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

4
Examples of Enantiomers
Molecules that have one carbon with 4 different substituents
have a nonsuperimposable mirror image – enantiomer
 Build molecular models to see this

5
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)

7
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

8
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
1.
2.
3.
4.
5.
Cl
B
A
CH3
Cl
20%
20%
20%
20%
3
4
20%
CH3
Br
C
A only
B only
C only
A and C
B and C
1
2
5
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.
20%
1
20%
2
20%
20%
3
4
20%
5
How many stereogenic centers are present in
the following molecule?
OH
20%
20%
20%
20%
3
4
20%
O
1.
2.
3.
4.
5.
0
1
2
4
7
1
2
5
5.3 Optical Activity
Light restricted to pass through a plane is planepolarized
 Plane-polarized light that passes through solutions
of achiral compounds remains in that plane
 Solutions of chiral compounds rotate planepolarized 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 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.

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):
[ ] 
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
24
5.4 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
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”)
•Counterclockwise
is designated S
(from Latin word
for “left” sinister)
27
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
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
20%
20%
20%
20%
3
4
20%
1
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
1
2
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
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?
20%
HO
O
3.
4.
5.
20%
3
4
20%
ascorbic acid
HO
2.
20%
O
HO
1.
20%
OH
1
2
3
4
8
1
2
5
What is the relationship between the two compounds
shown below?
Br
F
Cl
1.
2.
3.
4.
5.
F
H
H
Br
20%
20%
20%
20%
3
4
20%
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
1
2
5
A
B
C
20%
D
20%
20%
20%
3
4
20%
Which of the structures
above are identical?
1.
2.
3.
4.
5.
A and C only
B and D only
A and D only
B, C, and D only
all are the same
1
2
5
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
Achiral Intermediate Gives
Racemic Product
Addition 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-4methyl-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 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
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.
5.
The R enantiomers are
dextrorotatory.
20%
1
20%
2
20%
20%
3
4
20%
5
HO
OH
A
CH3
OH
OH
OH
B
H
HO
H
CH3
C
E
D
20%
20%
20%
20%
3
4
20%
Which of the above
molecules are achiral?
1.
2.
3.
4.
5.
A and C
A and E
B and C
B and D
D and E
1
2
5
How many stereoisomers exist for the molecule
shown below?
OH OH
HOOC
20%
20%
20%
20%
3
4
20%
COOH
OH
1.
2.
3.
4.
5.
1
2
3
4
8
1
2
5
How many meso dibromocyclopentanes,
C5H8Br2, are there?
20%
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
0
1
2
3
4
1
2
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?
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
20%
1
20%
2
20%
20%
3
4
20%
5
How many stereoisomers exist for 5methylhepta-2,3-diene?
1.
2.
3.
4.
5.
1
2
3
4
8
20%
1
20%
2
20%
20%
3
4
20%
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%
1.
2.
3.
4.
5.
20%
20%
20%
3
4
20%
1
2
3
4
5
1
2
5
What is the relation between the following two
compounds?
20%
Br
Br
20%
20%
20%
3
4
20%
Br
Br
1.
2.
3.
4.
5.
diastereomers
enatiomers
identical
constitutional isomers
meso
1
2
5
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
20%
1
20%
2
20%
20%
3
4
20%
5
How many different meso compounds will be produced by
the following reaction (assuming there are no carbocation
rearrangements)?
20%
Br
20%
20%
20%
3
4
20%
HBr
1.
2.
3.
4.
5.
1
2
3
4
5
1
2
5
Which of the following structures represents the lowest-energy
form of (1S, 3S)-3-chloromethylcyclohexane?
1.
2.
20%
20%
20%
20%
3
4
20%
3.
4.
5.
1
2
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
A
1.
2.
3.
4.
5.
20%
20%
20%
20%
3
4
20%
B
A and B are diastereomers
A and B are an exception to the rule
and do not have the same
properties.
The sense of smell cannot be used
to deduce anything about the
stereochemistry of A and B.
The receptors responsible for smell
are chiral
As can be observed by looking into
a mirror, our noses are chiral
1
2
5
How many prochirality centers does 1-butanol
(CH3CH2CH2CH2OH) have?
1.
2.
3.
4.
5.
none
1
2
3
4
20%
1
20%
2
20%
20%
3
4
20%
5