Organic Chemistry
Second Edition
David Klein
Chapter 5
Stereoisomerism
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Klein, Organic Chemistry 2e
Chapter 5: Stereochemistry
• The three-dimensional structure of a molecule can
greatly affect its physical and chemical properties. Can
you give some examples?
• Three dimensional structure is critical in biochemistry.
HOW?
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Klein, Organic Chemistry 2e
Chapter 5: Stereochemistry
• For pharmaceuticals, slight differences in 3D spatial
arrangement can make the difference between targeted
treatment and undesired side-effects. WHY?
• Isomers that have the same connectivity between atoms
but different 3D, spatial arrangement of their atoms are
called STEREOisomers
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5-3
Klein, Organic Chemistry 2e
5.1 Isomers
• Isomers are NONidentical molecules that have the same
formula
• There are two classifications of isomers
• Draw a pair of molecules that are constitutional isomers
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Klein, Organic Chemistry 2e
5.1 Isomers
• C-C bonds that are constrained in a cyclic structure can
not freely rotate
• Although the two molecules below have the same
connectivity, they are NOT identical.
• The naming system we have learned thus far would give
them the same name, but they are NOT identical, so we
need to learn additional nomenclature rules…to be
continued
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Klein, Organic Chemistry 2e
5.1 Isomers
• 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
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Klein, Organic Chemistry 2e
5.1 Isomers
• Identify the following pairs as either constitutional
isomers, stereoisomers, or identical. EXPLAIN
1.
4.
2.
5.
3.
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Klein, Organic Chemistry 2e
5.1 Isomers
• With rings and with C=C double bonds, cis-trans
notation is used to distinguish between stereoisomers
• Cis – identical groups are positioned on the SAME side
of a ring
• Trans – identical groups are positioned on OPPOSITE
sides of a ring
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Klein, Organic Chemistry 2e
5.1 Isomers
• Cis – identical groups are positioned on the SAME side
of a C=C double bond
• Trans – identical groups are positioned on OPPOSITE
sides of a C=C double bond
trans because of the H's
• Practice with SkillBuilder 5.1
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Klein, Organic Chemistry 2e
5.1 Isomers
• Identify the following as either cis, trans, or neither.
EXPLAIN
1.
4.
2.
5.
3.
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Klein, Organic Chemistry 2e
5.2 Stereoisomers
• Beyond cis-trans isomers, there are many other
important stereoisomers
• To identify such stereoisomers, we must be able to
identify chiral molecules
• A chiral object is NOT identical to its mirror image
• You are a chiral object. Look in a mirror and raise your
right hand. Your mirror image raises his or her left hand.
• You can test whether two objects are identical by seeing
if they are superimposable.
• Can you be superimposed upon your mirror image?
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Klein, Organic Chemistry 2e
5.2 Stereoisomers
• Some other chiral objects include gloves. HOW?
• Think of some other examples of chiral everyday objects
• 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
• It is highly recommended that you use handheld models
as visual aids until you get more experience
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Klein, Organic Chemistry 2e
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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Klein, Organic Chemistry 2e
5.2 Stereoisomers
• When an atom such as carbon forms a tetrahedral
center with 4 different groups attached to it, it is called a
chirality center (aka stereocenter or stereogenic center)
• Analyze the attachments for each chirality center below
• Practice with SkillBuilder 5.2
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Klein, Organic Chemistry 2e
5.2 Stereoisomers
• Identify all of the chirality centers (if any) in the
following molecules
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Klein, Organic Chemistry 2e
5.2 Enantiomers
• Some stereoisomers can also be classified as
enantiomers
• Enantiomers are TWO molecules that are MIRROR
IMAGES but are NONidentical and NONsuperimposable
• For the pair below, draw in the missing enantiomer
• Make handheld models for both structures to verify that
they are NONidentical mirror images
• Practice with SkillBuilder 5.3
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Klein, Organic Chemistry 2e
5.2 Enantiomers
• What is the relationship between the two molecules
below?
• Given that the molecules are so similar, how is it
possible that our noses can distinguish between them?
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• Enantiomers are NOT identical, so they must not have
identical names
• How would you name these molecules?
• Their names must be different, so we use the CahnIngold-Prelog system to designate each molecule as
either R or S.
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• The Cahn, Ingold and Prelog system
1. Using atomic numbers, prioritize the 4 groups attached to
the chirality center
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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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• 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
– Prioritize the groups on this molecule
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• 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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Klein, Organic Chemistry 2e
5.3 Designating Configurations
1. Using atomic numbers, prioritize the 4 groups attached to
the chirality center
2. Arrange the molecule in space so the lowest priority group
faces away from you
• Complete steps 1 and 2 for the following molecule
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• 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
4. Clockwise = R and Counterclockwise = S
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• Designate each chirality center below as either R or S.
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• 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
1
time
4
First layer
Tie
Second layer
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• Is this molecule R
or S?
3
2
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• Analyze the atomic numbers one layer of atoms at a
4 1
time
• The priority is
• First layer
based on the first
Tie
• Second layer
3
2
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point of difference,
NOT the sum of
the atomic
numbers
• Is this molecule R
or S?
Klein, Organic Chemistry 2e
5.3 Designating Configurations
• When prioritizing for the Cahn, Ingold and Prelog
system, double bonds count as two single bonds
• Determine R or S for the following molecule
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• 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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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• 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
• Work backwards to show how the original structure’s
configuration is also R
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• Practice with SkillBuilder 5.4
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Klein, Organic Chemistry 2e
5.3 Designating Configurations
• The R or S configuration is used in the IUPAC name for
a molecule to distinguish it from its enantiomer
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Klein, Organic Chemistry 2e
5.4 Optical Activity
• Because the structures of enantiomers are so similar,
many of their properties are identical.
• If you have a sample of a chiral compound, imagine
how can its enantiomeric purity be assessed? In other
words, how can one enantiomer be distinguished from
another?
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Klein, Organic Chemistry 2e
5.4 Optical Activity
• Enantiomers have opposite configurations (R vs. S), so
they will rotate plane-polarized light in opposite
directions
• What is plane-polarized light?
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Klein, Organic Chemistry 2e
5.4 Optical Activity
• To get light waves that travel in only one plane, light
travels through a filter
• When plane polarized light is directed through a
sample of a pure chiral compound, the plane that the
light travels on will rotate.
• Compounds that can rotate the plane or planepolarized light are called optically active
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Klein, Organic Chemistry 2e
5.4 Optical Activity
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Klein, Organic Chemistry 2e
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 light can also
affect rotation and must be reported with
measurements that are taken
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Klein, Organic Chemistry 2e
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
• The optical activity was measured at 589 nm, which is
the Sodium D line wavelength
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Klein, Organic Chemistry 2e
5.4 Optical Activity
• There is no relationship between the R/S configuration
and the direction of light rotation (+/-)
• Should the chirality center below be designated R or S?
• As long as its bonds are not rearranged, its
configuration CANNOT change
• It is levorotatory (-) at 20°C, while at 100°C, it is
dextrorotatory (+)
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Klein, Organic Chemistry 2e
5.4 Optical Activity
• The magnitude and direction of optical rotation can
not be predicted from a chiral molecule’s structure or
configuration. It can ONLY be determined
experimentally
• Predict the optical rotation for a racemic mixture (a
sample with equal amounts of two enantiomers)
• Can you predict the optical rotation for a sample of 2methylbutane
• Practice with SkillBuilder 5.5
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Klein, Organic Chemistry 2e
5.4 Optical Activity
• For unequal amounts of enantiomers, the
enantiomeric excess (% ee) can be determined from
the optical rotation
• For a mixture of 70% (R) and 30% (S), what is the % ee?
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5-40
Klein, Organic Chemistry 2e
5.4 Optical Activity
• If the mixture has an optical rotation of +4.6, use the
formula to calculate the % ee and the ratio of R/S
• Practice with SkillBuilder 5.5
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Klein, Organic Chemistry 2e
5.5 Stereoisomeric Relationships
• Categories of isomers
• Are cis/trans isomers enantiomers or diastereomers?
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Klein, Organic Chemistry 2e
5.5 Stereoisomeric Relationships
• Draw each of the four possible stereoisomers for the
following compound. It might be helpful to also make a
handheld model for each isomer
• Pair up the isomers in every possible combination and
label the pairs as either enantiomers or diastereomers
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Klein, Organic Chemistry 2e
5.5 Stereoisomeric Relationships
• Consider a cyclohexane with three substituents
• What patterns do you notice?
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Klein, Organic Chemistry 2e
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 5.7
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Klein, Organic Chemistry 2e
5.6 Symmetry and Chirality
• Any compound with only ONE chirality center will be
chiral and have an optical rotation
• However, compounds with an even number (2,4,6,
etc.) of chirality centers may or may not be chiral
• Identify each chirality center for both molecules below
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Klein, Organic Chemistry 2e
5.6 Symmetry and Chirality
• Both molecules have 2 chirality centers, but only one is
a chiral molecule, and the other is achiral
• If a molecule has a plane of symmetry, it will be achiral
• Half of the molecule reflects the other half
• Its optical activity will be canceled out
within the molecule, similar to how a pair
or mirror image enantiomers cancel out
each others optical rotation
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Klein, Organic Chemistry 2e
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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Klein, Organic Chemistry 2e
5.6 Symmetry and Chirality
• In another example, the plane of symmetry identifies it
as a meso compound
• meso compounds also have less than the predicted
number of stereoisomers based on the 2(n) formula
• Draw all four expected isomers and show how two of
them are identical. A handheld model might be helpful
• Practice with SkillBuilder 5.8
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5-49
Klein, Organic Chemistry 2e
5.6 Symmetry and Chirality
• Determine the relationship between the two
compounds below
• Analyze both molecules to see if either of them are
meso compounds
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5-50
Klein, Organic Chemistry 2e
5.6 Symmetry and Chirality
• Some compounds do NOT have a plane of
symmetry and yet are still achiral
• The molecule to the right has chirality
centers, yet because it is identical to its
mirror image, it is not chiral
• Draw the mirror image of the molecule above and
show that it can be superimposed on its mirror image
• Having handheld models to work with can simplify this
challenging task
• Practice with conceptual checkpoint 5.23
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5-51
Klein, Organic Chemistry 2e
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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Klein, Organic Chemistry 2e
5.7 Fischer Projections
• Fischer projections can be used to quickly draw
molecules with multiple chirality centers
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5-53
Klein, Organic Chemistry 2e
5.7 Fischer Projections
• Fischer projections can also be used to quickly assess
stereoisomeric relationships
• Practice with SkillBuilder 5.9
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5-54
Klein, Organic Chemistry 2e
5.8 Interconverting Enantiomers
• Molecules can rotate around single bonds.
• Recall the gauche rotational conformation
of butane
• Is the gauche conformation of butane
chiral?
• Draw its mirror image. Is it superimposable on its
mirror image?
• Why is butane’s optical rotation equal to zero?
• To be chiral, a compound cannot be a rotational
conformer of its mirror image
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5-55
Klein, Organic Chemistry 2e
5.8 Interconverting Enantiomers
• Compare the (cis)-1,2-dimethylcyclohexane chair with
the Haworth projection
• The Haworth image can be used to quickly identify the
compound as an achiral meso compound.
• However, a plane of symmetry can NOT be found in the
chair conformation
• Which conformation better represents the molecule’s
actual structure?
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5-56
Klein, Organic Chemistry 2e
5.8 Interconverting Enantiomers
• Should the (cis)-1,2-dimethylcyclohexane chair
conformation be chiral or achiral?
– It is not superimposable on its chair mirror image
– Is has two chirality centers and no plane of symmetry
• Recall that chairs can flip their conformation by
rotating single bonds and interconvert readily at room
temperature
• If the chair could interconvert with its mirror image,
would it be chiral?
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5-57
Klein, Organic Chemistry 2e
5.8 Interconverting Enantiomers
• The freely interconverting mirror images cancel out
their optical rotation, so it is achiral
• This analysis is much easier to do with a handheld
models than in your mind
• If the Haworth image has a mirror plane, then the chair
will be able to interconvert with its enantiomer, and it
will be achiral.
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Klein, Organic Chemistry 2e
5.9 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
– Can you think of more methods of separation or purification?
• Such methods often don’t work to separate one
enantiomer from its partner. WHY?
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5-59
Klein, Organic Chemistry 2e
5.9 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
• This method doesn’t work for most pairs of
enantiomers. WHY?
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5-60
Klein, Organic Chemistry 2e
5.9 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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5-61
Klein, Organic Chemistry 2e
5.9 Resolution of Enantiomers
• Affinity chromatography is often used to separate
compounds
• For example, a glass column or tube can be packed
with particles of a polar solid substance
• If a mixture of two compounds with different polarities
are passed through the column, what will happen?
• A pair of enantiomers will not have different polarities,
so how might such chromatography be modified to
resolve the enantiomers in a racemic mixture?
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Klein, Organic Chemistry 2e
Additional Practice Problems
• Draw a pair of constitutional isomers. EXPLAIN
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5-63
Klein, Organic Chemistry 2e
Additional Practice Problems
• Draw a pair of cis-trans isomers. EXPLAIN
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5-64
Klein, Organic Chemistry 2e
Additional Practice Problems
• Draw a pair of diastereomers that are not cis-trans
isomers. EXPLAIN
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5-65
Klein, Organic Chemistry 2e
Additional Practice Problems
• Draw a pair of enantiomers. Explain
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Klein, Organic Chemistry 2e
Additional Practice Problems
• Draw a molecule with 3 chiral centers.
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5-67
Klein, Organic Chemistry 2e
Additional Practice Problems
• For the molecule below, label each chiral center.
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Klein, Organic Chemistry 2e
Additional Practice Problems
• Designate each chirality center below as either R or S.
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Klein, Organic Chemistry 2e
Additional Practice Problems
• If pure R enantiomer has a specific rotation of +33
degrees, what will the rotation be when you have a
mixture with a R/S ratio = 44/56?
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5-70
Klein, Organic Chemistry 2e
Additional Practice Problems
• Determine the relationship between the pairs below.
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Klein, Organic Chemistry 2e