3: STEREOCHEMISTRY

Hu, Chem Dep. Meseret.A.

  Isomerism
 constitutional isomers
 Stereoisomers
 Chirality
 Types of Stereoisomers
 (R) and (S) Nomenclature
 Fischer Projections
 Multiple Stereogenic Centers
 Optical Activity
 Conformations

Hu, Chem Dep. Meseret.A. 2

Introduction Stereochemistry
To have a better understanding of the properties of organic
molecules, one has to study their three-dimensional (3-D) structure.

? Why is this important?

Our perception of smell and taste depends, in many instances, on the
3-D structure of molecules.
 Enzymes are very selective in the 3-D structure of the
molecules they interact with.
 The effectiveness of drugs is highly dependent on their 3-D
structure.
 Organic chemists need to be able to determine the 3-D
structures (stereochemistry) of new and existing molecules to
relate
Hu, Chem Dep. 3-D structure to reactivity
Meseret.A. 3
 Stereochemistry is defined as area of chemistry that
deals with the properties of molecules which arises due
4
to the three dimensional arrangement in space

 Three dimensional objects are either symmetryic or

dissymmetric

Hu, Chem Dep. Meseret.A.

 Achiral (Symmetry) molecule or an object which is
superimposable on its mirror image

 Chiral (asymmetric) carbon atom :- a tetrahedral

carbon atom that bears four different substituents

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 Chiral object is one that cannot be superimposed on its
mirror image
 Chiral center - stereogenic center

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Hu, Chem Dep. Meseret.A. 7
 A molecule (object) that is not superimposable on its
mirror image is said to be chiral
8

 “Handedness”: Right-hand glove does not fit the left hand

 A molecule (object) that is superimposable on its mirror
image is said to be achiral

Hu, Chem Dep. Meseret.A.

 Elements of Symmetry
9

 The most common elements symmetry are:

1. plane of symmetry
2. center of symmetry
 Plane of symmetry
 bisects a molecule in two parts one half of the
molecule is the mirror image of the other half

Hu, Chem Dep. Meseret.A.

Centre of Symmetry: Centre of Symmetry is the element
of symmetry in which, a line, when drawn from any group
of this molecule, passing through a point at the center of
the molecule, meets an identical group, when extended to
an equal distance, beyond the center point

Trans-1,4-Dimethyl Cyclohexane trans-1,3-dichlorocyclobutane

H2
C

Cl
H

H
Cl

C
H2

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 Isomerism
 Isomers are different compounds with the same
molecular formula

The Two Major Classes of Isomerism

– constitutional isomers
– Stereoisomers

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 12

Hu, Chem Dep. Meseret.A.

 Stereoisomers- same molecular formula, same
bonding sequence, different spatial orientation

cis -1,2- dichloroethene trans -1,2- dichloroethene

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 Constitutional isomers - same molecular formula but
different bonding sequence

 their atoms are connected differently

CH3 H3C CH3
CH2 CH3 C
CH3CH2CH2CH3 Cl C
CH3CHCH3 H2 Cl
n-butane isobutane 1-Chloropropane 2-Chloropropane

Q1. What is the relationship between cis -1,2-dimethyl cyclopentane

and trans -1,2-dimethyl cyclopentane. Are they constitutional isomers
or stereoisomers?

Hu, Chem Dep. Meseret.A. 14

Types of Stereoisomers
 Two types of stereoisomers:
 Enantiomers:
- are stereoisomers whose molecules are
nonsuperimposable mirror images of each other

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 Diastereomers
 are nonsuperimposable non–mirror image
stereoisomers

 Geometric isomers (cis-trans isomers) are one

type of diastereomer

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 • Enantiomers are chiral
• Chiral: Not superimposable on its mirror image

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Q1. What is the relationship between cis -1,2-dimethyl cyclopentane
and trans -1,2-dimethyl cyclopentane. Are they constitutional isomers
or stereoisomers?

Q2. What is the relationship between cis -1,2-dichlorocyclopentane

and trans -1,2-dimethyl cyclopentane. Are they constitutional isomers
or stereoisomers?

H H

Cl Cl

Hu, Chem Dep. Meseret.A. 18

 Optical isomers are configurational isomers which are
able to rotate plane-polarized light clockwise or
anticlockwise

 (R) and (S) Nomenclature of Enantiomers (The Cahn-

Ingold- Prelog (R-S) system)

 The Cahn-Ingold-Prelog convention is used to identify

the configuration of each asymmetric carbon atom
present
Hu, Chem in a stereoisomer19
Dep. Meseret.A.
Rules Needed to Assign Priority
1. Assign priorities (1, 2, 3, or 4) to the atoms
directly bonded to the stereogenic center in order
of decreasing atomic number.
4

H
3 F C Br 1
Cl

2
Hu, Chem Dep. Meseret.A. 20
 The atom of highest atomic number gets the highest
priority (1)

Example priorities:
• I > Br > Cl > S > F > O > N > 13C > 12C > 3H >
2H > 1H

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 Atomic number: F > N > C > H

Hu, Chem Dep. Meseret.A. 22

2. If two atoms on a stereogenic center are the same,
assign priority based on the atomic number of the
atoms bonded to these atoms

 use the next atoms along the chain as

tiebreakers

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• One atom of higher atomic number determines a
higher priority

1
OH
4 2
H C CH2CH3
CH3
3

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3. If two isotopes are bonded to the stereogenic
center, assign priorities in order of decreasing mass
number
• In comparing the three isotopes of hydrogen, the
order of priorities is:

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4. To assign a priority to an atom that is part of a
multiple bond, treat a multiply bonded atom as an
equivalent number of singly bonded atoms

CH3
CH2 CH Cl
C

CH2CH3
CH2
CH2 CH
is equivalent to H2C CH

Hu, Chem Dep. Meseret.A. 26

Hu, Chem Dep. Meseret.A. 27
5. Rotate the formula (model) so that the group with
lowest priority is directly away from us.

• If the lowest priority group is directly away from

us or the observer (in the hidden bond/ break
bond), simply name i.e. no need rotation using
certain degree

Hu, Chem Dep. Meseret.A. 28

6. Look the arrangement order from highest priority
to the third lowest priority (1 to 3)

 If they are found in a clockwise direction as you

go from priority 1 to 2 to 3 that isomer is assigned
to be R

 If they are found in anti clockwise direction it is

assigned to be S

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 Draw an arrow from the 1st priority group to the 2nd
group to the 3rd group
 Clockwise arrow → (R) configuration
 Counterclockwise arrow → (S) configuration

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 Its mirror image is R

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 Its mirror image is ?
Hu, Chem Dep. Meseret.A. 32
 CH3
CH2 CH Cl
C

CH2CH3

(S)-3-chloro-3-methyl-1-pentene

Exercise
Label the following compound as R or S.

Hu, Chem Dep. Meseret.A. 33

 Racemic(Racemate ) Mixture
 an equal amount of two enantiomers
 an equimolar mixture of the (+) and (-) enantiomers

 A racemic mixture is optically inactive

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 Optical Activity and Plane Polarized Light
 Optical activity is the ability of a chiral substance to rotate
the plane of plane-polarized light
 Polarimeter
 an instrument that measures the optical rotation of the
Chiral compound

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Optical Activity and Plane Polarized Light

 Chiral compounds rotate the plane of plane-polarized light

 Chiral- Optically active

 Achiral compounds not rotate the plane of plane-polarized

light

 Achiral - Optically inactive

Hu, Chem Dep. Meseret.A. 36

 Specific rotation, []D is defined as the observed
rotation when light of 589 nm wavelength is used with a
sample path length l of 1dm and a sample concentration
C of 1gm/mL.

Hu, Chem Dep. Meseret.A. 37

Q1. A 1.20 g sample of cocaine, []D -16, was dissolved in 7.50 mL of
chloroform and placed in a sample tube having a path length of 5.00
cm. What was the observed rotation in degrees?

Q2. 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, []D, for coniine.

Hu, Chem Dep. Meseret.A. 38

Specific rotations of selected organic compounds

Compound []D (degrees)

Camphor +44.26

Morphine -132

Sucrose +66.47
Cholestrol -31.5

Benzene 0

Cocaine -16
Hu, Chem Dep. Meseret.A. 39
Multiple Stereogenic Centers: Diastereomers
 Compounds with more than one stereocenters have more than two
stereoisomers
 Many molecules have more than one asymmetric center.
 The maximum number of stereoisomers is 2n, where n is the
number of stereocenters in a molecule.

Hu, Chem Dep. Meseret.A. 40

 I II I II

CH3 CH3 CH3 CH3

Br H
H Br
H C Br Br C H C C

H C Br Br C H C C
Br Br H
H
CH2CH3 CH2CH3 CH2CH3 CH2CH3

Mirror

III IV III IV
CH3 CH3 CH3 CH3
H Br Br H
H C Br Br C H C C
Br C H H C Br C C
H H Br
CH2CH3 CH2CH3 Br CH2CH3 CH2CH3

I and II are mirror image isomers and they are enantiomers also III & IV
are mirror image isomers and they are enantiomers.
I and III or II and IV they are not mirror image to each other while they
are still stereoisomers. What do you call this type of stereoisomerism?
Hu, Chem Dep. Meseret.A. 41
 Meso compounds
 Compounds with chiral centers but which are not
chiral
 Cis-1,2-dichlorocyclopentane is a meso compound
 an achiral compound that contains chiral centers
 Contains plane of symmetry

Hu, Chem Dep. Meseret.A. 42

 The 2n rule will not apply to compounds that may have a
plane of symmetry.
2,3-dibromobutane has only three stereoisomers
It is meso compound
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Hu, Chem Dep. Meseret.A. 44
 Fischer Projections
Fisher Projection Formulas: are three dimensional
formulas of chiral molecules
Asymmetric carbons can be represented by Fischer
projections, in which a tetrahedral carbon atom is
represented by two crossed lines
The vertical lines represent the bonds pointing into
the page (away from the reader),
The horizontal lines represent the bonds pointing out
of the page (towards the reader).

Hu, Chem Dep. Meseret.A. 45

Convention: 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.

(R)-2-hydroxypropanoic acid

Its mirror image is S

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1. Allowed motions for Fischer Projection: 180° rotation (not 90°
or 270°):

2. 90° rotation: Rotation of a Fischer projection by 90°

inverts its meaning.

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2. 90° rotation: Rotation of a Fischer projection by 90° inverts its
meaning.

–COOH and –CH3 go into plane of paper in one projection

but come out of plane of paper in other projection.
3. One group hold steady and the other three can rotate:

Hu, Chem Dep. Meseret.A. 48

 Assigning R,S Configurations to Fischer Projections:
 Procedures for assigning R, S designations:

1. Assign priorities to the four substituents

2. Perform one of the allowed motions to place the

group of lowest priority at the top of the Fischer
projection

3. Determine the direction of rotation in going from

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

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 Draw its mirror image →It has R
S-stereochemistry configuration

S-stereochemistry

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 Conformations
 Conformations are different arrangements of atoms that
are interconverted by rotation about single bonds
 conformer (conformational isomer)
 Specific conformation
 Conformational isomers can be represented by:
 Sawhorse representations or
 Newman projections
 conformational analysis
 An analysis of the energy changes that occur as a
molecule undergoes rotations about single bonds
Hu, Chem Dep. Meseret.A. 51
Conformations of ethane (CH3CH3)
 Rotation around the C-C bond produces two distinctive
conformation

 Eclipsed conformation
 C-H bonds on each carbon atom are as close as
possible

 Staggered conformation
 C-H bonds on each carbon atom are as far apart as
possible

Hu, Chem Dep. Meseret.A. 52

Hu, Chem Dep. Meseret.A. 53
 Fig. 3.1. Conformational analysis of ethane
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 Conformations of butane (CH3CH2CH2CH3)

 In butane, the staggered conformations do not all have

the same energy
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 Anti- conformation
 the most stable as the two methyl groups are as far apart as
possible & does not have torsional strain

 The staggered conformations are more stable than the eclipsed

conformation

Gauche conformations
 the two methyl groups are close enough to each other

 Eclipsed conformation
 have torsional strain and van der Waals repulsions arising from
the eclipsed methyl group and hydrogen atoms

Stability: Anti (Totally staggered) > Gauche (Skew staggered) >

Skew eclipsed > Totally eclipsed
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Figure 3.2. Energy changes that arise from rotation about the
C2 -C3 bond of butane
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Conformations of cycloalkanes

 The shape of cycloalkanes is determined by torsional

strain, steric strain and angle strain

 Steric strain: strain produced when atoms are forced too

close to each other

 Torsional strain: strain caused by eclipsing interactions

 Angle strain: strain produced when bond angles deviate

from 109.5° (for Sp3 hybridized atoms)

 Ring Strain – total strain (sum of torsional, steric and

angle strain)
Hu, Chem Dep. Meseret.A. 58
 Cycloalkanes can adopt different conformations
 cyclopropane is flat
 cyclobutane can form a butterfly shape
 cyclopentane can form an open-envelope shape

 Cyclopentane (5-membered) and cyclohexane (6-

membered) rings are the most stable
Hu, Chem Dep. Meseret.A. 59
• Cyclopropane has to be planar and therefore has
very strained bond angles of 60° and a great deal
of torsional energy

• Cyclobutane and cyclopentane can adopt non-

planar (puckered) shapes which decrease the
torsional strain by staggering the C-H bonds

Hu, Chem Dep. Meseret.A. 60

 Conformation of Cyclohexane
The four main conformations of cyclohexane are:
(a) Chair conformation

(b) Boat conformation

(c)Twist boat conformation

(d)Half chair conformation

Hu, Chem Dep. Meseret.A. 61

1. Chair conformation
 is more stable than any other possible conformation
 it eliminates angle strain (all C –C– C bond angles are
109.5°)

2. Half chair conformation

 the least stable conformation of cyclohexane
 carbon atoms at one end of the ring are planar

Hu, Chem Dep. Meseret.A. 62

3. Boat conformation
 Flagpole interactions cause the boat conformation to
have higher energy (less stable)
 Eclipsing interactions between H’s cause torsional
strain
 the flagpole H’s causes steric strain

 The boat form of cyclohexane is less stable than the

chair forms for two reasons

 Eclipsing interactions between H’s cause torsional strain

 The proximity of the flagpole H’s causes steric strain

Hu, Chem Dep. Meseret.A. 63

4. Twist boat conformation
 Flexible and slight twist the bond reduces the torsional
strain as well as flagpole interactions
 a little more stable than the boat conformation

Hu, Chem Dep. Meseret.A. 64

Stability: Chair conformation >> twist boat conformation
> boat conformation > half chair conformation

Chair conformation

 Cyclohexane has six axial H’s and six equatorial H’s

 Axial hydrogen's are located above and below the ring
(along a perpendicular axis)
 Equatorial hydrogen's are located in the plane of the ring

Hu, Chem Dep. Meseret.A. 65

Conformations of Monsubstituted Cyclohexane
 There are two possible chair conformations of a monosubstituted
cyclohexane

 Ring-flipping
• Axial and equatorial H atoms are interconverted during a ring
flip (converts axial bonds to equatorial bonds, and vice versa)

Hu, Chem Dep. Meseret.A. 66

Conformations of Disubstituted Cyclohexane
There are two possible chair conformations of a substituted
cyclohexane
 Two substituents present on same carbon

CH3
C2H5 bulkier group
at axial position
C2H5 bulkier group
CH3 ocupies
at equatorial position
Less stable More stable

Hu, Chem Dep. Meseret.A. 67

Cis- and trans- isomerism in disubstituted cyclohexanes
 Two substituents present on different carbon
 There are three possible disubstituted cyclohexanes

 1,2-disubstituted cyclohexanes

 1,3-disubstituted cyclohexanes

 l,4-disubstituted cyclohexanes

Hu, Chem Dep. Meseret.A. 68

 Cis- and trans- isomers in chair conformation
 the two substituents may occupy (e,e), (e,a), (a,e),
and (a,a)

1,2-Dimethylcyclohexane
CH3
CH3 down up
up down
CH3 CH3
CH3 CH3
down up up
CH3 down
CH3
trans- (a.a) trans- (e,e) cis (a,e) cis (e,a)

Hu, Chem Dep. Meseret.A. 69

1,3-Dimethylcyclohexane
up CH3 up CH3 CH3 up
down CH3
down down down up
H3C
CH3 CH3 H3C

cis- (a.a) cis (e,e) trans- (e,a) trans- (a,e)

1,4-Dimethylcyclohexane
up CH3 CH3
3 1 HC down down up
2 3

4 CH3 CH3
H3C
down up down up
CH3 CH3
cis-(a,e)
trans- (a.a) trans- (e,e) cis-(e,a)

Hu, Chem Dep. Meseret.A. 70

Exercise
1. Draw the mirror image of each compound, and label the
compound as chiral or achiral.

Cl H H
a. C H C CH3
Cl
C CH
b. e.
CH3CH2 CH3 T D H3C 3

NH2 Cl
H3C d. Br
c. C CH CH C H
H 2 3 BrCH2

2. Draw the chair conformations of each of the following

compounds
a) trans-1-tert-Butyl-3-methylcyclohexane
b) trans-1-tert-Butyl-4-methylcyclohexane
Hu, Chem Dep. Meseret.A. 71
1. Draw the mirror image of each compound, and label the
compound as chiral or achiral.

Hu, Chem Dep. Meseret.A. 72

2.Answer
a) trans-1-tert-Butyl-3-methylcyclohexane

CH3 C(CH3)3 C(CH3)3 CH3

H3C C(CH3)3
H3C
C(CH3)3

cis- (a.a) cis- (e.e) trans- (a,e) trans- (e,a)

b) trans-1-tert-Butyl-4-methylcyclohexane

C(CH3)3 C(CH3)3
C(CH3)3
H3C C(CH3)3 H3C

CH3 CH3

trans- (a,a) trans- (e,e) cis- (a.e) cis- (e.a)

Hu, Chem Dep. Meseret.A. 73