Organic Chemistry

Third Edition
David Klein

Chapter 5
Stereoisomerism

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 5.1 Isomers - Overview
• Isomers are different compounds that have the same formula
• There are two general types of isomers

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 5.1 Isomers - Overview
• Although the two molecules below have the same connectivity,
they are NOT identical. So they are stereoisomers

cis-1,2-dimethylcyclohexane trans-1,2-dimethylcyclohexane
(both groups in same side of ring) (Both groups on opposite sides)

• In order to give these compounds unique IUPAC names, we use

the cis and trans prefixes

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

cis-2-butene trans-2-butene
Groups on same side of pi bond Groups on opposite sides
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 5.1 Isomers - Overview
• Identify the following pairs as either constitutional isomers,
stereoisomers, or identical structures
OH

HO

OH OH

HO
OH

O *Answers on the next slide*

O

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 5.1 Isomers - Overview
• Identify the following pairs as either constitutional isomers,
stereoisomers, or identical structures
OH

HO

identical
OH OH identical

HO
OH
stereoisomers

O stereoisomers
O

Constitutional isomers
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 5.1 Isomers - Overview
• Identify the following as either cis, trans, or neither.
OH

OH
OH

HO

*answers on next slide*

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 5.1 Isomers - Overview
• Identify the following as either cis, trans, or neither.
OH
trans

cis
OH
OH
cis
neither
HO

trans
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 5.2 Stereoisomers
• 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.

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 5.2 Molecular Chirality
• Chirality is important in molecules.

– 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

3D 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
• Chirality most often results when a carbon atom is bonded to 4
unique groups of atoms.

• Make a handheld model to prove to yourself that they are

NOT superimposable

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 5.2 Stereoisomers
• When an atom (like carbon) forms a tetrahedral center with 4
different groups attached to it, it is called a chirality center

• Analyze the attachments for each chirality center below

each highlighted carbon

is bonded to 4 different
groups, and is a
chirality center

• Practice with SkillBuilder 5.1

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 5.2 Stereoisomers
• How many chirality centers are in each of the following
compounds? OH

HO HO

*answers on next slide*

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 5.2 Stereoisomers
• How many chirality centers are in each of the following
compounds? OH

HO HO

no chirality centers two chirality centers

two chirality centers two chirality centers

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 5.2 Stereoisomers
• Practice the Skill 5.4 - Identify and label all the chirality centers in
Vitamin D3

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 5.2 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

Cl

this is a chiral compound… … the mirror image will be its enantiomer

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 5.2 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

Cl

this is a chiral compound… … the mirror image will be its enantiomer

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

enantiomers enantiomers

this is not a chiral compound, so inverting the

dashes/wedges provides an identical structure

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 5.3 Designating R vs S configuration
• Enantiomers are different compounds, so they must not have
identical names
• They have opposite configuration at their chirality center(s)

Cl Cl

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

center as having either the “R” or “S” configuration.
• If a compound has the “R” configuration at a chirality center, then
the enantiomer will have the “S” configuration

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 5.3 Designating R vs S configuration
• “R” or “S” is assigned to a chirality center using a stepwise
procedure

1. Using atomic numbers, prioritize the 4 groups attached to

the chirality 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

• A handheld model can be very helpful visual aid for this process

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 5.3 Designating R vs S configuration
• The Cahn, Ingold and Prelog system

1. Using atomic numbers, prioritize the 4 groups attached to

the chirality 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…

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 5.3 Designating R vs S configuration
• The Cahn, Ingold and Prelog system

2. Arrange the molecule in space so the lowest priority group

faces away from you

**This is the step where it is most helpful to have a handheld

model

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 5.3 Designating R vs S configuration
• 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 chirality

Center has the (S) configuration

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 5.3 Designating R vs S configuration
• When the groups attached to a chirality center are similar, it can
be tricky to prioritize them
• Analyze the atomic numbers one layer of atoms at a time
4 1 4 1

2 3
Tie

The 1 and 4 groups are obvious, but So we have to compare the atomic
there is a tie for priority 2 and 3 weights of the atoms bonded to each
carbon to break the tie

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 5.3 Designating R vs S configuration
• Analyze the atomic numbers one layer of atoms at a time
4 1
• First layer

Tie The priority is based on

the first point of
difference!
• Second layer

3
2

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 5.3 Designating R vs S configuration
• 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
• 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 can use
– Switching two groups on a chirality center will produce its
opposite configuration

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 5.3 Rotating the Molecule
• Switching two groups on a chirality 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 4th 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 4 priority group pointing
away.
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 5.3 CIP Rules Summary

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 5.3 Designating R vs S configuration
• Skillbuilder 5.3 – Assign the configuration of the chiral center in
the following compound

• Get additional practice with Practice the Skill 5.9

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 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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 5.3 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

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

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 5.4 Optical Activity
• 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

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 5.4 Optical Activity - Polarimeter

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 5.4 Optical Activity
• 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

Temperature and the wavelength of temperature

light can also affect rotation and must
be reported with measurements that wavelength
are taken

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 5.4 Optical Activity
• Consider the enantiomers of 2-bromobutane

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

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

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 5.4 Optical Activity
• (+) 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 +/-

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 5.4 Optical Activity
• 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).

• 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.

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 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 specific

rotation of -4.6 ˚. This allows us to determine the % ee

• So, (-4.6) / (-23.1) x 100% = 20 % ee

• Practice with SkillBuilder 5.5

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

• Enantiomers: stereoisomers that are mirror images

• Diastereomers: stereoisomers that are not mirror images

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 5.5 Enantiomers and Diastereomers
• Consider the structures of cis- and trans-2-butene

• 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

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 5.5 Stereoisomeric Relationships
• Consider a cyclohexane with three substituents

• There are three stereocenters here, and so there are 8 possible

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

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 5.5 Stereoisomeric Relationships
• Notice these 8 stereoisomers are comprised of 4 pairs of
enantiomers

Can think of this as a family where there are 4 pairs of twins, for a
total of 8 kids. Each kid has 7 siblings, where one of them is their
twin (i.e. enantiomer) and the other 6 are diastereomers
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 5.5 Stereoisomeric Relationships
• The number of possible stereoisomers for a compound depends
on the number of chirality centers (n) in the compound

• What is the maximum number of possible cholesterol isomers?

• Practice with SkillBuilder 5.6

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

trans-1,2-dimethylcyclohexane cis-1,2-dimethylcyclohexane

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 5.6 Symmetry and Chirality
• 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

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 5.6 Symmetry and Chirality
• Molecules with an even number of chirality
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

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 5.6 Symmetry and Chirality
• 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 an reflectional symmetry through
inversion about a central point in the molecule

• The molecule to the right has two chirality

centers, and no plane of symmetry, but it is
still achiral because of inversion

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 5.6 Symmetry and Chirality

• OVERALL:

• The presence or absence of rotational symmetry is

irrelevant to chirality

• A compound that has a plane of symmetry is achiral

• A compound without a plane of symmetry will

usually be chiral, but there are exceptions (such as a
compound with an inversion center).

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 5.6 Meso Compounds
• A compound with chirality 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

• Practice with Skillbuilder 5.7

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 5.7 Fischer Projections
• Fischer projections can also be used to represent molecules with
chirality 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
• Fischer projections are most useful when drawing molecules
having multiple chirality centers (like sugars, shown below).

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 5.7 Fischer Projections
• Fischer projections are also useful to quickly assess
stereoisomeric relationships

• Practice with SkillBuilder 5.8

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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 rotatomers are interchangeable via bond

rotation, butane is not a chiral compound.

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 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)

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 5.9 Chirality without Chirality Centers
• 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 chirality centers (they instead
have an “axis of chirality.”
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 5.9 Chirality without Chirality Centers
• ALLENES: compounds that possess two adjacent C=C double
bonds. They may or may not be chiral depending on the
substituents,

• The the two groups on each end of the allene are different, than
it will be a chiral compound

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 5.10 Resolution of Enantiomers
• Most methods of separating compounds from one another take
advantages of the compounds’ different physical properties

– Distillation – separates compounds with different boiling

points

– Recrystallization – separates compounds with different

solubilities

• Such methods often don’t work to separate one enantiomer

from its racemate, because they have identical physical
properties/

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

• The differing physical properties of diastereomers allow them to

be more easily separated

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 5.10 Resolution of Enantiomers
• 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

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 5.11 E and Z Designations for Alkenes
• 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 and trans only works if there is a like group on each carbon of
the alkene

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 5.11 E and Z Designations for Alkenes
• 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

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 5.11 E and Z Designations for Alkenes
• 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)

• Practice with SkillBuilder 8.2

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