3
Organic
Chemistry
William H. Brown &
Christopher S. Foote
3-1
3
Chirality
Chapter 3
3-2
3 Isomers
 Isomers:
different compounds with the same
molecular formula
 Constitutional isomers: isomers with a different
connectivity
 Stereoisomers: isomers with the same molecular
formula and connectivity but a different
orientation of their atoms in space
3-3
3 Isomers
Compounds with the
same molecular formula
rotation about
a single bond
same different
connectivity connectivity
Stereoisomers
without
stereocenters
Chiral
Achiral
Enantiomers
Cis,Trans
(E,Z) Isomers
Constitutional
Isomers
Conformations
rotation
restricted
Conformational
Isomers
with stereocenters
Chiral
Enantiomers
Diastereomers
Achiral
Meso
Compounds
3-4
3 Chirality
 Mirror
image: the reflection of an object in a
mirror
 Chiral: an object that is not superposable on its
mirror image; an object that shows handedness
 Achiral: an object that lacks chirality; an object
that has no handedness
• an achiral object has at least one element of symmetry
3-5
3 Elements of Symmetry
 Plane
of symmetry: an imaginary plane passing
through an object dividing it so that one half is
the mirror image of the other half
H
Br
C
Cl
H
3-6
3 Elements of Symmetry
 Plane
of symmetry (contd.)
mirror
plane
HO
OH
3-7
3 Elements of Symmetry
 Center
of symmetry: a point so situated that
identical components of the object are located on
opposite sides and equidistant from the point
along any axis passing through it
Br
H
Cl
Cl
H Br
center of
symmetry
3-8
3 Stereocenter
 The
most common (but not the only) cause of
chirality in organic molecules is a tetrahedral
atom, most commonly carbon, bonded to four
different groups
 A carbon with four different groups bonded to it
is called a stereocenter or, alternatively, a
stereogenic center
3-9
3 Enantiomers
 Enantiomers:
stereoisomers that are
nonsuperposable mirror images; refers to the
relationship between pairs of objects
 On the three following screens are examples
chiral molecules. Each has one stereocenter and
can exist as a pair of enantiomers.
3-10
3 Enantiomers
 Lactic
acid
HO
HO
O
O
OH
C
C
C
C
H
CH3
H
H3 C
OH
3-11
3 Enantiomers
 2-Chlorobutane
H Cl
Cl
CH3 CHCH2 CH3
Cl H
3-12
3 Enantiomers
Cl
 3-Chlorocyclohexene
Cl
H
Cl
H
3-13
3 Enantiomers
A
nitrogen stereocenter
+
+
N
H3 C
N
CH2 CH3
CH3 CH2 CH3
A pair of enantiomers
3-14
3 R,S Convention
 Priority
rules
1. Each atom bonded to the stereocenter is assigned a
priority based on atomic number; the higher the
atomic number, the higher the priority
(1)
(6)
-H
-CH3
(7)
-N H2
(8)
(16)
(17)
- OH
- SH
- Cl
(35)
(53)
- Br
-I
Increasing priority
2. If priority cannot be assigned per the atoms bonded to
the stereocenter, look to the next set of atoms; priority
is assigned at the first point of difference
(1)
- CH 2 -H
(6)
- CH 2 -CH 3
(7)
- CH 2 -NH2
(8)
- CH 2 -OH
Increasing priority
3-15
3 R,S Convention
3. Atoms participating in a double or triple bond are
considered to be bonded to an equivalent number of
similar atoms by single bonds
- CH = CH 2
O
- CH
is treated as
is treated as
C
C
- CH -CH2
O C
C
O
H
3-16
3 Naming Enantiomers
1. Locate the stereocenter, identify its four substituents, and assign
priority from 1 (highest) to 4 (lowest) to each substituent
2. Orient the molecule so that the group of lowest priority (4) is
directed away from you
3. Read the three groups projecting toward you in order from
highest (1) to lowest priority (3)
4. If the groups are read clockwise, the configuration is R; if they are
read counterclockwise, the configuration is S
(S)-2-Chlorobutane
H Cl
S
2
1
3
3-17
3 R,S Configuration
• (R)-3-Chlorocyclohexene
3
Cl
1
2
H
R
• (R)-Mevalonic acid
1
1 4
HO CH3 O
HO
3
2
R
OH
3
2
3-18
3 Enantiomers & Diastereomers
a molecule with 1 stereocenter, 21 = 2
stereoisomers are possible
 For a molecule with 2 stereocenters, a maximum
of 22 = 4 stereoisomers are possible
 For a molecule with n stereocenters, a maximum
of 2n stereoisomers are possible
 For
3-19
3 Enantiomers & Diastereomers
 2,3,4-trihydroxybutanal
• two stereocenters; 22 = 4 stereoisomers exist
CHO
CHO
H
C
OH HO
C
H
H
C
OH HO
C
H
CH2 OH
CH2 OH
A pair of enantiomers
(Erythreose)
CHO
CHO
H
C
OH HO
C
H
HO
C
H
C
OH
CH2 OH
H
CH2 OH
A pair of enantiomers
(Threose)
3-20
3 Enantiomers & Diastereomers
 2,3-dihydroxybutanedioic
acid (tartaric acid)
• two stereocenters; 2n = 4, but for this molecule, only
three stereoisomers exist
COOH
COOH
H
C
OH HO
C
H
H
C
OH HO
C
H
COOH
COOH
A meso compound
(plane of symmetry)
COOH
COOH
H
C
OH HO
C
H
HO
C
H
C
OH
H
COOH
COOH
A pair of enantiomers
 Meso
compound: an achiral compound
possessing two or more stereocenters
3-21
3 Enantiomers & Diastereomers
2-methylcyclopentanol
CH 3 OH
HO H 3 C
H
H
H
H
cis-2-Methylcyclopentanol
(a pair of enantiomers)
CH3 H
diastereomers
H H3 C
H
OH
H
HO
trans-2-Methylcyclopentanol
(a pair of enantiomers)
3-22
3 Enantiomers & Diastereomers
1,2-cyclopentanediol
OH HO
H
OH HO
H
H
H
cis- 1,2-Cyclopentanediol
(a meso compound)
OH
H
H
diastereomers
HO
OH H
H HO
trans- 1,2-Cyclopentanediol
(a pair of enantiomers)
3-23
3 Enantiomers & Diastereomers
cis-3-methylcyclohexanol
H3 C
OH HO
CH3
3-24
3 Enantiomers & Diastereomers
trans-3-methylcyclohexanol
H3 C
CH3
OH
HO
3-25
3 Properties of Stereoisomers
 Enantiomers
have identical physical and
chemical properties in achiral environments
 Diastereomers are different compounds and have
different physical and chemical properties
 Meso-tartaric acid, for example, has different
physical and chemical properties from its
enantiomers (see Table 3.1).
3-26
3 Plane-Polarized Light
 Ordinary
light: light vibrating in all planes
perpendicular to its direction of propagation
 Plane-polarized light: light vibrating only in
parallel planes
• plane polarized light is the vector sum of left and right
circularly polarized light; these two forms of light are
enantiomers
• because of their handedness, each component of
circularly polarized light interacts in an opposite way
with a chiral molecule.
3-27
3 Plane-Polarized Light
QuickTime™ and a
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are needed to see this picture.
3-28
3 Plane-Polarized Light
• because of its handedness, circularly polarized light
reacts one way with an R stereocenter, and in an
opposite with its enantiomer
• the net effect of the interaction of plane polarized light
with a chiral compound is that the plane of polarization
is rotated
 Polarimeter:
a device for measuring the extent of
rotation of plane polarized light
3-29
3 Optical Activity
rotation: the number of degrees, ,
through which a compound rotates the plane of
polarized light
 Dextrorotatory (+): refers to a compound that
rotates the plane of polarized light to the right
 Levorotatory (-): refers to a compound that
rotates of the plane of polarized light to the left
 Observed
3-30
3 Optical Activity
 Specific
rotation: observed rotation of the plane
of polarized light when a sample is placed in a
tube 1.0 dm in length and at a concentration of
1g/mL
T
observed rotation (degrees)
[]
Specific rotation =
 = length (dm) x concentration (g/mL)
3-31
3 Optical Activity
 For
a pair of enantiomers, the value of the
specific rotation of each is the same, but
opposite in sign
OH
HO
C
H
CH3 CH2
C
CH3
(S)-(+)-2-Butanol
25
[ ] D +13.52
H
CH2 CH3
H3 C
(R)-(-)-2-Butanol
25
[ ] D -13.52
3-32
3 Enantiomeric Excess
 When
dealing with a mixture of enantiomers, it
is essential to describe the composition of the
mixture and the degree to which one
enantiomer is in excess
 The most common designation is enantiomeric
excess (ee)
ee =
[R] - [S]
x 100 = %R - %S
[R] + [S]
3-33
3 Enantiomeric Excess
Example: a commercial synthesis of naproxen, a
nonsteroidal antiinflammatory drug (NSAID), gives this
enantiomer in 97% ee. Assign an R or S configuration to
its stereocenter, and calculate the % R and S
enantiomers in the mixture.
H CH3
C
H 3 CO
COOH
Naproxen
3-34
3 Resolution
 Racemic
mixture: an equimolar mixture of two
enantiomers
• because a racemic mixture contains equal numbers of
dextrorotatory and levorotatory molecules, its specific
activity is zero.
 Resolution:
the separation of a racemic mixture
into its enantiomers
3-35
3 Resolution

One means of resolution is to convert the pair
of enantiomers into two diastereomers
• diastereomers are different compounds and have
different physical properties

A common reaction for chemical resolution is
salt formation
+
RCOOH
:B
(R,S)-Carboxylic
(R')-Base
acid
-
+
RCOO HB
(RR')-Salt + (SR')-Salt)
• after separation of the diastereomers, the
enantiomerically pure acids are recovered
3-36
3 Resolution
Examples of enantiomerically pure bases
H
H
H
H
H
H
N
HO
N
HO
H
H
CH3 O
N
(+)-Cinchonine
[ ]
23
= +228
D
N
(-)-Quinine
[ ]
25
= -165
D
3-37
3
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are needed to see this picture.
3-38
3 Resolution
 Enzymes
as resolving agents
O
OCH2 CH3
C
H
CH3
H 3 CO
Ethyl ester of (S)-naproxen
1. esterase
N aOH, H2 O
CH3 CH2 O
+
C
O
H
H3 C
OCH3
Ethyl ester of (R)-naproxen
(not affected by the esterase)
2 . HCl, H2 O
O
OH
C
H
CH3
H 3 CO
(S)-Naproxen
3-39
3 Chirality in the Biological World
 Except
for inorganic salts and a few lowmolecular-weight organic substances, the
molecules of living systems are chiral
 Although these molecules can exist as a number
of stereoisomers, generally only one is produced
and used in a given biological system
 It’s a chiral world!
3-40
3 Chirality in the Biological World
 Consider
chymotrypsin, a protein-digesting
enzyme in the digestive system of animals
• chymotrypsin contains 251 stereocenters
• the maximum number of stereoisomers possible is 2251
• there are only 238 stars in our galaxy!
3-41
3 Chirality in the Biological World
 Enzymes
are like hands in a handshake
• the substrate fits into a binding site on the enzyme
surface
• a left-handed molecule will only fit into a left-handed
binding site and
• a right-handed molecule will only fit into a righthanded binding site
• enantiomers have different physiological properties
because of their handedness of their interactions with
other chiral molecules in living systems
3-42
3 Chirality in the Biological World
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are needed to see this picture.
3-43
3 Prob 3.15
Draw mirror images for each molecule.
CHO
OH
(a)
H3 C
H
(d)
(b) H
C
COOH
O
C
OH
(e)
C
H
CH 3
H
OH
OH
(f)
OH
CH 3
CH 3
OH
CH 3
(c) H 2 N
CH 2 OH
H
(g)
COOH
(h)
H
H
OH
CH 3
OH
3-44
3 Prob 3.16
Which are identical with (a) and which are mirror images
of (a)?
COOH
(a)
H
H3 C
CH3
(b)
C
OH
HO
H OOC
HO
H
(d)
C
CH3
H
CH3
COOH
(c)
C
H
HO
C
COOH
3-45
3 Prob 3.17
Mark all stereocenters in each molecule.
CH3
(a) CH3 CCH= CH2
OH
O
(d) CH3 CCH2 CH 3
COOH
(b) HCOH
CH3
CH2 OH
(e) HCOH
CH2 OH
CH3
(c) CH3 CHCH COOH
N H2
OH
(f) CH3 CH2 CHCH= CH2
CH2 COOH
(g) HOCCOOH
CH2 COOH
3-46
3 Prob 3.20
Assign an R or S configuration to the stereocenter in
each enantiomer.
CH3
CH3
O
C H
H2 C
CH3
O
(-)-Carvone
C CH
2
CH3
(+)-Carvone
[ ] D -62.5°
[ ]
20
Spearmint oil
H
20
D
+62.5°
Caraway and
dill seed oil
3-47
3 Prob 3.21
Assign an R or S configuration to this enantiomer of 2butanol. Also draw a Newman production viewed along
the bond between carbons 2 and 3.
H3 C
H
H
H
OH
CH3
3-48
3 Prob 3.22
Assign an R or S configuration to each stereocenter in
this enantiomer of ephedrine.
H
C
HO
H
NH CH 3
C
CH3
Ephedrine [ ]
21
D
-41°
3-49
3 Prob 3.23
Assign an R or S configuration to this
enantiomer of carbon-14 labeled citric acid.
O C-COOH
CH2 COOH
Oxaloacetic acid
+
O
CH3 CSCoA
14
Acetyl-CoA
citrate
synthase
14
CH2 COOH
H OOC
C
OH
CH2 COOH
[2-14 C]Citric acid
3-50
3 Prob 3.24
Draw all stereoisomers possible for this compound. Label
which are meso and which are pairs of enantiomers.
H3 C
H OOC
CH 3
COOH
3-51
3 Prob 3.25
Mark are stereocenters in each molecule. How many
stereoisomers are possible for each molecule?
OH
CH2 - COOH
(a) CH3 CHCH COOH
HO OH
OH
(d)
(e)
O
(g)
(b) CH- COOH
HO CH- COOH
OH
(f)
O
(c)
COOH
(h)
O
OH
3-52
3 Prob 3.26
Label the eight stereocenters in cholesterol.
HO
3-53
3 Prob 3.27
Label the four stereocenters in amoxicillin.
HO
O
CH- C H N
NH 2
S
N
O
HO
CH3
CH3
C O
3-54
3 Prob 3.29
Are the formulas in each set identical, enantiomers, or
diastereomers?
Cl
H Cl
H
(a)
and
H OH
HO H
H Cl
HO H
(b)
and
H OH
H Cl
H Cl
(c)
HO H
and
HO H
Cl
H
3-55
3 Prob 3.30
Which are meso compounds?
Br
(a)
Br
Br
C
H
CH 3
(b)
C
C
H
CH3
H
CH3
CH3
OH
CH3
OH
(c)
OH
Br
CH2 OH
CH3
OH
OH
(d)
H CH
3
C
(f)
(e)
H
OH
H
OH
OH
CHO
(g)
H
H
OH
OH
CH2 OH
(h)
HO
H
CH2 OH
H
OH
CH2 OH
CH2 OH
H
(i)
H
CH 2 OH
OH
OH
CH 2 OH
3-56
3 Prob 3.31
Oxidation of this bicyclic alkene gives a dicarboxylic acid.
Is the product of this oxidation one enantiomer, a racemic
mixture, or a meso compound?
vigorous
oxidation
H OOC
COOH
3-57
3 Prob 3.35
Verify that although, this molecule has no stereocenter, it
is chiral.
O O
3-58
3 Prob 3.36
Verify that, although this substituted allene has no
stereocenter, it is chiral.
H
H
C C C
C( CH3 ) 3
( CH3 ) 3 C
[]
25
D
-314
3-59
3
Chirality
End of Chapter 3
3-60