Chapter 5
Stereochemistry
Chiral Molecules
Created by
Professor William Tam & Dr. Phillis Chang
Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.
About The Authors
These Powerpoint Lecture Slides were created and prepared by Professor
William Tam and his wife Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in
1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an
NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard
University (USA). He joined the Department of Chemistry at the University of
Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and
Associate Chair in the department. Professor Tam has received several awards
in research and teaching, and according to Essential Science Indicators, he is
currently ranked as the Top 1% most cited Chemists worldwide. He has
published four books and over 80 scientific papers in top international journals
such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her
M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She
lives in Guelph with her husband, William, and their son, Matthew.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
(hyperlinked)
Chirality and Stereochemistry
Isomerism: Constitutional Isomers and Stereoisomers
Enantiomers and Chiral Molecules
Molecules Having One Chirality Center Are Chiral
More about the Biological Importance of Chirality
How to Test for Chirality: Planes of Symmetry
Naming Enantiomers: The R,S-System
Properties of Enantiomers: Optical Activity
The Origin of Optical Activity
The Synthesis of Chiral Molecules
Chiral Drugs
Molecules with More than One Chirality Center
Fischer Projection Formulas
Stereoisomerism of Cyclic Compounds
Relating Configurations through Reactions in Which No Bonds to
the Chirality Center Are Broken
Separation of Enantiomers: Resolution
Compounds with Chirality Centers Other than Carbon
Chiral Molecules That Do Not Possess a Chirality Center
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Chirality and Stereochemistry
Isomerism: Constitutional Isomers and Stereoisomers
Enantiomers and Chiral Molecules
Molecules Having One Chirality Center Are Chiral
More about the Biological Importance of Chirality
How to Test for Chirality: Planes of Symmetry
Naming Enantiomers: The R,S-System
Properties of Enantiomers: Optical Activity
The Origin of Optical Activity
The Synthesis of Chiral Molecules
Chiral Drugs
Molecules with More than One Chirality Center
Fischer Projection Formulas
Stereoisomerism of Cyclic Compounds
Relating Configurations through Reactions in Which No Bonds to
the Chirality Center Are Broken
Separation of Enantiomers: Resolution
Compounds with Chirality Centers Other than Carbon
Chiral Molecules That Do Not Possess a Chirality Center
© 2014 by John Wiley & Sons, Inc. All rights reserved.
In this chapter we will consider:

How to identify, codify, and name the
three-dimensional arrangement of
atoms and molecules

How such arrangements can lead to
unique properties and behaviors
© 2014 by John Wiley & Sons, Inc. All rights reserved.
1. Chirality & Stereochemistry

An object is achiral (not chiral) if the
object and its mirror image are
identical
© 2014 by John Wiley & Sons, Inc. All rights reserved.

A chiral object is one that cannot be
superposed on its mirror image
© 2014 by John Wiley & Sons, Inc. All rights reserved.
1A. The Biological Significance of
Chirality

Chiral molecules are molecules that
cannot be superimposed onto their
mirror images
O
N
O
● One enantiomer
causes birth defects,
NH
O the other cures
morning sickness
O
Thalidomide
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HO
NH
HO
OMe
Tretoquinol
OMe
OMe
● One enantiomer is a bronchodilator, the
other inhibits platelet aggregation
© 2014 by John Wiley & Sons, Inc. All rights reserved.

66% of all drugs in development are
chiral, 51% are being studied as a single
enantiomer

Of the $475 billion in world-wide sales of
formulated pharmaceutical products in
2008, $205 billion was attributable to
single enantiomer drugs
© 2014 by John Wiley & Sons, Inc. All rights reserved.
2. Isomerisom: Constitutional
Isomers & Stereoisomers
2A. Constitutional Isomers

Isomers: different compounds that
have the same molecular formula
● Constitutional isomers: isomers
that have the same molecular
formula but different connectivity –
their atoms are connected in a
different order
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Examples
Molecular
Formula
C4H10
Constitutional
Isomers
and
Butane
2-Methylpropane
Cl
C3H7Cl
Cl
1-Chloropropane
and
2-Chloropropane
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
Examples
Molecular
Formula
C2H6O
Constitutional
Isomers
CH3 O CH3
OH and
Ethanol
Methoxymethane
O
C4H8O2
OCH3
OH and
Butanoic acid
O
Methyl propanoate
© 2014 by John Wiley & Sons, Inc. All rights reserved.
2B. Stereoisomers

Stereoisomers are NOT constitutional
isomers

Stereoisomers have their atoms
connected in the same sequence but
they differ in the arrangement of their
atoms in space. The consideration of
such spatial aspects of molecular
structure is called stereochemistry
© 2014 by John Wiley & Sons, Inc. All rights reserved.
2C. Enantiomers & Diastereomers
 Stereoisomers can be subdivided into
two general categories:
enantiomers & diasteromers
● Enantiomers – stereoisomers
whose molecules are
nonsuperimposable mirror images
of each other
● Diastereomers – stereoisomers
whose molecules are not mirror
images of each other
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Geometrical isomers
(cis & trans isomers) are:
● Diastereomers
e.g.
Ph
Ph
and
Ph
(cis)
Cl
Ph
(trans)
Cl
Cl
H
H
Cl
and
H
H
(cis)
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(trans)
Subdivision of Isomers
Isomers
(different compounds with same
molecular formula)
Constitutional Isomers
(isomers whose atoms
have a different
connectivity)
Stereoisomers
(isomers that have the same
connectivity but differ in spatial
arrangement of their atoms)
Enantiomers
(stereoisomers that are
nonsuperimposable mirror
images of each other)
Diastereomers
(stereoisomers that are
NOT mirror images of
each other)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
3. Enantiomers and Chiral
Molecules
Enantiomers occur only with compounds
whose molecules are chiral
 A chiral molecule is one that is NOT
superimposable on its mirror image
 The relationship between a chiral
molecule and its mirror image is one
that is enantiomeric. A chiral
molecule and its mirror image are said
to be enantiomers of each other

© 2014 by John Wiley & Sons, Inc. All rights reserved.
OH
H
(I)
OH
(2-Butanol)
HO
H
(I) and (II) are
nonsuperimposable
mirror images of
each other
(II)
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4. Molecules Having One Chirality
Center Are Chiral

A chirality center is a tetrahedral
carbon atom that is bonded to four
different groups

A molecule that contains one chirality
center is chiral and can exist as a pair
of enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.

The presence of a single chirality
center in a molecule guarantees that
the molecule is chiral and that
enantiomeric forms are possible

An important property of enantiomers
with a single chirality center is that
interchanging any two groups at the
chirality center converts one
enantiomer into the other
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Any atom at which an interchange of
groups produces a stereoisomer is
called a stereogenic center (if the
atom is a carbon atom it is usually
called a stereogenic carbon)
 If all of the tetrahedral atoms in a
molecule have two or more groups
attached that are the same, the
molecule does not have a chirality
center. The molecule is superimposable
on its mirror image and is achiral

© 2014 by John Wiley & Sons, Inc. All rights reserved.
Cl
Me C* Et
H
same
as
H
Cl
Cl
H
Me
Et
(III)
Et
Me
(IV)
mirror
(III) and (IV) are nonsuperimposable
mirror images of each other
© 2014 by John Wiley & Sons, Inc. All rights reserved.
same
as
mirror
(V) and (VI) are superimposable
⇒ not enantiomers ⇒ achiral
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4A. Tetrahedral vs. Trigonal
Stereogenic Centers

Chirality centers are tetrahedral
stereogenic centers
H
Tetrahedral
stereogenic
center
⇒ chiral
HO
OH
H
Et * Me
(B)
Me * Et
(A)
mirror
(A) & (B) are
enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Cis and trans alkene isomers contain
trigonal stereogenic centers
Trigonal
stereogenic
center
⇒ achiral
Ph
H
H
Ph
H
Ph
Ph
H
(D)
(C)
mirror
(C) & (D) are identical
© 2014 by John Wiley & Sons, Inc. All rights reserved.
5. More about the Biological
Importance of Chirality
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Thalidomide

The activity of drugs containing
chirality centers can vary between
enantiomers, sometimes with serious
or even tragic consequences

For several years before 1963
thalidomide was used to alleviate the
symptoms of morning sickness in
pregnant women
© 2014 by John Wiley & Sons, Inc. All rights reserved.

In 1963 it was discovered that thalidomide
(sold as a mixture of both enantiomers) was
the cause of horrible birth defects in many
children born subsequent to the use of the
drug
O
N
O
O
NH
O
O
Thalidomide
(cures morning sickness)
N
O
NH
O
O
enantiomer of
Thalidomide
(causes birth defects)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
6. How to Test for Chirality:
Planes of Symmetry
A molecule will not be chiral if it
possesses a plane of symmetry
 A plane of symmetry (mirror plane) is an
imaginary plane that bisects a molecule
such that the two halves of the molecule
are mirror images of each other
 All molecules with a plane of symmetry
in their most symmetric conformation
are achiral

© 2014 by John Wiley & Sons, Inc. All rights reserved.
Plane of symmetry
Cl
Me
Me
H
achiral
Cl
No plane of
Me
symmetry
Et
H
chiral
© 2014 by John Wiley & Sons, Inc. All rights reserved.
7. Naming Enantiomers:
The R,S -System
Recall:
OH
H
OH
(I)


HO
H
(II)
Using only the IUPAC naming that we have
learned so far, these two enantiomers will
have the same name:
● 2-Butanol
This is undesirable because each compound
must have its own distinct name
© 2014 by John Wiley & Sons, Inc. All rights reserved.
7A. How to Assign (R) and (S)
Configurations

Rule 1
● Assign priorities to the four different
groups on the stereocenter from
highest to lowest (priority bases on
atomic number, the higher the
atomic number, the higher the
priority)
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
Rule 2
● When a priority cannot be assigned
on the basis of the atomic number
of the atoms that are directly
attached to the chirality center, then
the next set of atoms in the
unassigned groups is examined.
This process is continued until a
decision can be made.
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Rule 3
● Visualize the molecule so that the
lowest priority group is directed
away from you, then trace a path
from highest to lowest priority. If
the path is a clockwise motion, then
the configuration at the asymmetric
carbon is (R). If the path is a
counter-clockwise motion, then the
configuration is (S)
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Example
①
Step 1:
② or ③
H
O
H
C
①
Step 2:
HO
H3C
④
C
H
O
③
(2-Butanol)
② or ③
④
C ② CH
3
C
H2
(H, H, H)
(C, H, H)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
①
④
③
OH
OH
Me
Et
②
Et
Me
OH
OH
Me
H
HO
Et
Me
H
Et
= H
Arrows are clockwise
Et
Me
(R)-2-Butanol
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Other examples
①
Cl
④
③
H
HO
Counterclockwise
Cl
CH3
HO
CH3
(S)
②
②
④
H3C
① Br
OCH3
③
OCH3
CH2CH3
Br
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Clockwise
(R)
CH2CH3

Other examples
● Rotate C–Cl bond such that H is pointed
to the back
②
Cl
Cl
④
Br
HO
H
③
H
OH
① Br
Cl
Br
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Clockwise
OH
(R)

Other examples
● Rotate C–CH3 bond such that H is
pointed to the back
②
H
I
H3C
OCH3
④
OCH3
①
H
I
H3C ③
Counter-clockwise
H 3C
© 2014 by John Wiley & Sons, Inc. All rights reserved.
OCH3
I
(S)

Rule 4
● For groups containing double or
triple bonds, assign priorities as if
both atoms were duplicated or
triplicated
e.g.
as
C O
C O
O C
C C
C C
as
as
C C
C C
C C
C C
C C
© 2014 by John Wiley & Sons, Inc. All rights reserved.

③
Example
④
CH3
②
H
HO ①
Compare
CH3
&
CH CH2
Thus,
CH3
(S)
CH=CH2
CH CH2 :
equivalent to
 (H, H, H)
CH CH2  (C, C, H)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H H
C C H
C C

Other examples
②
(R)
OH
④
③ CH3
H
Cl ① O
③
H2C
④
OH
H
② CH3
② C  (O, O, C)
① Cl
O (S)
③
C  (O, H, H)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
8. Properties of Enantiomers:
Optical Activity

Enantiomers
● Mirror images that are not
superimposable
H
Cl
H3CH2C
H
*
*
CH3
H 3C
mirror
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Cl
CH2CH3

Enantiomers have identical physical
properties (e.g. melting point, boiling
point, refractive index, solubility etc.)
Compound
bp (oC)
(R)-2-Butanol
99.5
(S)-2-Butanol
99.5
mp (oC)
(+)-(R,R)-Tartaric Acid
168 – 170
(–)-(S,S)-Tartaric Acid
168 – 170
(+/–)-Tartaric Acid
210 – 212
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Enantiomers
● Have the same chemical properties
(except reaction/interactions with
chiral substances)
● Show different behavior only when
they interact with other chiral
substances
● Rotate plane-polarized light in
opposite direction
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
Optical activity
● The property possessed by chiral
substances of rotating the plane of
polarization of plane-polarized light
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8A. Plane-Polarized Light
The electric field (like the magnetic
field) of light is oscillating in all
possible planes
 When this light passes through a
polarizer (Polaroid lens), we get planepolarized light (oscillating in only one
plane)
Polaroid
lens

© 2014 by John Wiley & Sons, Inc. All rights reserved.
8B. The Polarimeter

A device for measuring the optical
activity of a chiral compound
a =observed
optical rotation
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8C. Specific Rotation
observed
rotation
temperature
25
[a]D =
wavelength
of light
(e.g. D-line
of Na lamp,
l=589.6 nm)
c
a
x
ℓ
concentration length of cell
of sample
in dm
solution
(1 dm = 10 cm)
in g/mL
© 2014 by John Wiley & Sons, Inc. All rights reserved.

The value of a depends on the
particular experiment (since there are
different concentrations with each run)
● But specific rotation [a] should be
the same regardless of the
concentration
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Two enantiomers should have the
same value of specific rotation, but the
signs are opposite
CH3
CH3
*
H
HO
25
*
CH2CH3
[a] = + 13.5
D
o
H3CH2C
25
mirror
H
OH
[a] =  13.5
D
© 2014 by John Wiley & Sons, Inc. All rights reserved.
o
9. The Origin of Optical Activity
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9. The Origin of Optical Activity
© 2014 by John Wiley & Sons, Inc. All rights reserved.
9. The Origin of Optical Activity
© 2014 by John Wiley & Sons, Inc. All rights reserved.
9A. Racemic Forms
An equimolar mixture of two enantiomers
is called a racemic mixture (or racemate
or racemic form)
 A racemic mixture causes no net rotation
of plane-polarized light
equal & opposite

rotation by the
enantiomer
rotation
H
CH3
H 3C
OH
C2H5
(R)-2-Butanol
H
HO
C 2H 5
(S)-2-Butanol
(if present)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
9B. Racemic Forms and Enantiomeric
Excess

A sample of an optically active
substance that consists of a single
enantiomer is said to be
enantiomerically pure or to have an
enantiomeric excess of 100%
© 2014 by John Wiley & Sons, Inc. All rights reserved.

An enantiomerically pure sample of (S)-(+)2-butanol shows a specific rotation of
+13.52
25
[a]D


= +13.52
A sample of (S)-(+)-2-butanol that contains
less than an equimolar amount of (R)-(–)-2butanol will show a specific rotation that is
less than 13.52 but greater than zero
Such a sample is said to have an
enantiomeric excess less than 100%
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Enantiomeric excess (ee)
● Also known as the optical purity
● Can be calculated from optical
rotations
% enantiomeric
=
excess *
observed specific rotation
specific rotation of the
pure enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.
x 100

Example
● A mixture of the 2-butanol
enantiomers showed a specific
rotation of +6.76. The
enantiomeric excess of the (S)-(+)2-butanol is 50%
% enantiomeric
=
excess *
+6.76
+13.52
x 100 = 50%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
10. The Synthesis of Chiral
Molecules
10A. Racemic Forms
CH3CH2CCH3 + H H
Ni
(
)-CH 3CH2CHCH3
OH
O
Butanone
(achiral
molecules)
Hydrogen
(achiral
molecules)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
(
 )-2-Butanol
(chiral
molecules; but
50:50 mixture
(R) & (S))
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10B. Stereoselective Syntheses

Stereoselective reactions are reactions
that lead to a preferential formation of one
stereoisomer over other stereoisomers that
could possibly be formed
● enantioselective – if a reaction
produces preferentially one enantiomer
over its mirror image
● diastereoselective – if a reaction
leads preferentially to one diastereomer
over others that are possible
© 2014 by John Wiley & Sons, Inc. All rights reserved.
O
O
+
OEt
F
racemate ( 
)
O
OEt
F
racemate ( 
)
H , H2O
heat
OH + EtOH
F
racemate ( 
)
O
H2O
lipase
OH
F
()
(> 69% ee)
O
OEt + EtOH
+
F
(+)
(> 99% ee)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
11. Chiral Drugs

Of the $475 billion in world-wide sales of
formulated pharmaceutical products in
2008, $205 billion was attributable to single
enantiomer drugs
© 2014 by John Wiley & Sons, Inc. All rights reserved.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
12. Molecules with More than One
Chirality Center

In compounds with n tetrahedral
stereocenters, the maximum number
of stereoisomers is 2n
© 2014 by John Wiley & Sons, Inc. All rights reserved.
12A. How to Draw Stereoisomers for
Molecules Having More than One
Chirality Center
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Start by drawing the portion of the
carbon skeleton that contains the
chirality centers in such a way that as
many of the chirality centers are placed
in the plane of the paper as possible,
and as symmetrically as possible
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Next we add the remaining groups that
are bonded at the chirality centers in
such a way as to maximize the
symmetry between the chirality centers
© 2014 by John Wiley & Sons, Inc. All rights reserved.

To draw the enantiomer of the first
stereoisomer, we simply draw its mirror
image
© 2014 by John Wiley & Sons, Inc. All rights reserved.

To draw another stereoisomer, we
interchange two groups at any one of
the chirality centers
• All of the possible stereoisomers for a
compound can be drawn by successively
interchanging two groups at each chirality
center
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Next we examine the relationship
between all of the possible pairings of
formulas to determine which are pairs
of enantiomers, which are
diastereomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.


Structures 1 and 2 are enantiomers;
structures 3 and 4 are also enantiomers
Structures 1 and 3 are stereoisomers and they
are not mirror images of each other. They are
diastereomers
• Diastereomers have different physical
properties - different melting points and
boiling points, different solubilities, and so
forth
© 2014 by John Wiley & Sons, Inc. All rights reserved.

Diastereomers
● Stereoisomers that are not
enantiomers
● Unlike enantiomers, diastereomers
usually have substantially different
chemical and physical properties
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Br
Cl C H
HO C H
CH3
Br
H C Cl
OH
H C
CH3
(II)
Br
C H
Cl
(III)
CH3 C H
HO
Br
H C Cl
H C CH3
OH
(IV)
(I)
(I) & (II) are enantiomers of each other
 (III) & (IV) are enantiomers of each
other

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Br
Cl C H
HO C H
CH3
Br
H C Cl
OH
H C
CH3
(II)
Br
C H
Cl
(III)
CH3 C H
HO
Br
H C Cl
H C CH3
OH
(IV)
(I)

Diastereomers of each other:
● (I) & (III), (I) & (IV), (II) & (III),
(II) & (IV)
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12B. Meso Compounds
Compounds with two stereocenters do
not always have four stereoisomers
(22 = 4) since some molecules are
achiral (not chiral), even though they
contain stereocenters
 For example, 2,3-dichlorobutane has
two stereocenters, but only has 3
stereoisomers (not 4)

© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
(I)
CH3 C Br
CH3 C Br
H
H
C Br
CH
3
(III)
H C Br
CH3
Br
Br
Br
Br
H
C CH
3 (II)
C CH3
H
H
C CH
3 (IV)
C H
CH3
Note: (III) contains a plane of symmetry,
is a meso compound, and is achiral
([a] = 0o).
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
(I)
CH3 C Br
CH3 C Br
H
H
C Br
CH
3
(III)
H C Br
CH3
Br
Br
Br
Br
H
C CH
3 (II)
C CH3
H
H
C CH
3 (IV)
C H
CH3
(I) & (II) are enantiomers of each
other and chiral
 (III) & (IV) are identical and achiral

© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
(I)
CH3 C Br
CH3 C Br
H
H
C Br
CH
3
(III)
H C Br
CH3
Br
Br
Br
Br
H
C CH
3 (II)
C CH3
H
H
C CH
3 (IV)
C H
CH3
(I) & (III), (II) & (III) are diastereomers
 Only 3 stereoisomers:
● (I) & (II) {enantiomers}, (III) = (IV)
{meso}

© 2014 by John Wiley & Sons, Inc. All rights reserved.
12C. How to Name Compounds with
More than One Chirality Center

2,3-Dibromobutane
H
Br
a
Br
2
3
4
1
● Look through C2–Ha bond
① Br
③
C2: (R) configuration
C1
a④
H
2
②
C3
(H, H, H) (Br, C, H)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
b
● Look through C3–Hb bond
Br
a
H
Br
2
1
b
①
4
③
H
3
CH3
CH3
b
H
Br
C4
3
④
②
C2
(H, H, H) (Br, C, H)
C3: (R) configuration
● Full name:

(2R, 3R)-2,3-Dibromobutane
© 2014 by John Wiley & Sons, Inc. All rights reserved.
13. Fischer Projection Formulas
13A. How To Draw and Use Fischer
Projections
Fischer
Projection
HO
H3C
Et
Br
COOH
Ph
COOH
COOH
Br
Ph
Br
Ph
Et
OH
Et
OH
CH3
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
H
Me
COOH
Ph
H
Me OH
H
H
Ph
OH
COOH
COOH
HO
Fischer
Me
Projection
COOH
H
HO
H
H
Me
H
Ph
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Ph
Cl
H
H
H3C
Cl
CH3
H
Cl
(I)
(2S, 3S)-Dichlorobutane
H3C
H
CH3
(II)
(2R, 3R)-Dichlorobutane
CH3
CH3
H
Cl
Cl
H
Cl
H
H
Cl
enantiomers
CH3
CH3

Cl
(I) and (II) are both chiral and they are
enantiomers of each other
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Cl
H3C
H
H
CH3
Cl
CH3
H
Cl
H
Cl
(III)
(2S, 3R)-Dichlorobutane
CH3
Plane of
symmetry
(III) is achiral (a meso compound)
 (III) and (I) are diastereomers of each
other

© 2014 by John Wiley & Sons, Inc. All rights reserved.
14. Stereoisomerism of Cyclic
Compounds
a meso compound
mirror
achiral
H
Me
H
Me
Me
Me
Me
H
Me
H
H
H
enantiomers
Plane of
symmetry
© 2014 by John Wiley & Sons, Inc. All rights reserved.
14A. Cyclohexane Derivatives
 1,4-Dimethylcyclohexane
Me
Plane of
symmetry
Me
Me
Me
H
Me
Me
• Both cis- & trans1,4-dimethylcyclohexanes are
achiral and
optically inactive
H
H
cis-1,4-dimethyl
cyclohexane
Me
• The cis & trans
Me forms are
H
trans-1,4-dimethyl
cyclohexane
diastereomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.

1,3-Dimethylcyclohexane
Plane of
symmetry
Me
*
*
Me
Me
cis-1,3-dimethyl
cyclohexane
Me
H
H
(meso)
● cis-1,3-Dimethylcyclohexane has a
plane of symmetry and is a meso
compound
© 2014 by John Wiley & Sons, Inc. All rights reserved.

1,3-Dimethylcyclohexane
NO plane of symmetry
Me
*
*
Me
trans-1,3-dimethyl
cyclohexane
Me
H
Me
H
Me
H
H
Me
enantiomers
● trans-1,3-Dimethylcyclohexane
exists as a pair of enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.

1,3-Dimethylcyclohexane
● Has two chirality centers but only
three stereoisomers
cis-1,3-dimethyl
cyclohexane
Me
H
H
Me
(meso)
trans-1,3-dimethyl
cyclohexane
Me
H
Me
H
Me
H
H
Me
enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.

1,2-Dimethylcyclohexane
mirror
H
H
Me
Me
Me
Me
H
H
enantiomers
● trans-1,2-Dimethylcyclohexane
exists as a pair of enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.

1,2-Dimethylcyclohexane
● With cis-1,2-dimethylcyclohexane
the situation is quite complicated
mirror
Me
H
Me
(I)
H
Me
H
Me
H
(II)
● (I) and (II) are enantiomers to each
other
© 2014 by John Wiley & Sons, Inc. All rights reserved.
● However, (II) can rapidly be
interconverted to (III) by a ring flip
Me
2'
1'
(I)
H
Me
Me
H 2
Me
H
1
(II)
H
Me
Me
2
H
© 2014 by John Wiley & Sons, Inc. All rights reserved.
1
H
(III)
● Rotation of (III) along the vertical
axis gives (I)
Me
2'
1'
(I)
H
Me
Me
H 2
Me
H
1
(II)
H
C1 of (II) and (III)
become C2’ of (I) &
C2 of (II) and (III)
become C1’ of (I)
Me
Me
2
H
1
H
© 2014 by John Wiley & Sons, Inc. All rights reserved.
(III)
Me
2'
1'
(I)
H
Me
Me
H 2
Me
H
Although (I) and (II)
are enantiomers to
each other, they can
interconvert rapidly
 (I) and (II) are
1
(II)
H
Me
Me
2
H
achiral
© 2014 by John Wiley & Sons, Inc. All rights reserved.
1
H
(III)
15. Relating Configurations through
Reactions in Which No Bonds to
the Chirality Center Are Broken

A reaction is said to proceed with
retention of configuration at a
chirality center if no bonds to the chirality
center are broken. This is true even if the
R,S designation for the chirality center
changes because the relative priorities of
groups around it changes as a result of
the reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Same configuration
O
Me H
Me
Ph
H
OH
H
H
Me H
NaBH4
MeOH
Me
NaCN
H
Br
DMSO
Ph
Same configuration
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
CN
15A. Relative & Absolute Configurations
 Chirality centers in different molecules have
the same relative configuration if they
share three groups in common and if these
groups with the central carbon can be
superimposed in a pyramidal arrangement
© 2014 by John Wiley & Sons, Inc. All rights reserved.

The absolute configuration of a chirality
center is its (R) or (S) designation, which
can only be specified by knowledge of the
actual arrangement of groups in space at
the chirality center
(R)-2-Butanol
(S)-2-Butanol
H OH
HO H
enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.
16. Separation of Enantiomers:
Resolution

Resolution – separation of two enantiomers
O
e.g.
OH
R * R'
(racemic)
O
O
Cl
OMe
Ph CF3
(Mosher acid
chloride)
R
R'
OMe
CF3
Ph
(1
O
O
+
R
:
R'
OMe
CF3
Ph
1)
diastereomers
usually separable
either by flash column
chromatography or
recrystallization etc.
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
Kinetic Resolution
OH
OH
R
*
R1
R2
(racemic)
R
*
OH
R1
+
R2
R
*
R1
O R2
● One enantiomer reacts “fast” and
another enantiomer reacts “slow”
© 2014 by John Wiley & Sons, Inc. All rights reserved.

e.g.
Me3Si
t
i
BuOOH, Ti(O Pr)4
Me3Si
OH
(-)-DET
C5H11
HO
COOEt
HO
COOEt
*
(-)-DET:
(racemic)
(D)-(-)-Diethyl Tartrate
Me3Si
C5H11
R'
43%
(99%ee)
42%
(99%ee)

Me3Si
S OH
H
H
R OH
R'
* stop reaction at  50%
* maximum yield = 50%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
OH
C5H11

Me3Si
O
OH +
17. Compounds with Chirality
Centers Other than Carbon
R4
R1
R3
Si
H
R2
R1
R4
R1
R3
Ge
R2
R2
R3
N
R2
X
© 2014 by John Wiley & Sons, Inc. All rights reserved.
R1
S
O
18. Chiral Molecules That Do Not
Possess a Chirality Center
© 2014 by John Wiley & Sons, Inc. All rights reserved.
mirror
H
C
Cl
C
C
H
H
Cl
Cl
H
C
enantiomers
© 2014 by John Wiley & Sons, Inc. All rights reserved.
C
C
Cl
 END OF CHAPTER 5 
© 2014 by John Wiley & Sons, Inc. All rights reserved.