Chapter 7 Stereochemistry

1
Chapter 7Stereochemistry
2
Molecular Chirality Enantiomers
3
Chirality

• A molecule is chiral if its two mirror image
  forms are not superposable upon one another.
  ASYMMETRIC!
• A molecule is achiral if its two mirror image
  forms are superposable. SYMMETRIC!

4
Bromochlorofluoromethane is chiral
Cl

• It cannot be superposed point for point on its
  mirror image.

Br
H
F
5
Bromochlorofluoromethane is chiral
Cl
Cl
Br
Br
H
H
F
F

• To show nonsuperposability, rotate this model
  180 around a vertical axis.

6
Bromochlorofluoromethane is chiral
Cl
Br
Cl
Br
H
H
F
F
7
Another look
8
Enantiomers
nonsuperposable mirror images are called
enantiomers
and

• are enantiomers with respect to each other

9
Isomers
constitutional isomers
stereoisomers
10
Isomers
constitutional isomers
stereoisomers
enantiomers
diastereomers
11
Chlorodifluoromethaneis achiral
12
Chlorodifluoromethaneis achiral

• The two structures are mirror images, but are
  not enantiomers, because they can be superposed
  on each other.

13
The Chirality Center
14
The Chirality Center

• a carbon atom with fourdifferent groups attached
  to it
• also called
• chiral centerasymmetric centerstereocenter
• stereogenic center

15
Chirality and chirality centers

• A molecule with a single chirality center is
  chiral.
• Bromochlorofluoromethane is an example.

16
Chirality and chirality centers

• A molecule with a single chirality center is
  chiral.
• 2-Butanol is another example.

17
Examples of molecules with 1 chirality center
a chiral alkane
18
Examples of molecules with 1 chirality center
Linalool, a naturally occurring chiral alcohol
19
Examples of molecules with 1 chirality center
1,2-Epoxypropane a chirality center can be part
of a ring

• attached to the chirality center are
• H
• CH3
• OCH2
• CH2O

20
Examples of molecules with 1 chirality center
Limonene a chirality center can be part of a
ring

• attached to thechirality center are
• H
• CH2CH2
• CH2CHC
• CC

21
Examples of molecules with 1 chirality center
Chiral as a result of isotopic substitution
22
A molecule with a single chirality centermust be
chiral.

• But, a molecule with two or more chirality
  centers may be chiral or it may not (Sections
  7.10-7.13).

23
Symmetry in Achiral Structures
24
Symmetry tests for achiral structures

• Any molecule with a plane of symmetryor a center
  of symmetry must be achiral.

25
Plane of symmetry

• A plane of symmetry bisects a molecule into two
  mirror image halves. Chlorodifluoromethane has
  a plane of symmetry.

26
Plane of symmetry

• A plane of symmetry bisects a molecule into two
  mirror image halves.1-Bromo-1-chloro-2-fluoroeth
  ene has a planeof symmetry.

27
Center of symmetry

• A point in the center of themolecule is a center
  of symmetry if a line drawn from it to any
  element, when extended an equal distance in the
  opposite direction, encounters an identical
  element.

28
Properties of Chiral MoleculesOptical Activity
29
Optical Activity

• A substance is optically active if it rotates
  the plane of polarized light.
• In order for a substance to exhibit
  opticalactivity, it must be chiral and one
  enantiomer must be present in excess of the
  other.

30
Light

• has wave properties
• periodic increase and decrease in amplitude of
  wave

31
Light

• optical activity is usually measured using light
  having a wavelength of 589 nm
• this is the wavelength of the yellow light from
  a sodium lamp and is called the D line of sodium

32
Polarized light

• ordinary (nonpolarized) light consists of
  many beams vibrating in different planes
• plane-polarized light consists of only those
  beams that vibrate in the same plane

33
Polarization of light
34
Rotation of plane-polarized light
35
Specific rotation

• observed rotation (?) depends on the number of
  molecules encountered and is proportional
  to path length (l), and concentration (c)
• therefore, define specific rotation ? as

36
Racemic mixture

• a mixture containing equal quantities of
  enantiomers is called a racemic mixture
• a racemic mixture is optically inactive (? 0)
• a sample that is optically inactive can
  beeither an achiral substance or a
  racemicmixture

37
Optical purity

• an optically pure substance consists exclusively
  of a single enantiomer
• enantiomeric excess one enantiomer
  other enantiomer
• optical purity enantiomeric excess
• e.g. 75 (-) 25 () 50 opt. pure (-)

38
AbsoluteandRelative Configuration
39
Configuration

• Relative configuration compares the arrangement
  of atoms in space of one compound with those of
  another. until the 1950s, all configurations
  were relative
• Absolute configuration is the precise
  arrangement of atoms in space. we can now
  determine the absolute configuration of almost
  any compound

40
Relative configuration
H2, Pd
a 33.2
a 13.5

• No bonds are made or broken at the stereogenic
  centerin this experiment. Therefore, when
  ()-3-buten-2-ol and ()-2-butanol have the same
  sign of rotation, the arrangement of atoms in
  space is analogous. The twohave the same
  relative configuration.

41
Two possibilities

H2, Pd
H2, Pd

• But in the absence of additional information, we
  can't tell which structure corresponds
  to()-3-buten-2-ol, and which one to
  ()-3-buten-2-ol.

42
Two possibilities

H2, Pd
H2, Pd

• Nor can we tell which structure corresponds
  to()-2-butanol, and which one to ()-2-butanol.

43
Absolute configurations

H2, Pd
a 13.5
a 33.2
H2, Pd
a 33.2
a 13.5
44
Relative configuration
HBr
a -5.8
a 4.0

• Not all compounds that have the same
  relativeconfiguration have the same sign of
  rotation. No bondsare made or broken at the
  stereogenic center in thereaction shown, so the
  relative positions of the atoms are the same.
  Yet the sign of rotation changes.

45
The Cahn-Ingold-Prelog R-S Notational System
46
Two requirements for a systemfor specifying
absolute configuration

• 1. need rules for ranking substituents at
  stereogenic center in order of decreasing
  precedence
• 2. need convention for orienting molecule so
  that order of appearance of substituents can be
  compared with rank
• The system that is used was devised by R. S.
  Cahn, Sir Christopher Ingold, and V. Prelog.

47
The Cahn-Ingold-Prelog Rules(Table 7.1)

• 1. Rank the substituents at the stereogenic
  center according to same rules used in E-Z
  notation.
• 2. Orient the molecule so that lowest-ranked
  substituent points away from you.

48
Example

• Order of decreasing rank4 gt 3 gt 2 gt 1

49
The Cahn-Ingold-Prelog Rules(Table 7.1)

• 1. Rank the substituents at the stereogenic
  center according to same rules used in E-Z
  notation.
• 2. Orient the molecule so that lowest-ranked
  substituent points away from you.
• 3. If the order of decreasing precedence traces
  a clockwise path, the absolute configuration is
  R. If the path is anticlockwise, the
  configuration is S.

50
Example

• Order of decreasing rank4 3 2

clockwise
anticlockwise
R
S
51
Enantiomers of 2-butanol
(S)-2-Butanol
(R)-2-Butanol
52
Very important!
Two different compounds with the same sign of
rotation need not have the same configuration.

53
Chirality center in a ring
CH2CC gt CH2CH2 gt CH3 gt H
54
Fischer Projections

• Purpose of Fischer projections is to show
  configuration at chirality center without
  necessity of drawing wedges and dashes or using
  models.

55
Rules for Fischer projections
H
Cl
Br
F

• Arrange the molecule so that horizontal bonds at
  chirality center point toward you and vertical
  bonds point away from you.

56
Rules for Fischer projections
H
Br
Cl
F

• Projection of molecule on page is a cross. When
  represented this way it is understood that
  horizontal bonds project outward, vertical bonds
  are back.

57
Rules for Fischer projections
H
Br
Cl
F

• Projection of molecule on page is a cross. When
  represented this way it is understood that
  horizontal bonds project outward, vertical bonds
  are back.

58
Physical Properties of Enantiomers
59
Physical properties of enantiomers

• Same melting point, boiling point, density,
  etc
• Different properties that depend on shape of
  molecule (biological-physiological properties)
  can be different

60
Odor
CH3
CH3
O
O
H3C
H3C
CH2
CH2
()-Carvonespearmint oil
()-Carvonecaraway seed oil
61
Chiral drugs

• Ibuprofen is chiral, but normally sold asa
  racemic mixture. The S enantiomer is the one
  responsible for its analgesic and
  antiinflammatory properties.

62
Reactions That Create A Chiral Center
63
Many reactions convert achiral reactants to
chiral products.

• It is important to recognize, however, that if
  all of the components of the starting state
  (reactants, catalysts, solvents, etc.) are
  achiral, any chiral product will be formed as a
  racemic mixture.
• This generalization can be more simply stated
  as "Optically inactive starting materials can't
  give optically active products." (Remember In
  order for a substance to be optically active, it
  must be chiral and one enantiomer must be present
  in greater amounts than the other.

64
Example

• Chiral, but racemic

Achiral
65
epoxidation from this direction gives R epoxide
R
66
epoxidation from this direction gives R epoxide
R
S
epoxidation from this direction gives S epoxide
67
epoxidation from this direction gives R epoxide
50
R
50
S
epoxidation from this direction gives S epoxide
68
Example
Br2, H2O
CH3CHCH2Br
OH

• Chiral, but racemic

Achiral
69
Example
HBr
CH3CHCH2CH3
Br

• Chiral, but racemic

Achiral
70
Many reactions convert chiral reactants to
chiral products.

• However, if the reactant is racemic, the product
  will be racemic also.
• Remember "Optically inactive starting
  materials can't give optically active products."

71
Example
HBr

• Chiral, but racemic

Chiral, but racemic
72
Many biochemical reactions convertan achiral
reactant to a singleenantiomer of a chiral
product

• Reactions in living systems are catalyzed by
  enzymes, which are enantiomerically homogeneous.
• The enzyme (catalyst) is part of the reacting
  system, so such reactions don't violate the
  generalization that "Optically inactive starting
  materials can't give optically active products."

73
Example
HO2C
H
H2O
fumarase
CO2H
H
Fumaric acid
(S)-()-Malic acid
Achiral
Single enantiomer
74
Chiral MoleculeswithTwo Chirality Centers

• How many stereoisomers when a particular
  molecule contains two chiral centers?

75
2,3-Dihydroxybutanoic acid
2
3

• What are all the possible R and S combinations
  of the two chirality centers in this molecule?

76
2,3-Dihydroxybutanoic acid
2
3

• What are all the possible R and S combinations
  of the two chirality centers in this molecule?

Carbon-2 R R S S Carbon-3 R S R S
77
2,3-Dihydroxybutanoic acid
2
3

• 4 Combinations 4 Stereoisomers

Carbon-2 R R S S Carbon-3 R S R S
78
2,3-Dihydroxybutanoic acid
2
3

• 4 Combinations 4 Stereoisomers
• What is the relationship between these
  stereoisomers?

Carbon-2 R R S S Carbon-3 R S R S
79
2,3-Dihydroxybutanoic acid
2
3
enantiomers 2R,3R and 2S,3S 2R,3S and 2S,3R
Carbon-2 R R S S Carbon-3 R S R S
80
a -9.5
a 9.5
enantiomers
enantiomers
a -17.8
a 17.8



81
2,3-Dihydroxybutanoic acid
2
3
but not all relationships are enantiomeric

• stereoisomers that are not enantiomers are
  diastereomers.
• similar but not identical chemical and physical
  properties

Carbon-2 R R S S Carbon-3 R S R S
82
Isomers
constitutional isomers
stereoisomers
enantiomers
diastereomers
83
a -9.5
a 9.5
enantiomers
diastereomers
enantiomers
a -17.8
a 17.8



84
Fischer Projections

• recall for Fischer projection horizontal bonds
  point toward you vertical bonds point away
• staggered conformation does not have correct
  orientation of bonds for Fischer projection

CO2H
CH3
85
Fischer projections

• transform molecule to eclipsed conformation in
  order to construct Fischer projection

86
Fischer projections
87
Erythro and Threo

• stereochemical prefixes used to specify relative
  configuration in molecules with two chirality
  centers
• easiest to apply using Fischer projections
• orientation vertical carbon chain

88
Erythro

• when carbon chain is vertical, same (or
  analogous) substituents on same side of Fischer
  projection

CO2H
H
HO
HO
H
CH3
9.5
9.5
89
Threo

• when carbon chain is vertical, same (or
  analogous) substituents on opposite sides of
  Fischer projection

17.8
17.8
90
Two chirality centers in a ring
S
R
S
R
trans-1-Bromo-2-chlorocyclopropane

• nonsuperposable mirror images enantiomers

91
Two chirality centers in a ring
S
S
R
R
cis-1-Bromo-2-chlorocyclopropane

• nonsuperposable mirror images enantiomers

92
Two chirality centers in a ring
S
S
R
R
cis-1-Bromo-2-chloro-cyclopropane
trans-1-Bromo-2-chloro-cyclopropane

• stereoisomers that are not enantiomers
  diastereomers

93
Achiral MoleculeswithTwo Chirality Centers

• It is possible for a molecule to have chirality
  centers yet be achiral.

94
2,3-Butanediol
3
2

• Consider a molecule with two equivalently
  substituted chirality centers such as 2,3
  butanediol.

95
Three stereoisomers of 2,3-butanediol
2R,3R
2S,3S
2R,3S
chiral
chiral
achiral
96
Three stereoisomers of 2,3-butanediol
2R,3R
2S,3S
2R,3S
chiral
chiral
achiral
97
Three stereoisomers of 2,3-butanediol
these two areenantiomers
2R,3R
2S,3S
chiral
chiral
98
Three stereoisomers of 2,3-butanediol
these two areenantiomers
2R,3R
2S,3S
chiral
chiral
99
Three stereoisomers of 2,3-butanediol
the third structure is superposable on
its mirror image
2R,3S
achiral
100
Three stereoisomers of 2,3-butanediol

• therefore, this structure and its mirror
  imageare the same
• it is called a meso form
• a meso form is an achiral molecule that has
  chirality centers

2R,3S
achiral
101
Three stereoisomers of 2,3-butanediol
CH3

• therefore, this structure and its mirror image
  are the same
• it is called a meso form
• a meso form is an achiral molecule that has
  chirality centers

H
HO
H
HO
CH3
2R,3S
achiral
102
Three stereoisomers of 2,3-butanediol

• meso forms have a plane of symmetry and/or a
  center of symmetry
• plane of symmetry is most common case
• top half of molecule is mirror image of bottom
  half

2R,3S
achiral
103
Three stereoisomers of 2,3-butanediol
A line drawnthe center ofthe Fischer
projection of ameso formbisects it intotwo
mirror-image halves.
2R,3S
achiral
104
Cyclic compounds
meso
S
R
There are three stereoisomers of
1,2-dichloro-cyclopropane the achiral (meso)
cis isomer and two enantiomers of the trans
isomer.
105
MoleculeswithMultiple Chirality Centers
106
How many stereoisomers?

• maximum number of stereoisomers 2n
• where n number of structural units capable of
  stereochemical variation
• structural units include chirality centers and
  cis and/or trans double bonds
• number is reduced to less than 2n if meso forms
  are possible

107
Example

• 4 chirality centers
• 16 stereoisomers

108
Cholic acid

• 11 chirality centers
• 211 2048 stereoisomers
• one is "natural" cholic acid
• a second is the enantiomer of natural cholic acid
• 2046 are diastereomers of cholic acid

109
How many stereoisomers?

• maximum number of stereoisomers 2n
• where n number of structural units capable of
  stereochemical variation
• structural units include chirality centers and
  cis and/or trans double bonds
• number is reduced to less than 2n if meso forms
  are possible

110
How many stereoisomers?

• 3-Penten-2-ol

R
E
E
S
H
OH
HO
H
R
Z
Z
S
OH
H
H
HO
111
Chemical Reactions That Produce Diastereomers
112
Stereochemistry of Addition to Alkenes

• In order to know understand stereochemistry of
  product, you need to know two things
• (1) stereochemistry of alkene (cis or trans Z
  or E)
• (2) stereochemistry of mechanism (syn or anti)

113
Bromine Addition to trans-2-Butene
S
R
Br2
S
R
meso

• anti addition to trans-2-butene gives meso
  diastereomer

114
Bromine Addition to cis-2-Butene
R
S
Br2

S
R
50
50

• anti addition to cis-2-butene gives racemic
  mixture of chiral diastereomer

115
Epoxidation of trans-2-Butene
S
R
RCO3H

R
S
50
50

• syn addition to trans-2-butene gives racemic
  mixture of chiral diastereomer

116
Epoxidation of cis-2-Butene
R
S
RCO3H
S
R
meso

• syn addition to cis-2-butene gives meso
  diastereomer

117
Stereospecific reaction

• Of two stereoisomers of a particular starting
  material, each one gives differentstereoisomeri
  c forms of the product
• Related to mechanism terms such assyn addition
  and anti addition refer tostereospecificity

118
.

• Stereospecific reactions

119
Stereoselective reaction

• A single starting material can give two or
  morestereoisomeric products, but gives one of
  themin greater amounts than any other

H
CH3

H
CH3
32
68
120
Resolution of Enantiomers

• Separation of a racemic mixture into its two
  enantiomeric forms

121
Strategy
enantiomers
122
Strategy
enantiomers
2P()
diastereomers
123
Strategy
enantiomers
C()P()
2P()
C(-)P()
diastereomers
124
Strategy
C()
enantiomers
P()
C()P()
2P()
C(-)P()
P()
diastereomers
C(-)
125
Stereoregular Polymers

• atactic
• isotactic
• syndiotactic

126
Atactic Polypropylene

• random stereochemistry of methyl groups attached
  to main chain (stereorandom)
• properties not very useful for fibers etc.
• formed by free-radical polymerization

127
Isotactic Polypropylene

• stereoregular polymer all methyl groups
  onsame side of main chain
• useful properties
• prepared by coordination polymerization under
  Ziegler-Natta conditions

128
Syndiotactic Polypropylene

• stereoregular polymer methyl groups alternate
  side-to-side on main chain
• useful properties
• prepared by coordination polymerization under
  Ziegler-Natta conditions

129
Chirality CentersOther Than Carbon
130
Silicon
b
b
a
a
d
d
Si
Si
c
c

• Silicon, like carbon, forms four bonds in its
  stable compounds and many chiral silicon
  compounds have been resolved

131
Nitrogen in amines
b
b
very fast
a
a


N
N
c
c

• Pyramidal geometry at nitrogen can produce a
  chiral structure, but enantiomers equilibrate too
  rapidly to be resolved

132
Phosphorus in phosphines
b
b
slow
a
a


P
P
c
c

• Pyramidal geometry at phosphorus can produce a
  chiral structure pyramidal inversion slower
  than for amines and compounds of the type shown
  have been resolved

133
Sulfur in sulfoxides
b
b
slow
a
a


S
S


O_
O_

• Pyramidal geometry at sulfur can produce a
  chiral structure pyramidal inversion is slow
  and compounds of the type shown have been resolved

134
End of Chapter 7