CHAPTER 3

Stereochemistry
 Chapter 3 - Stereochemistry

• STRUCTURAL ISOMERISM (CONSTITUTIONAL)

• GEOMETRICAL ISOMERISM AND OPTICAL ISOMERISM (CONFIGURATIONAL)

Structural Isomerism

• Compounds that have same molecular formula but have the atoms joined
together in a different way

• Have different carbon skeletons

• Have different physical and chemical properties

 Chapter 3 – Stereochemistry

Structural/constitutional Isomerism
C5H12

H2 H2
C H3C H2
H3C C C CH CH C
H2 3 H3C CH3

pentane 2 methyl butane

CH3
H3C
C CH3
CH3

2,2-dimethyl propane
 Chapter 3 – Stereochemistry
GEOMETRICAL ISOMERISM/OPTICAL ISOMERISM
(CONFIGURATIONAL)

• Isomers that have the same molecular formula

and same molecular structure: same atoms and
bonds
• However, the isomers are different because some
of the atoms are arranged differently in space
• Isomers that cannot be interconverted without
breaking and remaking covalent bonds
 Chapter 3 – Stereochemistry
GEOMETRICAL ISOMERISM/OPTICAL ISOMERISM
(CONFIGURATIONAL)

• Configurational isomers are different

compounds having different properties
• Common examples are substituted alkenes
and substituted cycloalkanes
 Chapter 3 – Stereochemistry

GEOMETRICAL ISOMERISM/ (CONFIGURATIONAL)

CH3 H
H CH3 2-butene H CH3 2-methylpropene
H CH3

both methyl groups

on the same side
methyl groups
opposite to one another
CH3 H
CH3 H3C CH3
H
H H
cis-2-butene trans-2-butene
 Alkenes- (Z) and (E) nomenclature
• Cis and trans nomenclature is an old
method of classifying configurational
isomers of alkenes
• It is only suitable for simple 1,2-
disubstituted alkenes
• The Z and E nomenclature allows a clear,
unambiguous definition of alkenes
 E or Z alkenes
P P P = priority atom

H H
Z-alkenes (Z = zusammen, together)

P H

H P

E-alkenes (E = entgegen, across)

 Examples
priority

8 6
H3CO CH3 8 6
C C Is it Z or E H3CO CH3
H CH2-CH3 C C no difference
1 6 H CH2-CH3
1 6

priority

8 6 priority
H3CO CH3 E-1-methoxy 2-methyl 1-butene
C C
H CH2-CH3
1 6
 Substituted Cycloalkanes

H H H CH3
H3C CH3 H3C H

cis-1,2-dimethyl cyclopropane trans-1,2-dimethylcyclopropane

Chapter 3 - Stereochemistry
CONFIGURATIONAL ISOMERS-
OPTICAL ISOMERS
 OPTICAL ISOMERS
Definition
• Optical isomers are configurational isomers
that have the ability to rotate plane polarized
light clockwise or anticlockwise. They have
identical chemical and physical properties
(apart from light) but can have different
biological properties
 Stereoisomers – Mirror Images
• Molecules exist as three-dimensional objects
• Some molecules are the same as their mirror image
• Some molecules are different than their mirror
image
– These stereoisomers are called enantiomers
Examples of Enantiomers
 Examples of Enantiomers
• Molecules that have one carbon with 4 different substituents
have a nonsuperimposable mirror image – enantiomer
• Build molecular models to see this
Examples of Enantiomers
 Chirality Centers
• A point in a molecule where four different groups (or atoms)
are attached to a carbon is called a chirality center
• There are two nonsuperimposable ways that 4 different
different groups (or atoms) can be attached to one carbon
atom
– If two groups are the same, then there is only one way
• A chiral molecule usually has at least one chirality center
 Chirality Centers in Chiral Molecules
• Groups are considered “different” if there is any structural
variation (if the groups could not be superimposed if
detached, they are different)
• In cyclic molecules, we compare by following in each
direction in a ring
 Asymmetric carbon centers
• Carbon that have four different substituents
• Molecules having asymmetric centers will usually be
chiral (few exceptions)
• Nonsuperimposable mirror images of a molecule are
called enantiomers
• An equal mixture of two enantiomers is called a
racemate and does not rotate a plane polarized light
• Asymmetric carbon centers are only possible for sp3
carbons
 Fisher diagrams
• To represent chiral molecules
• Vertical bonds in a Fisher diagram
represents bonds pointing into the
page while the horizontal bonds
represent bonds coming out of the
page
CH3
H2N H
COOH
 Fischer projections
H H
Br Cl Br Cl
F F
Fischer projection (R)-Bromochlorofluoromethane

The molecule is drawn in such a way that the carbon chain

is vertical with the lowest numbered carbon at the top

CH3 CH3
HO H
HO H
CH2CH2CH3 CH2CH2CH3
 R and S nomenclature
To determine the absolute configuration
at asymmetric centers
The groups attached to the asymmetric
centers are given priorities based on their
atomic weights of the atoms directly attached
to the centers
 R and S configuration
X = lowest priority atom, lowest atomic weight
behind the page
P X
R C Q
*

P, Q, R are atoms attached directly to carbon center

Find which has the highest priority, second and third
Then look at the arrangement of the highest, second and third priority
whether it is clockwise (R) or anticlockwise (S)

P X P X
R C Q R C Q
* *

R configuration S configuration
 R and S nomenclature
• Structure of an enantiomer can be specified using R and S
nomenclature, determined by the Cahn-Ingold-Prelog rules

highest priority lowest priority

8
HO H 8 O H1
O H1
H3C C COOH C C C O
* C C C 6
6 6
6

?
?

lowest priority
first priority
8
O H1
Clockwise
C C C O
6
6
second priority

third priority The molecule has R-configuration

R and S nomenclature
CHIRAL DRUGS

Ibuprofen (Advil, Motrin, Nuprin): an anti-inflammatory agent

CHIRAL DRUGS
 (+) and (-)
• Symbols are used to show which direction an
enantiomer rotates plane polarised light
• The direction of the rotation can only be
determined by experimentation
 Specific Rotation
• To have a basis for comparison, define specific
rotation, []D for an optically active compound
• []D = observed rotation/(pathlength x
concentration)
= /(l x C) = degrees/(dm x g/mL)
• Specific rotation is that observed for 1 g/mL in
solution in cell with a 10 cm path using light from
sodium metal vapor (589 nanometers)
 PLANE POLARISED LIGHT


[]D = Observed Rotation (degrees) =
Path length (dm) x Concentration (g/ml) lxc
 A Simple Polarimeter
• Measures extent of
rotation of plane polarized
light
• Operator lines up
polarizing analyzer and
measures angle between
incoming and outgoing
light
 (+) and (-)
• Assignment of an asymmetric center as R or S has
got nothing to do with whichever direction the
molecules rotates plane-polarized light
• Molecules which rotate plane polarized light
clockwise are defined as (+) or d
• Molecules which rotate plane polarized light anti-
clockwise are defined as (-) or l
• An R enantiomer of lactic acid is found to rotate
plane-polarized light anticlockwise is defined as
(R)-(-) –lactic acid
 Question
Calculate the observed rotation of a solution
of 0.5445 g of S-1-amino-1-phenylethane
diluted to a volume of 10 ml with methanol at
200C using the D line of a sodium lamp and a
1.00 dm tube. Specific rotation of this
material:
[]D = -30.00
 Meso Structures
• Molecule can have two identical asymmetric
centers but it is not chiral when it has a plane
of symmetry
• The mirror images of this structure are
superimposable
 Meso Compound

HO
H
COOH rotate around C-C bond *
H * H COOH
HO OH HO
H *
*
COOH COOH
Plane of symmetry
* asymmetric centers
 Diastereoisomers
• Occurs when there are two or more
asymmetric centers
• For a molecule having n asymmetric centers,
the number of possible stereoisomers
(enantiomers) is 2n and the number of
diastereoisomers is 2n-1
 Example of diastereoisomer

Mirror Mirror

COOH COOH COOH COOH

H2N H H NH2 H2N H H NH2
* * * *
* * * *
H OH HO H HO H H OH
CH3 CH3 CH3 CH3
2S, 3R 2R, 3S 2S, 3S 2R, 3R

enantiomers enantiomers

Diastereoisomers
 Racemic Mixture
• Racemic mixture (racemate or racemic form) is an
equimolar mixture of two enantiomers
• A racemic mixture causes no net rotation of plane
polarized light
• In a racemic mixture the effect of each molecule of
one enantiomer on the polarized light cancels the
effect of molecules of the other enantiomer
• The racemic form of a sample is often designated as
(±)