations.
• Different conformations also are called conformational
isomers or conformers

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 3.2 Molecular Chirality: Enantiomers
• Everything has a mirror image, but not all things are superimposable
on their mirror images.
• Mirror-image superimposability characterizes many objects we use
every day.
• Cups and dishes, forks and spoons, chairs and beds are all identical
with their mirror images.
• Left and right hand are not superposable.
• An object is chiral if it is not superimposable on its mirror image.

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 Cont’d
• Enantiomers occur only with those compounds whose molecules
are chiral.
• A chiral molecule is defined as one that is not identical with its
mirror image. (Non-super impossible mirror images)
• molecule lacks a plane of symmetry. That is the molecule cannot be
divided in to two equal parts that are mirror images of each other if
it is chiral.
• In the contrary, an achiral molecule has a plane of symmetry. An
achiral molecule is super impossible on its mirror image or they are
the same (not enantiometric).
• The word chiral is derived from the Greek word cheir, meaning
"hand," and it is entirely appropriate to speak of the "handedness"
of molecules.
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• In organic chemistry, chirality most often occurs in molecules that
contain a carbon that is attached to four different groups.
• It is impossible to divide the molecules in two equal parts by any
plane that passes through the molecules.
• Now, let us take an organic molecule (CXWYZ) which contains one
carbon atom attached to four different groups (X, W, Y and Z).

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Cont’d
• The carbon atom that is surrounded by four different
groups is known as chiral carbon or chiral center or
asymmetric center or asymmetric carbon, stereogenic
center.
• The Chirality Center (*): It is a tetrahedral carbon atom
that bears four different atoms or groups.

• NB: A chiral center cannot be:

sp- or sp2-hybridized (must be sp3)
an atom with 2 identical substituents (e.g., any -CH2- group)
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Tests for Chirality: Planes of Symmetry
1. Superposibility of the models of a molecule and its
image:
• If the models are superposable, the molecule that they
represent is achiral.
• If the models are nonsuperposable, the molecules that they
represent are chiral.
2. The presence of a single tetrahedral stereocenter ⇒ chiral
molecule.
3. The presence of a plane of symmetry ⇒ achiral molecule
• A plane of symmetry (also called a mirror plane) is an
imaginary plane that bisects a molecule in such a way that the
two halves of the molecule are mirror images of each other.

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 Cont….

• The plane may pass through atoms, between

atoms, or both

a) 2-Chloropropane has a plane of symmetry (b) 2-Chlorobutane does not possess a plane of
and is achiral. symmetry and is chiral.

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Cont…
4. The achiral hydroxyacetic acid molecule versus the
chiral lactic acid molecule:

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PROBLEM: Identify the stereogenic centers, if any, in
(a) 2-Cyclopenten-1-ol and 3-cyclopenten-1-ol
(b) 1,1,2-Trimethylcyclobutane and 1,1,3 Trimethylcyclobutane
(a)

H3C
H3C

(b) H3C
H3C CH3
1,1,3 Trimethylcyclobutane
CH3

1,1,2-Trimethylcyclobutane

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 3.3 Nomenclature of Enantiomers
Designation of stereocenter
• Configuration: the absolute stereochemistry of a
stereocenter
• Configuration-relates to the three dimensional
sense of attachment for groups attached to a chiral
atom or group of atoms (i.e., attached to a stereocenter)
• (R) and (S) are from the Latin words rectus and sinister:
R configuration: clockwise (rectus, “right”)
S configuration: counterclockwise (sinister, “left”)

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1. The (R-S) System: (Cahn-Ingold-Prelog System)
1. Each of the four groups attached to the stereocenter
is assigned a priority
Priority is first assigned on the basis of the atomic number of
the atom that is directly attached to the stereocenter
The group with the lowest atomic number is given the lowest
priority, 4; the group with next higher atomic number is given
the next higher priority, 3; and so on.
In the case of Isotopes, the isotope of greatest atomic mass has
highest priority

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• Priorities are assigned as follows (Sequence rule)
Atoms directly attached to the stereogenic center are
compared.
Atoms with higher atomic number are given higher priority
(1).
Lowest atomic number is given the lowest priority (4).
Align the lowest priority group (4) behind the chiral carbon.
 If the direction of 1 2 3 is clockwise, the enantiomer is R.
If 1 2 3 is counterclockwise, the enantiomer is S.

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If two different groups with the same atom are present
look out the second atom in each groups. E.g. -CH2CH3
has priority over -CH3 as shown below.

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Compounds in which a chirality center is part of a ring are handled
in an analogous fashion. To determine, for example, whether the
configuration of (+)-4-methylcyclohexene is R or S; treat the right-
and left hand paths around the ring as if they were independent
substituents.

Groups with double or triple bonds are assigned priorities as if

their atoms were duplicated or triplicated.

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• If the group (or atom) with the lowest priority (4) is not
bonded by a hatched wedge (not away from the viewer)
flip or rotate the structure to put it behind the chiral
carbon.

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 Cont’d
2. E/Z-CONFIGURATION
• Configuration is the arrangement of atoms/groups in molecules. It
is used to assign E/Z descriptor.
• As long as each of the sp2 carbons of an alkene is bonded to only
one substituent, we can use the terms cis and trans- to designate
the structure of the alkene.
• If the hydrogens are on the same side of the double bond, it is the
cis- isomer; if they are on opposite sides of the double bond, it is
the trans- isomer.
• But how would you designate the isomers of a compound such as
1-bromo-2-chloropropene?

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 Cont’d
• For a compound such as 1-bromo-2-chloropropene, the cis–trans
system of nomenclature cannot be used because there are four
different substituents on the two vinylic carbons.
• The E, Z system of nomenclature was devised for these kinds of
situations
• CIP system to assign E/Z- configuration
Step 1: Identification of double bond or ring.
Step 2: Assignment of priority to the group on each sp2 carbons
according the sequence rule.
Step 3: Assign E/Z to the molecule based up on the orientation of the
priority number round sp2 carbons.

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 Cont’d
• If the high-priority groups are on the same side of the double
bond, the isomer has the Z-configuration (Z is for zusammen,
German word for “together”).
• If the high-priority groups are on opposite sides of the double
bond, the isomer has the E-configuration (E is for entgegen,
German word for “opposite”).

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3. The D and L naming
cont’d
• The notations D and L are used to describe the configurations of
carbohydrates and amino acids.
• It is the old naming system used for glyceraldehyde (2,3-
dihyroxypropanal) as the standard.
• If the OH group attached to the bottom-most asymmetric carbon
(the carbon that is second from the bottom) is on the right, then the
compound is a D-glyceraldehyde.
• If the OH group is on the left, then the compound is an L-
glyceraldehyde.
• All those compound which have generic relationships with D-
glyceraldehyde belongs to D-series and similar for L-series.

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 Properties of Enantiomers: Optical Activity
Enantiomers have the same:
 Index of refraction
 Solubility in common solvents
 IR spectra
 Rate of reaction with ordinary reagents

Physical Properties of (R)- and (S)-2-Butanol

• Enantiomers show different behaviors only when they interact with other
chiral substances and they also differ in behavior in their response towards
plane-polarized light.
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3.5. Optical activity and plane polarized light
• Optical activity is the ability of a chiral substance to rotate the
plane of plane-polarized light and is measured using an
instrument called a polarimeter.
• A beam of light consists of two mutually perpendicular
oscillating fields: an oscillating electric field and an oscillating
magnetic field.

• If normal light or sunlight is passed through a plane polarizing

filter (such as polarized sunglasses), the light rays all vibrate in
the same plane.

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Con’d
• When plane-polarized light is passed through a solution of a
pure enantiomer of a chiral compound, the plane of
polarization is rotated to the right by one enantiomer, and
to the left by the other enantiomer.

• The enantiomer rotating light to the right was termed

the “+” enantiomer. Similarly, the one rotating light to
the left was termed the “−” enantiomer.
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Measurement of Optical Rotation
• Rotation of the plane of polarized light in the clockwise sense is
taken as positive (+), and rotation in the counterclockwise sense is
taken as a negative (-) rotation.
1. Dextrorotatory [ (+)-or d-]: Rotates the plane of plane-polarized
light to the right.
2. Levorotatory [(-)-or l-]: Rotates the plane of plane-polarized light to
the left
• Specific Rotation [α]D
Specific rotation
calculated in this way is α= observed rotation
c = concentration ( g/mL )
a physical property of an optically l = length of cell ( dm )
active substance D = yellow light from sodium lamp

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 con’d
• It is convenient to distinguish between enantiomers by
prefixing the sign of rotation to the name of the substance.

• Note that there is no straightforward correlation between

the absolute configurations (R, S designation) of an
enantiomer
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• Achiral molecules have zero degree of rotation as in 2-
propanol which have [α] = 0.
• Example: A 1.5g sample of coniine, the toxic extract of
poison hemlock, was dissolve in 10mL ethanol and
placed in a sample cell with a 5.0cm path length. The
observed rotation at the sodium D line with +1.20.
Calculate the specific rotation, [α]D, for coniine.

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 Racemic Mixture
• Mixtures containing equal quantities of enantiomers are
called racemic mixtures.
• Racemic mixtures are optically inactive.
• It is an equimolar mixture of the (+) and (-) enantiomers.
• If a sample contains 50% of one enantiomer and 50% of its
mirror image isomer, the sample will not have a response to
a plane polarized light.
• The (+) rotation from one enantiomer is exactly cancelled by
the (-) rotation of the other enantiomer hence has zero net
rotation.
• Conversely, when one enantiomer is present in excess, a net
rotation of the plane of polarization is observed.
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 3. 8. Fischer Projection Formulas
• It is a two-dimensional representation of chiral molecules (3D
structure).

• The Fischer projection formula are useful to draw compounds

with many stereo centers because it saves space and easy to
write.
• Fischer projections are always generated the same way: the
molecule is oriented so that the vertical bonds at the chirality
center are directed away from you and the horizontal bonds
point toward you.
• A projection of the bonds onto the page is a cross. The
chirality center lies at the center of the cross but is not
explicitly shown.

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cont’d
• The convention to draw the Fischer projection formula is
as follows.
Step 1: The carbon chain is drawn along the vertical line of
the Fischer projection, usually with the most highly
oxidized end carbon atom at the top.
Vertical lines : Bonds going into the page or groups align away
from the viewer.
Horizontal lines :Bonds coming out of the page or groups
align toward viewer.
Step 2: The lowest priority group bonded to the chiral
carbon must always be shown as a horizontal bond.
Step 3: Intersection point represents carbon atoms, usually
stereo center.
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Cont’d
• For example for lactic acid CH3CH (OH) COOH, the
Fischer projections are written as

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Cont’d
• The Fischer projection of a compound with more
than one chiral center can be written in the same
wayusing more than one horizontal line. For
example: the Fischer projection formula for (2R, 3R)
-2,3- dibromobutane is written as follows.

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Manipulation of Fischer projection
• A Fischer projection can be rotated through 180o in the plane of the
paper; since this does not change the configuration, that is, spatial
arrangement of groups around chiral carbon

• Rotation of Fischer projection by 180o does not change the configuration

of stereoisomer.
• The Fischer projection of IA and IB (of lactic acid) represent the same
stereo isomer. Similarly, IIA and IIB (of 2- hydroxypropanal) represent the
same stereoisomer.

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Cont’d
• 90o or 270o rotation of Fischer projection are not
allowed; because it exchange groups that going in to
the plane and those out of the plane.

• If one group of the Fischer projection held steady,

we can rotate others either clockwise or counter
clockwise.

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 con’d
Assigning R, S-Configurations to Fischer Projections:
• Procedures for assigning R, S designations:
I) Assign priorities to the four substituents.

II) Perform one of the two allowed motions to place the

group of lowest (fourth) priority at the top or bottom of
the Fischer projection.

III) Determine the direction of rotation in going from

priority 1 to 2 to 3, and assign R or S configuration

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Generally:
• When the lowest priority is on the top or bottom, we
can assign R/S directly as the usual R/S rule.
• When the lowest priority is on horizontal line, we can
assign R/S by taking the opposite direction of R/S
rule.

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Molecules with more than One Stereocenter

DIASTEREOMERS:
• Diastereomers are stereoisomers that are not mirror images
of each other.

• Diastereomers must have opposite configurations at

some(one or more) stereogenic centers, but the same
configurations at other stereogenic centers

• have different chemical and physical properties in any type

of environment.

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 Diastereomers:...
• Relationships between four stereoisomeric threonines

• Enatiomers must have opposite (mirror-image) configurations at

all stereogenic centers.
• Diastereomers must have opposite configurations at some(one
or more) stereogenic centers, but the same configurations at
other stereogenic centers

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The four diastereomers of threonine (2-amino
hydroxybutanoic acid)

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Meso Compounds
• The best way to identify a meso compound is to prove that
it is superimposable with its mirror image. However, a quick
test is to see if it contains a plane of symmetry:

• Compounds containing a plane of

symmetry are achiral!
• This plane divides the molecule into
halves that are mirror images of each
other.

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Meso Compounds…

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 Conformational Analysis in Alkanes:
• Conformational analysis: the analysis of the energy
changes that a molecule undergoes as groups rotate
about single bonds
• Conformations can be represented in 2 ways: Newman
and Sawhorse formula
• In a sawhorse projection, you are looking at the carbon–
carbon bond from an oblique angle.
• In a Newman projection, you are looking down the
length of a particular carbon-carbon bond.

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