Chapter 4 Stereochemistry

Objectives
1. Examine the “handedness” of molecules
2. Recognize the stereochemistry of organic molecules
3. Understand the causes and consequences of molecular handedness which is crucial in
understanding organic and biological chemistry

LESSON 1 Isomers: Identical or Not

Recall from Lesson 2.5 in Chapter 1 that stereochemistry is the three-dimensional
structure of a molecule.
O Isomers are different compounds with the same molecular formula.

1.1 THE TWO MAJOR CLASSES OF ISOMERS

1. Constitutional (or structural) isomers differ in the way the atoms are connected to
each other.
▪ different IUPAC names;
▪ the same or different functional groups;
▪ different physical properties, so they are separable by physical techniques
such as distillation;
▪ different chemical properties. They behave differently or give different
products in chemical reactions. 41

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 2. Stereoisomers differ only in the way atoms are oriented in space
▪ have identical IUPAC names (except for a prefix like cis or trans)
▪ A particular three-dimensional arrangement is called a configuration

1.2 LOOKING GLASS CHEMISTRY—CHIRAL AND ACHIRAL MOLECULES

O Everything has a mirror image. What’s important in chemistry is whether a molecule is

identical to or different from its mirror image.
O Some molecules are like hands. Left and right hands are mirror images of each other,
but they are not identical.

A molecule (or object) that is not superimposable on its mirror image is

said to be chiral

A molecule (or object) that is superimposable on its mirror image is said to

be achiral.

To test chirality:
• Draw the molecule in three
dimensions.
• Draw its mirror image.
• Try to align all bonds and atoms. To
superimpose a molecule and its
mirror image you can perform any
rotation but you cannot break
bonds.

Example:
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H2O and CH2BrCl are both achiral molecules
because each molecule is superimposable on
its mirror image.

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A and B are stereoisomers because they are
isomers differing only in the three-dimensional
arrangement of substituents. These
stereoisomers are called enantiomers.

O Enantiomers are mirror images that are not superimposable.

O carbon atom bonded to four different groups is called a tetrahedral stereogenic center
O A plane of symmetry is a mirror plane that cuts a molecule in half, so that one half of
the molecule is a reflection of the other half.
O Achiral molecules usually contain a plane of symmetry but chiral molecules do not.
O A carbon atom with four different groups is a tetrahedral stereogenic center because the
interchange of two groups converts one enantiomer into another.

O When trying to distinguish between chiral and achiral compounds, keep in mind the
following:
• A plane of symmetry is a mirror plane that cuts a molecule in half, so that one
half of the molecule is a reflection of the other half.
• Achiral molecules usually contain a plane of symmetry but chiral molecules
do not.

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1.3 STEREOGENIC CENTERS ON CARBON ATOMS THAT ARE NOT PART OF
A RING
O To locate a stereogenic center, examine each tetrahedral carbon atom in a molecule,
and look at the four groups—not the four atoms—bonded to it.

Example:

O Molecules can contain zero, one, or more stereogenic centers.

• With no stereogenic centers, a molecule generally is not chiral. H2O and
CH2BrCl have no stereogenic centers and are achiral molecules.
• With one tetrahedral stereogenic center, a molecule is always chiral.
CHBrClF is a chiral molecule containing one stereogenic center.
• With two or more stereogenic centers, a molecule may or may not be chiral

1.4 DRAWING A PAIR OF ENANTIOMERS

O Any molecule with one tetrahedral stereogenic center is a chiral compound and
exists as a pair of enantiomers.

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1.5 STEREOGENIC CENTERS IN CYCLIC COMPOUNDS
O Stereogenic centers may also occur at carbon atoms that are part of a ring.

O Because 3-methylcyclohexene has one

tetrahedral stereogenic center it is a chiral compound
and exists as a pair of enantiomers.

Example: thalidomide, which

contains one such stereogenic
center, was used as a popular
sedativeccand anti-nausea
drug for pregnant women in
Europe and Great Britain from
1959–1962.

1.6 LABELING STEREOGENIC CENTERS WITH R OR S

O Because enantiomers are two different compounds, we need to distinguish them by name.
O This is done by adding the prefix R or S to the IUPAC name of the enantiomer.
O To designate an enantiomer as R or S, first assign a priority (1, 2, 3, or 4) to each group 45
bonded to the stereogenic center, and then use these priorities to label one enantiomer R
and one S.

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Rules Needed to Assign Priority
Rule 1 Assign priorities (1, 2, 3, or 4) to the atoms directly bonded to the
stereogenic center in order of decreasing atomic number. The
atom of highest atomic number gets the highest priority (1).
Rule 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. One atom of higher atomic
number determines a higher priority.

Rule 3 If two isotopes are bonded to the stereogenic center, assign priorities in order of
decreasing mass number.

Rule 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.

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Examples of assigning priorities to stereogenic centers

HOW TO Assign R or S to a Stereogenic Center

Example Label each enantiomer as R or S.

Step [1] Assign priorities from 1 to 4 to each group bonded to the stereogenic center.

Step [2] Orient the molecule with the lowest priority group (4) back (on a dash), and visualize
the relative positions of the remaining three groups (priorities 1, 2, and 3).

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Step [3] Trace a circle from priority group 1 → 2 → 3.

Example: Label the following compound as R or S.

LESSON 2 Diastereomers

There are only two types of stereoisomers:

1. Enantiomers are stereoisomers that are mirror images.
2. Diastereomers are stereoisomers that are not mirror images.

O a molecule with two stereogenic centers may or may not be chiral

O stereoisomers that are not related as object and mirror image and are not
enantiomers
O not mirror images of each other and non-superimposable

Meso Compound
o an achiral compound that contains tetrahedral stereogenic centers

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Summary: The three stereoisomers of 2,3-dibromobutane

✓ Pair of enantiomers:
A and B.
✓ Pairs of diastereomers:
A and C; B and C.

LESSON 3 Physical Properties of Stereoisomers

The chemical and physical properties of two enantiomers

are identical except in their interaction with chiral substances.

• Optical Activity
O Two enantiomers have identical physical properties—melting point, boiling point,
solubility — except for how they interact with plane-polarized light.
O What is plane-polarized light?
o Ordinary light consists of
electromagnetic waves that
oscillate in all planes
perpendicular to the direction in
which the light travels. Passing
light through a polarizer allows
light in only one plane to come 49
through.

O A polarimeter is an instrument that allows plane-polarized light to travel through a

sample tube containing an organic compound.
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 o After the light exits the sample tube, an analyzer slit is rotated to determine
the direction of the plane of the polarized light exiting the sample tube.
o With achiral compounds, the light exits the sample tube unchanged
o A compound that does not change the plane of polarized light is said to be
optically inactive.

O With chiral compounds, the plane of the polarized light is rotated through an angle α.
O The angle α, measured in degrees (°), is called the observed rotation.
O A compound that rotates the plane of polarized light is said to be optically active.

▪ If the rotation is clockwise (to the right from the noon position),
the compound is called dextrorotatory. The rotation is labeled d or
(+).
▪ If the rotation is counterclockwise (to the left from noon), the
compound is called levorotatory. The rotation is labeled l or (–).
▪ Two enantiomers rotate plane-polarized light to an equal
extent but in the opposite direction.

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Chiral Drugs
▪ A living organism is a sea of chiral molecules.
o Many drugs are chiral, and often they must interact with a chiral receptor or a chiral
enzyme to be effective.
o One enantiomer of a drug may effectively treat a disease whereas its mirror image
may be ineffective.
o one enantiomer may trigger one biochemical response and its mirror image may
elicit a totally different response

For example, the drugs ibuprofen and fluoxetine

✓ (S)-Ibuprofen is the active component of the
anti-inflammatory agents Alaxan and Advil
✓ (R)-fluoxetine is the active component in the
antidepressant Prozac

▪ The S enantiomer of naproxen is an active

anti-inflammatory agent, but the R
enantiomer is a harmful liver toxin.

▪ (S)-carvone is
responsible for the odor of
caraway, whereas (R)-carvone
is responsible for the odor of
spearmint.

The shape of molecules and the sense of smell

▪ Cyclooctane and other

molecules similar in
shape bind to a particular
olfactory receptor on the
nerve cells that lie at the
top of the nasal passage.
▪ Binding results in a nerve
impulse that travels to
the brain, which
interprets impulses from 51
particular receptors as
specific odors.

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 PROBLEM SET

Name____________________________ Program/Year/Section____________

1. Classify each pair of compounds as constitutional isomers or stereoisomers.

Answer: (a) ________________________ (c) ________________________

(b) ________________________ (d) ________________________

2. Draw the mirror image of each compound. Label each molecule as chiral or achiral.

3. Locate the stereogenic center(s) in each compound. A molecule may have zero, one, or
more stereogenic centers.

a. CH3CH2CH2CH2CH2CH3 c. CH3CH2OCH(CH3)CH2CH3 52

b. (CH3)2CHCH(OH)CH(CH3)2 d. CH3)2CHCH2CH(CH3)CH2CH(CH3)CH(CH3)CH2CH

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 e.

4. Locate the stereogenic centers in each compound. A molecule may have zero, one, or more
stereogenic centers. Gabapentin [part (d)] is used clinically to treat seizures and certain
types of chronic pain. Gabapentin enacarbil [part (e)] is a related compound that is three
times more potent.

5. Which group in each pair is assigned the higher priority in R,S nomenclature? Encircle your
answer.
a. – OH, – NH2 d. – CH2Cl, – CH2CH2CH2Br

b. – CD3, – CH3 e. – CHO, – COOH

c. – CH(CH3)2, – CH2OH f. – CH2NH2, – NHCH3

6. Rank the following groups in order of decreasing priority.

a. –C  CH, –CH(CH3)2, – CH2CH3, –CH  CH2 d. – COOH, – CH2OH, – H, –
CHO

___________________________________ ___________________________
b. –CH3, –CH2CH3, –CH2CH2CH3, –(CH2)3CH3 e. – Cl, – CH3, – SH, – OH

__________________________________ ___________________________ 53
c. –NH2, –CH2NH2, –CH3, –CH2NHCH3 f. – F, – NH2, – CH3, –OH

_________________________________ ____________________________
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7. Label each compound as R or S.

8. Locate the stereogenic centers in each drug.

9. How is each compound related to the simple sugar D-erythrose? Is it an enantiomer,

diastereomer, or identical?

____________ ______________ ______________ ______________

10. How are the compounds in each pair related to each other? Are they identical, enantiomers,
diastereomers, constitutional isomers, or not isomers of each other?

___________________ ______________________

___________________ _______________________
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 _______________________ _____________________

_______________________ ______________________

_______________________ ______________________

_______________________ ______________________

11. Draw a meso compound for each of the following molecules.

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