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
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

3
 Examples of Enantiomers
 Molecules that have one carbon with 4 different substituents
have a nonsuperimposable mirror image – enantiomer
 Build molecular models to see this

4
 Carvones:
R-(-)-carvone S-(+)-carvone

Spearmint Caraway
(Dill)
(Manderine Orange Peel)
 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)

6
 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

7
 Plane of Symmetry
 The plane has the
same thing on both
sides for the flask

 There is no mirror
plane for a hand

8
 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

9
 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

10
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 20% 20% 20% 20% 20%
CH3

Cl CH3
Br Cl Br
A B C

1. A only
2. B only
3. C only
4. A and C
5. B and C

1 2 3 4 5
Which of the following statements about enantiomers
is false?

1. They have identical 20% 20% 20% 20% 20%

melting points.
2. They have identical boiling
points.
3. The magnitude of their
specific rotations is
identical.
4. They have identical
densities.
5. They react at the same
rate with optically active
reagents. 1 2 3 4 5
How many stereogenic centers are present in
the following molecule?
OH
20% 20% 20% 20% 20%

1. 0
2. 1
3. 2
4. 4
5. 7
1 2 3 4 5
 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

18
 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

19
 Measurement of Optical Rotation
 A polarimeter measures the rotation of plane-polarized
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.

20
 Specific Rotation
 To have a basis for comparison, define specific
rotation, []D for an optically active compound
 []D = observed rotation
(pathlength x concentration)

=  = degrees
(l x C) (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)
21
The specific rotation, [], of a sample is defined for each
chiral molecule (the value is solvent dependent):

[ ] 
to

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)
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

23
 Pasteur’s 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

24
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

25
 Rule 1: Sequence Rules (IUPAC)
• 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”)
•Counterclockwise
is designated S
(from Latin word
for “left” sinister)

26
 Rule 2:
 If decision can’t 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

27
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 20% 20% 20% 20% 20%
2 1
HO

1. 1: R, 2: R
2. 1: R, 2: S
3. 1: S, 2: S
4. 1: S, 2: R
5. because of the ring
structure, the compound
does not have chiral
centers 1 2 3 4 5
 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

31
Diastereomers

32
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 20% 20% 20% 20% 20%
O O
HO ascorbic acid
HO OH

1. 1
2. 2
3. 3
4. 4
5. 8
1 2 3 4 5
 What is the relationship between the two compounds
shown below?
Br F
F H 20% 20% 20% 20% 20%
H Cl
Cl Br

1. they are identical

2. they are constitutional
isomers
3. they are nonsuperimposable
mirror images of each other
4. they are different
conformations of the same
compound
5. they have different atom
connectivity
1 2 3 4 5
 A B C D
20% 20% 20% 20% 20%
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

1 2 3 4 5
 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

37
Enantiomers Meso

Table 9-3, p. 306

 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

39
Resolution of Enantiomers

Inseparable
by normal
extraction
techniques
due to
identical
chemical
properties

40
Resolution of Enantiomers

Separable
by normal
extraction
techniques
due to
different
chemical
properties

41
 A Review of Isomerism

 The flowchart summarizes the types of isomers we have

seen

42
 Constitutional Isomers
 Different order of connections gives different carbon
backbone and/or different functional groups

43
 Stereoisomers
 Same connections, different spatial arrangement of atoms
◦ Enantiomers (nonsuperimposable mirror images)
◦ Diastereomers (all other stereoisomers)
 Includes cis, trans and configurational

44
 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

45
 Achiral Intermediate Gives
Racemic Product
 Addition via carbocation
 Top and bottom are equally accessible

46
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

47
Fig. 9-16, p. 313
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

49
 Also applies to phosphorus but it flips
more slowly

50
p. 315
 Prochirality
 A molecule that is achiral but that can become
chiral by a single alteration is a prochiral molecule

52
 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

53
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

54
 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

55
Examples

p. 317
 Learning Check:
Identify the indicated H’s as Pro R or Pro S

p. 317
 Solution:
Identify the indicated H’s 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 Re

Si 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

63
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 non-
superimposable 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
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.
9. 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 20% 20% 20% 20% 20%
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 plane-
polarized 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.
5. The R enantiomers are
dextrorotatory.
1 2 3 4 5
 OH CH3
OH
HO H

HO H
OH OH CH3

A B C D E

20% 20% 20% 20% 20%

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

1 2 3 4 5
How many stereoisomers exist for the molecule
shown below?
20% 20% 20% 20% 20%
OH OH

HOOC COOH
OH

1. 1
2. 2
3. 3
4. 4
5. 8
1 2 3 4 5
How many meso dibromocyclopentanes,
C5H8Br2, are there?
20% 20% 20% 20% 20%

1. 0
2. 1
3. 2
4. 3
5. 4

1 2 3 4 5
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?
20% 20% 20% 20% 20%
1. A and B are diastereomers
2. A and B are not
superimposable
3. A and B are enantiomers
4. A is meso and B is chiral
5. A and B are E and Z
isomers

1 2 3 4 5
How many stereoisomers exist for 5-
methylhepta-2,3-diene?
20% 20% 20% 20% 20%
1. 1
2. 2
3. 3
4. 4
5. 8

1 2 3 4 5
E-3-Hexene reacts with one equivalent of HBr. If there
are no carbocation rearrangements, how many different
isomeric products (including stereoisomers) will form?
20% 20% 20% 20% 20%

1. 1
2. 2
3. 3
4. 4
5. 5

1 2 3 4 5
What is the relation between the following two
compounds?
20% 20% 20% 20% 20%
Br
Br
Br
Br

1. diastereomers
2. enatiomers
3. identical
4. constitutional isomers
5. meso
1 2 3 4 5
Which is the best accounting for the stereochemistry of the
product formed by addition of HCl to (R)-4-chloro-1-pentene?
20% 20% 20% 20% 20%
1. two enantiomers in equal
amounts
2. two enantiomers in
different amounts
3. two diastereomers in
equal amounts
4. two diastereomers in
different amounts
5. three stereoisomers, two
of them in equal amounts
1 2 3 4 5
How many different meso compounds will be produced by
the following reaction (assuming there are no carbocation
rearrangements)?
Br 20% 20% 20% 20% 20%

HBr

1. 1
2. 2
3. 3
4. 4
5. 5
1 2 3 4 5
Which of the following structures represents the lowest-energy
form of (1S, 3S)-3-chloromethylcyclohexane?

1. 2. 20% 20% 20% 20% 20%

3.

4. 5.

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 H 20% 20% 20% 20% 20%

A B

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 noses are chiral 1 2 3 4 5
How many prochirality centers does 1-butanol
(CH3CH2CH2CH2OH) have?
20% 20% 20% 20% 20%
1. none
2. 1
3. 2
4. 3
5. 4

1 2 3 4 5