5.

Stereochemistry
Why this Chapter?
Handedness is important in organic and
biochemistry
Molecular handedness makes possible
specific interactions between enzymes and
substrates

Stereochemistry
Some

objects are not the

same as their mirror
images (technically, they
have no plane of
symmetry)
A right-hand glove is
different than a left-hand
glove. The property is
commonly called
handedness
Organic molecules
(including many drugs)
have handedness that
results from substitution
patterns on sp3 hybridized
carbon
2

5.1 Enantiomers and the Tetrahedral Carbon

In Muscle Tissue
In Sour Milk
p. 290

Enantiomers
Enantiomers

are molecules that are not the

same as their mirror image
They are the same if the positions of the atoms
can coincide on a one-to-one basis (we test if they
are superimposable, which is imaginary)
This is illustrated by enantiomers of lactic acid

Examples of Enantiomers
Molecules

that have one carbon with 4 different

substituents have a nonsuperimposable mirror image
enantiomer
Build molecular models to see this

Carvones:
R-(-)-carvone

Spearmint

S-(+)-carvone

Caraway
(Dill)
(Manderine Orange Peel)

5.2 Chirality
Molecules

that are not superimposable

with their mirror images are chiral (have
handedness)
A plane of symmetry divides an entire
molecule into two pieces that are exact
mirror images
A molecule with a plane of symmetry is
the same as its mirror image and is said to
be achiral (See Figure 9.4 for examples)

Chirality
If

an object has a plane of symmetry it is

necessarily the same as its mirror image
The lack of a plane of symmetry is called
handedness, chirality
Hands, gloves are prime examples of
chiral object
They have a left and a right version

Plane of Symmetry
The

plane has the

same thing on both
sides for the flask

There

is no
mirror plane for
a hand
9

Chirality Centers
A

point in a molecule where four different groups (or

atoms) are attached to 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

10

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

11

Examples:

p. 293

p. 293

Learning Check:
Label the chiral centers.

p. 294

Solution:
Label the chiral centers.

*
**

How many possible stereoisomers? (2n)

2n = 21 = 2

2n = 23 = 8

2n = 23 = 8
p. 294

Which of the following molecules

possesses a plane of symmetry?
Cl
Br
A

1.
2.
3.
4.
5.

CH3
Cl

A only
B only
C only
A and C
B and C

Cl

CH3
Br
C

Which of the following statements about

enantiomers is false?
1.
2.
3.

4.
5.

They have identical

melting points.
They have identical
boiling points.
The magnitude of
their specific
rotations is identical.
They have identical
densities.
They react at the
same rate with
optically active
reagents.

How many stereogenic centers are

present in the following molecule?
OH

1.
2.
3.
4.
5.

0
1
2
4
7

5.3 Optical Activity

Light

restricted to pass through a plane is

plane-polarized
Plane-polarized light that passes through
solutions of achiral compounds remains in
that plane
Solutions of chiral compounds rotate
plane-polarized light and the molecules
are said to be optically active
Phenomenon discovered by Jean-Baptiste
Biot in the early 19th century

19

Optical Activity
Light

passes through a plane polarizer

Plane polarized light is rotated in
solutions of optically active
compounds
Measured with polarimeter
Rotation, in degrees, is []
Clockwise rotation is called
dextrorotatory
Anti-clockwise is levorotatory
20

Measurement of Optical Rotation

A

polarimeter measures the rotation of planepolarized that has passed through a solution
The source passes through a polarizer and
then is detected at a second polarizer
The angle between the entrance and exit
planes is the optical rotation.

21

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 nm)

22

The specific rotation, [], of a sample is defined for each

chiral molecule (the value is solvent dependent):

[ ]
l c
where [ ] = specific rotation
t = temperature in degrees Celsius
= wavelength of incident light
(D = 589 nm, the yellow D line from Na)
= observed optical rotation in degres
l = sample container length in dm
c = concentration (g/ml)
to

Specific rotation is a physical constant for a substance as is

melting point, boiling point, density, etc.

Specific Rotation and Molecules

Characteristic

property of a compound that is

optically active the compound must be chiral

The

specific rotation of the enantiomer is equal in

magnitude but opposite in sign

24

5.4 Pasteurs Discovery of Enantiomers

Louis

Pasteur discovered that sodium ammonium

salts of tartaric acid crystallize into right handed
and left handed forms
The optical rotations of equal concentrations of
these forms have opposite optical rotations
The solutions contain mirror image isomers,
called enantiomers and they crystallized in
distinctly different shapes such an event is rare

25

5.5 Sequence Rules for Specification of

Configuration
A

general method applies to the

configuration at each chirality center
(instead of to the whole molecule)
The configuration is specified by the
relative positions of all the groups with
respect to each other at the chirality center
The groups are ranked in an established
priority sequence and compared
The relationship of the groups in priority
order in space determines the label applied
to the configuration, according to a rule

26

Sequence Rules (IUPAC)

Rule 1:
Assign each group priority according to the Cahn
Ingold-Prelog scheme
With the lowest priority group pointing away,
look at remaining 3 groups in a plane

Clockwise is
designated R
(from Latin for
right)
Counterclock
wise is
designated S
(from Latin
word for left
sinister)

27

Rule 2:
If decision cant be reached by ranking the first
atoms in the substituents, look at the second,
third, or fourth atoms until difference is found

Rule 3:
Multiple-bonded atoms are equivalent to the
same number of single-bonded atoms

28

Examples:

Fig. 9-8, p. 299

Examples:

Fig. 9-8, p. 299

What are the absolute configurations of the

chiral centers in the molecule shown below?
O
H
2

HO

1.
2.
3.
4.
5.

1: R, 2: R
1: R, 2: S
1: S, 2: S
1: S, 2: R
because of the ring
structure, the
compound does not
have chiral centers

5.6 Diastereomers
Molecules

with more than one chirality

center have mirror image stereoisomers
that are enantiomers

In

addition they can have stereoisomeric

forms that are not mirror images, called
diastereomers

32

Diastereomers
33

Epimers

p. 304

Despite its name, ascorbic acid (vitamin C) is not a

carboxylic acid, but rather has the structure shown
below. How many stereoisomers of this compound
are possible?
HO

O
HO
HO

1.
2.
3.
4.
5.

1
2
3
4
8

O
OH

ascorbic acid

What is the relationship between the two

compounds shown below?
Br
F
Cl

1.
2.
3.

4.

5.

F
H

H
Br

Cl

they are identical

they are constitutional
isomers
they are
nonsuperimposable
mirror images of each
other
they are different
conformations of the
same compound
they have different
atom connectivity

Which of the
structures above are
identical?
1. A and C only
2. B and D only
3. A and D only
4. B, C, and D only
5. all are the same

5.7 Meso Compounds

Tartaric acid has two chirality

centers and two
diastereomeric forms
One form is chiral and the
other is achiral, but both have
two chirality centers
An achiral compound with
chirality centers is called a
meso compound it has a
plane of symmetry
The two structures on the right
in the figure are identical so
the compound (2R, 3S) is
achiral

38

Enantiomers

Meso

Table 9-3, p. 306

5.8 Racemic Mixtures and The

Resolution of Enantiomers
A

50:50 mixture of two chiral compounds that

are mirror images does not rotate light called
a racemic mixture (named for racemic acid
that was the double salt of (+) and (-) tartaric
acid
The pure compounds need to be separated or
resolved from the mixture (called a racemate)
To separate components of a racemate
(reversibly) we make a derivative of each with a
chiral substance that is free of its enantiomer
(resolving agent)
This gives diastereomers that are separated by
their differing solubility
The resolving agent is then removed
40

Resolution of Enantiomers

Inseparable
by normal
extraction
techniques
due to
identical
chemical
properties
41

Resolution of Enantiomers

Separable
by normal
extraction
techniques
due to
different
chemical
properties
42

5.9 A Review of Isomerism

The

flowchart summarizes the types of

isomers we have seen

43

Constitutional Isomers
Different

order of connections gives different carbon

backbone and/or different functional groups

44

Stereoisomers
Same

connections, different spatial arrangement of atoms

Enantiomers (nonsuperimposable mirror images)
Diastereomers (all other stereoisomers)
Includes cis, trans and configurational

45

Stereochemistry of Reactions: Addition

of H2O to Alkenes
Many

reactions can produce new chirality

centers from compounds without them
What is the stereochemistry of the chiral
product?
What relative amounts of stereoisomers form?
Example addition of H2O to 1-butene

46

Addition

Achiral Intermediate Gives

Racemic Product

via carbocation
Top and bottom are equally accessible

47

Stereochemistry of Reactions: Addition of

H2O to a Chiral Alkene
What

is the sterochemical result

of the addition of H2O to a chiral
alkene R-4-methyl-1-hexene
Product has 2 chiral centers

48

Fig. 9-16, p. 313

5.10 Chirality at Nitrogen, Phosphorus,

and Sulfur
N,

P, S commonly found in organic compounds, and

can have chirality centers
Trivalent nitrogen is tetrahedral
Does not form a chirality center since it rapidly flips
Individual enantiomers cannot be isolated

50

Also

applies to phosphorus but it

flips more slowly

51

p. 315

5.11 Prochirality
A

molecule that is achiral but that can become

chiral by a single alteration is a prochiral
molecule

53

Prochiral Distinctions: Faces

Planar

faces that can become tetrahedral are

different from the top or bottom
A center at the planar face at a carbon atom is
designated re if the three groups in priority
sequence are clockwise, and si if they are
counterclockwise

54

Prochiral distinctions, paired atoms or groups

An

sp3 carbon with two groups that are the same

is a prochirality center
The two identical groups are distinguished by
considering either and seeing if it was increased
in priority in comparison with the other
If the center becomes R the group is pro-R and
pro-S if the center becomes S

55

Prochiral Distinctions in Nature

Biological

reactions often involve making

distinctions between prochiral faces or or
groups
Chiral entities (such as enzymes) can always
make such a distinction
Example: addition of water to fumarate

56

Examples

p. 317

Learning Check:
Identify the indicated Hs as Pro R or Pro S

p. 317

Solution:
Identify the indicated Hs as Pro R or Pro S
Pro S

Pro R

Pro R

Pro S

p. 317

Learning Check:
Identify the indicated faces as Re or Si

p. 318

Solution:
Identify the indicated faces as Re or Si
Re

Si

Re

Si

p. 318

Learning Check:
Lactic acid in tired muscles results from
reduction (addition of H) of pyruvate from the Re
face. What is the stereochem of the product?

p. 318

Solution:
Lactic acid in tired muscles results from
reduction (addition of H) of pyruvate from the Re
face. What is the stereochem of the product?

H OH
C
CH3
CO2
(S)p. 318

5.12 Chirality in Nature and

Chiral Environments
Stereoisomers

are readily distinguished by

chiral receptors in nature
Properties of drugs depend on stereochemistry
Think of biological recognition as equivalent to
3-point interaction
See Figure 9-17

64

p. 318

p. 319

p. 321

p. 321

Important Concepts
1. Isomers - Same molecular formula different
compounds.

Constitutional Individual atoms are connected differently

Stereoisomers Same connectivity different 3D
arrangement.
Mirror-Image Stereoisomers Related as image mirror
image.

2. Chiral Molecule - Not superimposable on its mirror

image.

3. Stereocenter Carbon atom bearing 4 different

substituents.

4. Enantiomers Two stereoisomers, each a nonsuperimposable mirror images of the other.

Important Concepts
5. Racemate A one to one mixture of enantiomers.
6. Mirror Plane Chiral molecules cannot contain a
mirror plane.

7. Diastereomers Stereoisomers not related to each

other as mirror images (ie. cis/trans).

8. Two Stereocenters In A Molecule Create up

9.

to 4 stereoisomers: 2 diastereomerically related pairs

of enantiomers. If the 2 stereocenters generate a
mirror plane in the molecule, the molecule is known as
a meso compound and is achiral.
Physical Properties of Stereoisomers Most
are the same except for the rotation of plane polarized
light. One enantiometer rotates the plane of
polarization to the right, the other to the left. This
rotation is expressed as the specific rotation, [].

Important Concepts
10. Absolute Configuration - Determined by x-ray

diffraction. Assignment of R or S, as determined by

the Cahn, Ingold, and Prelog sequence rules.
11. Stereoselectivity - Preference for the formation of
one stereoisomer when several are possible.
12. Resolution Separation of enantiomers.
Reaction with a pure enantiomer of a second chiral
compound and separation of the diastereomers.
Chiral chromatography.

Which statement about chirality and optical

activity is false?
1.

If a solution shows optical

activity, it must have a
compound present whose
mirror image is not
superimposable on the
compound itself.

2.

Molecules with plane of

symmetry will show no optical
activity.

3.

The angle of rotation of planepolarized light depends on how

many chiral molecules does
the light interact with while
passing through the sample.

4.

Enantiomers will always have

opposite signs of optical
rotation.

OH
OH
A

OH
OH
B

HO

CH3
H

HO
CH3

Which of the above

molecules are
achiral?
1. A and C
2. A and E
3. B and C
4. B and D
5. D and E

How many stereoisomers exist for the

molecule shown below?
OH OH
HOOC

COOH
OH

1.
2.
3.
4.
5.

1
2
3
4
8

How many meso

dibromocyclopentanes, C5H8Br2, are
there?
1. 0
2. 1
3. 2
4. 3
5. 4

An aqueous solution of A (one stereoisomer) and B

(one stereoisomer) shows no optical activity. A and
B are stereoisomers. Which statement cannot be
true?
1.
2.
3.
4.
5.

A and B are
diastereomers
A and B are not
superimposable
A and B are
enantiomers
A is meso and B is
chiral
A and B are E and Z
isomers

How many stereoisomers exist for 5methylhepta-2,3-diene?

1.
2.
3.
4.
5.

1
2
3
4
8

E-3-Hexene reacts with one equivalent of

HBr. If there are no carbocation
rearrangements, how many different
isomeric products (including stereoisomers)
will form?
1.
2.
3.
4.
5.

1
2
3
4
5

What is the relation between the

following two compounds?
Br
Br
Br

1.
2.
3.
4.
5.

diastereomers
enatiomers
identical
constitutional
isomers
meso

Br

Which is the best accounting for the

stereochemistry of the product formed by addition
of HCl to (R)-4-chloro-1-pentene?
1.
2.
3.
4.
5.

two enantiomers in
equal amounts
two enantiomers in
different amounts
two diastereomers in
equal amounts
two diastereomers in
different amounts
three stereoisomers,
two of them in equal
amounts

How many different meso compounds will be

produced by the following reaction (assuming
there are no carbocation rearrangements)?
Br
HBr

1.
2.
3.
4.
5.

1
2
3
4
5

Which of the following structures represents the

lowest-energy form of (1S, 3S)-3chloromethylcyclohexane?
1.

2.

3.

4.

5.

Enantiomers have identical chemical and physical properties

in achiral environments, while diastereomers have different
properties in chiral and achiral surroundings. What can be
deduced based on the observation that A smells like citrus
fruits, while B has an odor of pine trees?
H

1.

A and B are diastereomers

2.

A and B are an exception to

the rule and do not have the
same properties.

3.

The sense of smell cannot be

used to deduce anything
about the stereochemistry of
A and B.

4.

The receptors responsible for

smell are chiral

5.

As can be observed by
looking into a mirror, our

How many prochirality centers does 1butanol (CH3CH2CH2CH2OH) have?

1.
2.
3.
4.
5.

none
1
2
3
4