Organic Chemistry

Fourth Edition
David Klein

Chapter 5

Stereoisomerism
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Copyright ©2021 John Wiley & Sons, Inc.

5.1 Isomers – Overview / Two Types
• Isomers are different compounds that have the same
formula
• There are two general types of isomers
Isomers

Constitutional isomers Stereoisomers

Same molecular formula but Same molecular formula
different constitution (order and constitution but
of connectivity of atoms) different spatial
arrangement of atoms
Copyright ©2021 John Wiley & Sons, Inc. 2
5.1 Isomers – Overview / Stereoisomers
• Although the two molecules below have the same connectivity,
they are not identical. So they are stereoisomers

(Both groups on (Both groups on

same side of ring) opposite sides)
• In order to give these compounds unique IUPAC names, we use
the cis and trans prefixes

Copyright ©2021 John Wiley & Sons, Inc. 3

5.1 Isomers – Overview / Examples
• To maintain orbital overlap in the pi bond, C=C double bonds
cannot freely rotate.
• Although the two molecules below have the same connectivity,
they are not identical… they are stereoisomers

Groups on same Groups on

side of pi bond opposite sides

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5.1 Isomers – Overview / Practice One
• Identify the following pairs as either constitutional
isomers, stereoisomers, or identical structures

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5.1 Isomers – Overview / Practice Two
• Identify the following as either cis, trans, or neither.

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5.2 Stereoisomers / Definition of a
Chiral Molecule
• cis-trans isomerism is only one type… there are other
important stereoisomeric relationships
• To identify such stereoisomers, we must be able to
identify chiral molecules
• A chiral object is asymmetric, which means it is not
the same as its mirror image (i.e. not superimposable
on its mirror image)
• You can test whether two objects are identical by
seeing if they are superimposable.
Copyright ©2021 John Wiley & Sons, Inc. 7
5.2 Molecular Chirality
• Chirality is important in molecules.
o Because two chiral molecules are mirror images, they
will have many identical properties, but because they are
not identical, their pharmacology may be very different
• Visualizing mirror images of molecules and
manipulating them in 3-D space to see if they are
superimposable can be very challenging, so…
…it is absolutely critical that you use handheld models as
visual aids

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5.2 Stereoisomers / Mirror Images
• Chirality most often results when a carbon atom is bonded to
four unique groups of atoms.

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5.2 Stereoisomers / Practice One
• When an atom (like carbon) forms a tetrahedral center with four
different groups attached to it, it is called a chiral center
• Analyze the attachments for each chiral center below

Each highlighted
carbon is bonded to
4 different groups
and is a chiral center

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5.2 Stereoisomers / Practice Two
• How many chiral centers are in each of the following
compounds?

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SkillBuilder 5.1
Propoxyphene, sold under the trade name Darvon, is an
analgesic and antitussive. Identify all chiral centers in
propoxyphene:

Copyright ©2021 John Wiley & Sons, Inc. 12

5.2 Enantiomers / Definition of
Enantiomers
• Some stereoisomers can also be classified as enantiomers
• Enantiomers are two molecules that are mirror images but are
not superimposable, therefore not identical
• Only a chiral compound can have an enantiomer

this is a chiral … the mirror image

compound… will be its enantiomer

Copyright ©2021 John Wiley & Sons, Inc. 13

5.2 Enantiomers / Example of Two
Enantiomers
• Some stereoisomers can also be classified as enantiomers
• Enantiomers are two molecules that are mirror images but are
not superimposable, therefore not identical
• Only a chiral compound can have an enantiomer

this is a chiral … the mirror image

compound… will be its enantiomer

Copyright ©2021 John Wiley & Sons, Inc. 14

5.2 Enantiomers / Drawing
Enantiomers
• Another, often easier way to draw the enantiomer of a chiral
compound is to invert the dashes and wedges of a chiral center

enantiomers enantiomers

this is not a chiral compound, so inverting the

dashes/wedges provides an identical structure
Copyright ©2021 John Wiley & Sons, Inc. 15
5.3 Designating R vs. S Configuration /
Introduction
• Enantiomers are different compounds, so they must not have
identical names
• They have opposite configuration at their chiral center(s)

• We use the Cahn-Ingold-Prelog system to designate each chiral

center as having either the “R” or “S” configuration.
• If a compound has the “R” configuration at a chiral center, then
the enantiomer will have the “S” configuration
Copyright ©2021 John Wiley & Sons, Inc. 16
5.3 Designating R vs. S Configuration /
Four Steps
• “R” or “S” is assigned to a chiral center using a stepwise
procedure
1. Using atomic numbers, prioritize the four groups attached to the
chiral center (1, 2, 3 and 4)
2. Arrange the molecule in space so the lowest priority group faces
away from you
3. Count the group priorities 1…2…3 to determine whether the
order progresses in a clockwise or counterclockwise direction
4. Clockwise = R and Counterclockwise = S

Copyright ©2021 John Wiley & Sons, Inc. 17

5.3 Designating R vs. S Configuration /
Step One
• The Cahn, Ingold and Prelog system
1. Using atomic numbers, prioritize the four groups attached to the
chiral center. The higher the atomic number, the higher the
priority

• The atom with the largest atomic number is assigned the highest
priority (1), and so on…
Copyright ©2021 John Wiley & Sons, Inc. 18
5.3 Designating R vs. S Configuration /
Step Two
• The Cahn, Ingold and Prelog system end
2. Arrange the molecule in space so the lowest priority group
faces away from you

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5.3 Designating R vs. S Configuration /
Step Three
• The Cahn, Ingold and Prelog system
3. Counting the other group priorities, 1…2…3, determine
whether the order progresses in a clockwise or
counterclockwise direction
Clockwise = R and Counterclockwise = S

and so we just determined

this chiral center has the (S)
configuration
Copyright ©2021 John Wiley & Sons, Inc. 20
5.3 Designating R vs. S Configuration /
Challenges
• When the groups attached to a chiral center are similar, it can be
tricky to prioritize them
• Analyze the atomic numbers one layer of atoms at a time

The 1 and 4 groups are So we have to compare the

obvious, but there is a tie atomic weights of the atoms
for priority 2 and 3 bonded to each carbon to
break the tie
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5.3 Designating R vs. S Configuration /
First and Second Layers
• Analyze the atomic numbers one layer of atoms at a time

• First layer

The priority is based on the

first point of difference!
• Second layer

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5.3 Designating R vs. S Configuration /
Double Bonds
• When prioritizing for the Cahn, Ingold and Prelog system,
double bonds count as two single bonds

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5.3 Rotating the Molecule / Useful
Trick
• Handheld molecular models can be very helpful when
arranging the molecule in space so the lowest priority
group faces away from you
• Here are some other tricks that you can use
o Switching two groups on a chiral center will produce its
opposite configuration

Copyright ©2021 John Wiley & Sons, Inc. 24

5.3 Rotating the Molecule / More
Useful Tricks
• Switching two groups on a chiral center will produce its
opposite configuration
• You can use this trick to adjust a molecule so that the lowest
priority group faces away from you.

• With the fourth priority group facing away, you can designate the
configuration as R.
• Switching two of the groups, twice, returns the original
configuration but allows us to put the priority 4 group pointing
away.
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5.3 CIP Rules
A review of Cahn-Ingold-Prelog rules: assigning the
configuration of a chiral center

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SkillBuilder 5.3
The following bond-line structure represents one enantiomer of
2-amino-3-(3,4-dihydroxyphenyl)propanoic acid, used in the
treatment of Parkinson’s disease. Assign the configuration of the
chiral center in this compound.

Copyright ©2021 John Wiley & Sons, Inc. 27

5.3 (R) and (S) in IUPAC
Nomenclature
• The (R) or (S) configuration is used in the IUPAC name for a
compound to distinguish it from its enantiomer

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5.4 Optical Activity
• Because the structures of enantiomers only differ in the same
way your right hand differs from your left, they have the same
physical properties.

• Enantiomers only differ in (1) how they interact with other

chiral compounds, and (2) their optical activity

Copyright ©2021 John Wiley & Sons, Inc. 29

5.4 Optical Activity / Plane-Polarized
Light
• Enantiomers have opposite configurations (R vs. S), and rotate
plane-polarized light in opposite directions

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5.4 Optical Activity / Chiral
Compounds
• To get light waves that travel in only one plane, light travels
through a filter.

• When plane-polarized light is passed through a sample of

chiral compound, the plane that the light travels on will rotate.
• Compounds that can rotate plane-polarized light are optically
active. Only chiral compounds are optically active.
Copyright ©2021 John Wiley & Sons, Inc. 31
5.4 Optical Activity - Polarimeter

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5.4 Optical Activity - Polarimeter

from Rudolph Research Analytical

(https://rudolphresearch.com/wp-
content/uploads/2021/05/Polarimeter-AUTOPOL.jpg)

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5.4 Optical Activity / Specific Rotation
• Enantiomers will rotate the plane of the light to equal degrees but
in opposite directions
• The degree to which light is rotated depends on the sample
concentration and the pathlength of the light
• Standard optical rotation measurements are taken with 1 gram of
compound dissolved in 1 mL of solution, and with a pathlength of
1 dm for the light
α
Temperature and the Specific rotation =  α  =
wavelength of light can also c×l

αλ wavelength
affect rotation and must be T
temperature
reported with measurements
that are taken
Copyright ©2021 John Wiley & Sons, Inc. 34
5.4 Optical Activity / Examples
• Consider the enantiomers of 2-bromobutane

• (R) and (S) refer to the configuration of the chiral center

• (+) and (−) signs refer to the direction that the plane of light is
rotated

Copyright ©2021 John Wiley & Sons, Inc. 35

5.4 Optical Activity / Dextrorotary
and Levorotary
• (+) rotation is called dextrorotary, and (−) is levorotary
• The compound below has the (S) configuration

• Its optical rotation is levorotatory (−) at 20° C, but it is

dextrorotatory (+) at 100 ° C
• There is no correlation between R/S and +/ −

Copyright ©2021 John Wiley & Sons, Inc. 36

5.4 Optical Activity / Racemic
Mixtures
• The magnitude and direction of optical rotation cannot
be predicted, and has to be measured experimentally
• However, we can predict the rotation of a racemic
mixture to be 0° (the optical rotation of each
enantiomer cancels each other).
o Racemic mixture: 50/50 mixture of two enantiomers
• If one enantiomer is present in excess, relative to the
other, then the mixture will have an optical rotation,
but it will be less than the pure enantiomer.

Copyright ©2021 John Wiley & Sons, Inc. 37

5.4 Enantiomeric Excess
• For unequal amounts of enantiomers, the enantiomeric excess
(% ee) can be determined from the optical rotation

• Suppose a mixture of (R) and (S) 2-bromobutane has a spcific

rotation of −4.6°. This allows us to determine the % ee
observed α (−4.6)
% ee = ×100% 100% = 20% ee
α of pure enantiomer (−23.1)

Copyright ©2021 John Wiley & Sons, Inc. 38

SkillBuilder 5.4
When 0.300 g of sucrose is dissolved in 10.0 mL of water and
placed in a sample cell 10.0 cm in length, the observed rotation is
+1.99o using the D line of sodium at 20oC. Calculate the specific
rotation of the sucrose.

Copyright ©2021 John Wiley & Sons, Inc. 39

SkillBuilder 5.5
The specific rotation of optically pure adrenaline in water at 25oC is
-53. A chemist devised a synthetic route to prepare optically pure
adrenaline, but it was suspected that the product was contaminated
with a small amount of the undesirable enantiomer. The specific
rotation of the mixture was found to be -45. Calculate the %ee of
the product.

Copyright ©2021 John Wiley & Sons, Inc. 40

5.5 Enantiomers and Diastereomers /
Definitions
• Categories of isomers * there are two sub-categories
of stereoisomers

• Enantiomers: stereoisomers that are mirror images

• Diastereomers: stereoisomers that are not mirror images

Copyright ©2021 John Wiley & Sons, Inc. 41

5.5 Enantiomers and Diastereomers /
Examples
• Consider the structures of cis- and trans-2-butane.

• They are stereoisomers, but not mirror images of each other. So,
they are diastereomers!
• Recall that enantiomers have identical physical properties.
• Diastereomers have different physical properties.

Copyright ©2021 John Wiley & Sons, Inc. 42

5.5 Stereoisomeric Relationships /
Introduction
• Consider a cyclohexane with three substituents

• There are three stereocenters here, and so there are eight

possible stereoisomers (all drawn above). Consider the
relationship among them (enantiomers vs. diastereomers)

Copyright ©2021 John Wiley & Sons, Inc. 43

5.5 Stereoisomeric Relationships /
Eight Stereoisomers
• Notice these eight stereoisomers are comprised of four pairs of
enantiomers

You can think of this as a family where there are four pairs of twins,
for a total of eight kids. Each kid has seven siblings, where one of
them is their twin (i.e. enantiomer) and the other six are
diastereomers
Copyright ©2021 John Wiley & Sons, Inc. 44
5.5 Stereoisomeric Relationships /
Effect of Number of Chiral Centers
• The number of possible stereoisomers for a compound depends
on the number of chiral centers (n) in the compound
Maximum number of stereoisomers = 2n
• What is the maximum number of possible cholesterol isomers?

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SkillBuilder 5.6
Identify whether each pair of compounds are enantiomers or
diastereomers.

Copyright ©2021 John Wiley & Sons, Inc. 46

5.6 Symmetry and Chirality /
Introduction
• Any compound with only one chiral center will be a chiral
compound
• With more than one chiral center, a compound may not be
chiral; it may have a plane of symmetry
• Consider the stereoisomers below, which possess TWO chiral
centers:

trans-1,2-dimethylcyclohexane cis-1,2-dimethylcyclohexane
Copyright ©2021 John Wiley & Sons, Inc. 47
5.6 Symmetry and Chirality / cis vs
trans
• The trans isomer is chiral, but the cis isomer is not (it is achiral)

• If a molecule has a plane of

symmetry, it will be achiral
The cis isomer has a plane of
symmetry, which means it
will be superimposable on its
mirror image, and is not a
chiral compound

Copyright ©2021 John Wiley & Sons, Inc. 48

5.6 Symmetry and Chirality / Meso
Compounds
• Molecules with an even number of
chiral centers that have a plane of
symmetry are called meso compounds
• Another way to test if a compound is a
meso compound is to see if it is
identical to its mirror image
• Draw the mirror image of the cis isomer and show that it can be
superimposed on its mirror image
• By definition, when a compound is identical to its mirror image,
it is not chiral. It is achiral.

Copyright ©2021 John Wiley & Sons, Inc. 49

5.6 Symmetry and Chirality / Achiral
Compounds
• If a compound has a plane of symmetry, it is achiral
• But… a compound that lacks a plane of symmetry may still be
an achiral compound… if it has reflectional symmetry through
inversion about a central point in the molecule
• The molecule to the right has two chiral
centers, and no plane of symmetry, but
it is still achiral because of inversion

Copyright ©2021 John Wiley & Sons, Inc. 50

5.6 Symmetry and Chirality /
Summary
• Overall:
o The presence or absence of rotational symmetry is
irrelevant to chirality.
o A compound that has a plane of symmetry is achiral.
o A compound without a plane of symmetry will
usually be chiral, but there are exceptions (such as a
compound with an inversion center).

Copyright ©2021 John Wiley & Sons, Inc. 51

5.6 Meso Compounds
• A compound with chiral centers, but is achiral because of
symmetry is called a meso compound
• The molecules below are meso compounds:

• meso compounds have less than the predicted number of

stereoisomers based on the 2(n) formula

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SkillBuilder 5.7
Draw all possible stereoisomers of 1,3-dimethylcyclopentane.

Copyright ©2021 John Wiley & Sons, Inc. 53

5.7 Fischer Projections / Introduction
• Fischer projections can also be used to represent molecules with
chiral centers
• Horizontal lines represent attachments coming out of the page
• Vertical lines represent attachments going back into the page

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5.7 Fischer Projections / Examples
• Fischer projections are most useful when drawing molecules
having multiple chiral centers (like sugars, shown below).

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5.7 Fischer Projections / Enantiomers
vs Diastereomers
• Fischer projections are also useful to quickly assess
stereoisomeric relationships

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SkillBuider 5.8
Assign the configuration of the chiral center in the following
compound:

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5.8 Conformationally Mobile
Compounds
• Molecules can rotate around single bonds.
• Recall the gauche rotational conformations of butane.

• Realize that these conformations are chiral and are actually

enantiomeric.
• But, because these rotamers are interchangeable via bond
rotation, butane is not a chiral compound.
Copyright ©2021 John Wiley & Sons, Inc. 58
5.8 Interconverting Enantiomers
• Compare both possible chair conformations of (cis)-1,2-
dimethylcyclohexane

• These conformations are chiral, and also enantiomeric

• However, these conformations interconvert, and overall this is
an achiral compound (possesses a plane of symmetry)

Copyright ©2021 John Wiley & Sons, Inc. 59

5.9 Chirality without Chiral Centers /
Atropisomers
• Atropisomers: stereoisomers that would be interchangeable
through the rotation of a sigma bond, but because the bond is
unable to rotate, the different conformations are “stuck” and not
interchangeable.

• (R) and (S)-BINAP are chiral, and enantiomers of one another,

even though they do not have any chiral centers (they instead
have an “axis of chirality.”
Copyright ©2021 John Wiley & Sons, Inc. 60
5.9 Chirality without Chiral Centers /
Allenes
• Allenes: compounds that possess two adjacent C=C double
bonds. They may or may not be chiral depending on the
substituents

• The two groups on

each end of the
allene are different;
it will be a chiral
compound

Copyright ©2021 John Wiley & Sons, Inc. 61

5.10 Resolution of Enantiomers /
Challenge
• Most methods of separating compounds from one another
take advantages of the compounds’ different physical
properties
o Distillation– separates compounds with different boiling
points
o Recrystallization– separates compounds with different
solubilities
• Such methods often don’t work to separate enantiomers
from one another, because they have identical physical
properties
Copyright ©2021 John Wiley & Sons, Inc. 62
5.10 Resolution of Enantiomers /
Pasteur Method
• In 1847, Pasteur performed the first resolution of enantiomers
from a racemic mixture of tartaric acid salts

• The different enantiomers formed different shaped crystals that

were separated by hand using tweezers
• However, this method doesn’t work for most pairs of
enantiomers

Copyright ©2021 John Wiley & Sons, Inc. 63

5.10 Resolution of Enantiomers /
Resolving Agent
• Another method is to use a chiral resolving agent

• The differing physical properties of diastereomers allow them to

be more easily separated
Copyright ©2021 John Wiley & Sons, Inc. 64
5.10 Resolution of Enantiomers /
Additional Methods
• Affinity chromatography is often used to separate
compounds
• A glass column (or tube) is packed with a solid substance
to act as an adsorbent, and a mixture is passed through it.
• If a chiral adsorbent is used, then enantiomers will
interact with it differently, and travel through the column at
different rates, allowing for their individual collection (thus
separation).
• This is a very common way for resolving enantiomers

Copyright ©2021 John Wiley & Sons, Inc. 65

5.11 E and Z Designations for Alkenes /
Introduction
• For molecules with different groups attached to the C=C double
bond, the E/Z notation is used instead of cis/trans notation

Cis/trans isn’t adequate to differentiate

between these two diastereomers

• cis/trans only works if there are like groups on each carbon of

the alkene

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5.11 E and Z Designations for Alkenes /
Step One
• Assigning E or Z to a C=C double bond:
1. Prioritize the groups attached to the C=C double bond based on
atomic number

Copyright ©2021 John Wiley & Sons, Inc. 67

5.11 E and Z Designations for Alkenes /
Step Two
• Assigning E or Z to a C=C double bond:
1. Prioritize the groups attached to the C=C double bond based
on atomic number
2. If the top priority groups are on the same side of the C=C
double bond, it is Z (for zussamen, which means together)
If the top priority groups are on opposite sides of the C=C
double bond, it is E (for entgegen, which means opposite)

Copyright ©2021 John Wiley & Sons, Inc. 68

SkillBuilder 5.9
Identify the configuration of the following alkene:

Copyright ©2021 John Wiley & Sons, Inc. 69