AKSUM UNIVERSITY

College of Natural and Computational Sciences

Department of Chemistry

Organic chemistry (Chem1012) For Medicine year I

Students

Chapter TWO

Stereochemistry

06/14/2024 by: ZENEBE HAGOS(Assis. Professor))

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 Stereochemistry is the study of the three
dimensional structure of organic molecules.
 It is the subdiscipline of chemistry that studies the
properties of stereoisomers

 It has its own language and terms that need to be

learned in order to fully communicate and
understand the concepts.

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 ISOMERS
 Isomers are molecules that have the same molecular formula but
different arrangement of their atoms/groups.
Classification of Isomers
Isomers

Conformational
Stereoisomers
Constitutional (structural) isomers

Configurational
Chain isomers Functional group isomers

Diastereomers
Positional isomers Enantiomers
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 Stereoisomers: are Compounds that have the same molecular
formula and bond connectivity, but different arrangement of the
atoms in 3-dimensional space. They are two types :

1. Enantiomers: stereoisomers that are nonsuperposable mirror

images. They are the same as their mirror image
Example:

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2. Diastereomers: stereoisomers that are nonsuperposable nonmirror
images. They are not mirror images of one another.
 They are molecules that have more than one stereogenic (chiral)
center.
Examples:

(I) (II)
(I). (2R,3R)-2-amino-3-hydroxybutanoic acid
(II). (2R,3S)-2-amino-3-hydroxybutanoic acid
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Symmetry and Dissymmetry of Objects

 An object is said to be symmetric if it can be divided in to equal

and the same parts.

 If not, it is called dissymmetric (asymmetric)

Examples of symmetric objects:

- Tennis ball - Nail
- T-shirt (with no Pocket) - Four Legged chair(with no arm)
 On the other hand if an object can be superimposable on its
mirror image, it is recognized as symmetric.

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 Dissymmetric objects are non-superimposable on their mirror
images.
Remark: Superimposability implies the alignment of two images
on top of the other, or an object is said to be superimposable if it
is identical and indistinguishable from its mirror image.
Example:

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Example of Dissymmetric Objects:
Our left hand and right hand are mirror image to each other, but are
non-superimposable.

Many objects like key, screws, gloves posses this “hand like” property
(property of handedness).
Such property of objects is called Chirality.
Therefore, any dissymmetric object is called chiral.
Symmetric objects are called achiral
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 Chiral: any molecule that is nonsuperposable with its mirror
image (“handedness”) . They are Enantiomers.
 Achiral: are Molecules that are superimposable on their mirror
images. Achiral molecules are not Enantiomers.
 Chirality center: a carbon atom bearing 4 different atoms or
group of atoms. It is also called Stereocenter, stereogenic center,
chiral center, asymmetric center or asymmetric carbon.
i.e. w Example:
* y H
x C
z CH C* CH2CH3
3

OH 2-Butanol
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 There are also organic molecules, including many drugs, that
show the same property like chiral objects (property of
handedness, dissymmetric) and symmetric property.
Example:

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Question. How do we know whether a given organic molecule
is symmetric or dissymmetric?
 There are elements of symmetry!
 Elements of symmetry, as the name implies, are used to decide
(determine) whether a given organic molecule is symmetric or
dissymmetric.
 There are three elements of symmetry
a. Plane of symmetry (mirror plane)
b. Center of symmetry
c. Alternate axis of symmetry

 Plane of symmetry divides a molecule in to two equal parts that

are related to each other as an object and mirror image.

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Example: Propanoic acid has planes of symmetry while
2-hydroxypropanoic acid (Lactic acid) has no plane of
symmetry.

 Axis of symmetry is an axis through which rotation of the

molecule, by a certain angle, will result in an arrangement
indistinguishable or identical with initial molecule.
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 Center of symmetry is defined as a point in the molecule through
which if a line is drawn in one direction and extended to equal
distance in opposite direction, it meets another similar group or
atom.
 The following molecules have center of symmetry.
H H Br
H
Cl H Br
C
Cl Br
H
H
H H Br
Generally:
– If any symmetry of element is present in a molecule, then the
molecule will be symmetric molecule or achiral.
– A molecule will be Dissymmetric (chiral or asymmetric) if it
has no any of the elements of symmetry.

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 Naming Enantiomers:
The R,S System of Nomenclature
 In naming stereoisomers, the Cahn-Ingold-Prelog convention is
used to identify the configuration (arrangement) of each
asymmetric carbon present in a molecule.
The Sequence Rules are:
1. Rank the groups (or atoms) bonded to the asymmetric carbon in
order of priority. The atomic numbers of the atoms directly
attached to the asymmetric carbon determine the relative priorities.
The higher the atomic number, the higher the priority.
Example priorities:
I > Br > Cl > S > F > O > N > 13C > 12C > 3H > 2H > 1H
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2. Orient the molecule so that lowest-ranked substituent (4th ranked)
points away from you.
 Then draw an imaginary arrow from the group (or atom) with the
highest priority (1) to the group (or atom) with the next highest
priority (2).
 If the arrow points clockwise, the asymmetric carbon has the R
configuration (R is for rectus, which is Latin for “right”). If the
arrow points counterclockwise, the asymmetric carbon has the S
configuration (S is for sinister, which is Latin for “left”).

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Example:

3. If two or more of the atoms directly attached to the chiral center

are of the same type, look at the next atom to break the tie.
Repeat this process until the tie is broken.
4. If there are atoms containing double or triple bonds, count them
twice or thrice respectively. This holds for each of the atoms
involved in the double or triple bonding.
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Examples:
2
CH2CH2Br
C 4
3 H
CH3CH2
CH(CH3)2
1
(S)-1-Bromo-3-ethyl-4-methylpentane

(S)-2,3-Dihydroxypropanal

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 Properties of Enantiomers
• A pair of enantiomer is possible for a molecule that contain a
tetrahedral carbon atom with four different groups attached to it.
(i.e. chiral carbon).
• Enantiomers have the same physical properties like m.pt, b.pt,
color, hardness, density, solubility, etc, except “Optical Activity”.
• Enantiomers have the same chemical properties (reactivities)
except towards chiral substances where they behave differently.
Optical Activity:
 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.
 Optically active substances interact with plane polarized light there
by resulting in rotation of the plane polarized light.
• Two enantiomers of a molecule rotate the plane polarized light in
different direction with equal degree.
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Question: What is a plane polarized light?
• It is a polarized light vibrating in a single plane perpendicular to
the direction of propagation.

Viewer

Figure: Polarimeter

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 To be optically active, the sample must contain a chiral substance

and one enantiomer must be present in excess of the other.

 A substance that does not rotate the plane of polarized light is
said to be optically inactive. All achiral substances are optically
inactive.
 A solution containing equal quantities of enantiomers therefore
exhibits no net rotation because all the tiny increments of
clockwise rotation produced by molecules of one “handedness”
are canceled by an equal number of increments of
counterclockwise rotation produced by molecules of the opposite
handedness.
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 If an optically active compound rotates the plane of polarization
clockwise, it is called Dextrorotatory, indicated by positive
sign(+).
 If an optically active compound rotates the plane of polarization
counterclockwise, it is called Levorotatory, indicated by
negative sign (-).
 Dextro and Levo are Latin prefixes for “to the right” and “to the
left,” respectively.
N.B: Do not confuse (+) and (-) with R and S. The (+) and (-)
symbols indicate the direction in which an optically active
compound rotates the plane of polarization, whereas R and S indicate
the arrangement of the groups about an asymmetric carbon. Some
compounds
06/14/2024 with the R configuration are (+) and some are (-). 21
 Racemic mixtures
 Mixtures containing equal amounts of two enantiomers are called
racemic mixtures or racemates.
 Racemic mixtures are optically inactive. Conversely, when one
enantiomer is present in excess, a net rotation of the plane of
polarization is observed. At the limit, where all the molecules are
of the same handedness, we say the substance is optically pure.
 Optical purity, or percent enantiomeric excess, is defined as:
Optical purity = percent enantiomeric excess
= % of one enantiomer - % of other enantiomer

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 Resolution of Racemic mixtures
 A racemic mixture is a 50:50 mixture of two enantiomers. Because they
are mirror images, each enantiomer rotates plane-polarized light in an
equal but opposite direction and is optically inactive. If the enantiomers
are separated, the mixture is said to have been resolved.
 Separation of racemates into their component enantiomers is a process
called resolution.
 Since enantiomers have identical physical properties, such as solubility
and melting point, resolution is extremely difficult. Diastereomers, on
the other hand, have different physical properties, and this fact is used
to achieve resolution of racemates. Reaction of a racemate with an
enantiomerically pure chiral reagent gives a mixture of diastereomers,
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which can be separate
 There are three methods of Resolving Racemic mixtures:
I) Using of chiral reagents
 Chiral reagents are compounds that selectively react with one
enantiomer over the other, leading to the formation of a
diastereomeric product that can be separated using traditional
methods such as chromatography.
II) Using of enzymatic reactions
 Enzymes are highly chiral molecules that can selectively react
with one enantiomer over the other, leading to the formation of a
single product.
III) Using physical methods such as crystallization can also be
used to resolve racemic mixtures.
 In this method, a racemic mixture is dissolved in a solvent and
allowed to crystallize. If the crystals that form are
enantiomerically pure, they can be separated using traditional
methods such as filtration or chromatography.
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 Meso compounds
A meso compound is a molecule with multiple stereocenters that is
superimposable on its mirror image.
Meso compounds contain a plane of symmetry so that they
possess two mirror image halves. Thus, they are achiral molecules.
It is a non-optically active member of a set of stereoisomers.
Example:
Plane of symmetry

meso-2, 3-dibromobutane
 This molecule has a plane of symmetry. The plane divides the
molecule into halves that are mirror images of each other.
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Example: stereoisomers of 2,3-Dibromobutane .
Mirror
Plane of symmetry

Remark:

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 Fischer Projections
 A Fischer projection or Fischer projection formula is a convention
used to depict a three dimensional formula in two dimension
without destroying the stereochemical information, i.e.,
absolute configuration, at chiral centers.
Rules for drawing Fischer projection of a molecule
 a chiral carbon is placed at the intersection of horizontal and
vertical lines.
 The longest carbon chain is on vertical position.
 The lowest numbered carbon is at the top
 Vertical line represents the bond that project behind the plane of
the paper;
 Horizontal line represents the bond that project out of the plane
of the paper.
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 Example 1. Fischer projection formula of 2-butanol
H CH3 CH3
CH2CH3
HO C HO C H HO H
CH3 CH2CH3
CH2CH3
Example 2. Fischer projection of (R)-1,2-propanediol

 Highest oxidized carbon is placed at the top

 Rotation of 180 in plane doesn’t change molecule. Do not rotate 900!
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Determining R and S in Fischer Projections
 Determining whether a chiral carbon is R or S may seem difficult
when using Fischer projections, but it is actually quite simple.
 If the lowest priority group (often a hydrogen) is on a vertical bond,
the configuration is given directly from the relative positions of the
three higher-ranked substituents.
 If the lowest priority group is on a horizontal bond, the positions of
the remaining groups give the wrong answer (you are in looking at
the configuration from the wrong side), so you simply reverse it.

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• Example: Determine if carbon #2 in D-glucose is R or S.
Answer: When deciding whether a stereocenter in a
Fischer projection is R or S, realize that the hydrogen,
in a horizontal bond. Therefore, the orientation of the
three remaining substituents is reversed to create the
correct answer or a counterclockwise circle means R,
and a clockwise circle means S. For carbon #2 in D-
Glucose substituent 1, 2, and 3 form a
counterclockwise circle so the carbon is R.

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 Molecules with Multiple asymmetric centers
Chirality centers in molecules that are two or more are called
multiple asymmetric centers.
Molecules with “n” asymmetric carbons(chiral centers) have
maximum of 2n stereoisomers.
Example: 2-bromo-3-chlorobutane

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Question: How many possible stereoisomers does 2,3-dibromobutane
have?
Solution: * * , has two stereocenters. Thus, it will have
22 = 4 stereoisomers

N.B.
The 2n rule will not apply to compounds that may have a plane
of symmetry. 2,3-dibromobutane has only 3 stereoisomers:
(±) Diastereomers and the meso Diastereomer.
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 Conformational Isomerism
 Isomers that differ as a result of sigma bond rotation of C-C bond
by some degree in alkanes.
Consider ethane: H H H
60 0
H 0 0

H H H HH
H C C H
H H
H H H H
H

Dihedral angle(ϕ) is the degree measure between one of the front

substituent and the substituent on the back carbon.
Based on the dihedral angle, conformers can be two type:
Eclipsed or Staggered.
Eclipsed Dihedral angle(ϕ) : 0, 120, 240, 360
Staggered Dihedral angle(ϕ): 60, 180, 300

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 H CH3 00 CH 600
Example: H H3C
3
CH3 H
H CH3 H3C
H3C C
1200
C H H H
H H H
H H H H
H H CH3
Butane Eclipsed Staggered
Eclipsed
Goach

H
CH3 CH3 H3C CH3
H3C
H3C H 2400 H H
1800
H H H H H
H H3C H H
H H H H CH3
0
3600 300 Eclipsed
Staggered
Eclipsed Staggered Anti
Goach

 Different conformers have different energy and hence different

stability depending on torsional strain, steric strain and angle strain.
 Generally, the staggered conformer is found to be more stable than
eclipsed; and from the two staggered structures, the anti conformer
is again more stable.
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