Chapter 7 Stereochemistry

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Chapter 7Stereochemistry
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7.1Molecular Chirality Enantiomers
3
Chirality

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

4
Bromochlorofluoromethane is chiral
Cl

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

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

• To show nonsuperimposability, 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
nonsuperimposable mirror images are called
enantiomers
and

• are enantiomers with respect to each other

9
Isomers
constitutional isomers
stereoisomers
10
Chlorodifluoromethaneis achiral
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Chlorodifluoromethaneis achiral

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

12
7.2The Chirality Center
13
The Chirality Center

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

14
Chirality and chirality centers

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

15
Chirality and chirality centers

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

16
Examples of molecules with 1 chirality center
a chiral alkane
17
Examples of molecules with 1 chirality center
Linalool, a naturally occurring chiral alcohol
18
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

19
Examples of molecules with 1 chirality center
Limonene a chirality center can be part of a
ring

• attached to thechirality center are
• H
• CH2CH2
• CH2CH
• C

20
Examples of molecules with 1 chirality center
Chiral as a result of isotopic substitution
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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).

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7.3Symmetry in Achiral Structures
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Symmetry tests for achiral structures

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

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Plane of symmetry

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

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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.

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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.

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7.4Properties of Chiral MoleculesOptical
Activity
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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.

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Light

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

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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

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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

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Polarization of light
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Rotation of plane-polarized light
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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

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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

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Optical purity

• an optically pure substance consists exclusively
  of a single enantiomer
• enantiomeric excess one enantiomer
  other enantiomer
• optical purity enantiomeric excess

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7.5AbsoluteandRelative Configuration
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Configuration

• Relative configuration compares the arrangement
  of atoms in space of one compound with those of
  another.
• Absolute configuration is the precise
  arrangement of atoms in space.

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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

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Relative configuration
Pd
? 33.2
? 13.5

• No bonds are made or broken at the chirality
  centerin this experiment. Therefore, the two
  have the same
• relative configuration - the arrangement of atoms
  in space
• is analogous. The value and sign of rotation of
  each
• must be determined by experiment

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.

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Absolute configurations

H2, Pd
? 33.2
? 13.5
H2, Pd
? 13.5
? 33.2
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Relative configuration
HBr
? -5.8
? 4.0

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

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7.6The Cahn Ingold PrelogR-S Notational System
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Two requirements for a systemfor specifying
absolute configuration

• 1. need rules for ranking substituents at
  chirality 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.

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The Cahn-Ingold-Prelog Rules(Table 7.1)

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

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Example

• Order of decreasing rank4 gt 3 gt 2 gt 1

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The Cahn-Ingold-Prelog Rules(Table 7.1)

• 1. Rank the substituents at the chirality
  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 counterclockwise, the
  configuration is S.

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Example

• Order of decreasing rank4 ? 3 ? 2

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Enantiomers of 2-butanol
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Very important! Two different compounds with
the same sign of rotation need not have the same
configuration.

• Verify this statement by doing Problem 7.7 on
  page 306. All four compounds have positive
  rotations. What are their configurations
  according to the Cahn-Ingold-Prelog rules?

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Chirality center in a ring
CH2CC gt CH2CH2 gt CH3 gt H
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7.7 Fischer Projections
Purpose of Fischer projections is to show
configuration at chirality center without
necessity of drawing wedges and dashes or using
models.
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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.

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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.

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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.

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7.8Physical Properties of Enantiomers
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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

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

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

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7.9Reactions That Create A Chirality Center
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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.

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Example

• Chiral, but racemic

Achiral
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epoxidation from this direction gives R epoxide
R
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Example
Br2, H2O
CH3CHCH2Br
OH

• Chiral, but racemic

Achiral
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Example
HBr
CH3CHCH2CH3
Br

• Chiral, but racemic

Achiral
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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."

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Example
HBr

• Chiral, but racemic

Chiral, but racemic
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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."

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Example
HO2C
H
H2O
fumarase
CO2H
H
Fumaric acid
(S)-()-Malic acid
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7.10Chiral MoleculeswithTwo Chirality Centers

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

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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
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2,3-Dihydroxybutanoic acid
2
3

• 4 Combinations 4 Stereoisomers

Carbon-2 R R S S Carbon-3 R S R S
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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
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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
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2,3-Dihydroxybutanoic acid
2
3
but not all relationships are enantiomeric

• stereoisomers that are not enantiomers are
  diastereomers

Carbon-2 R R S S Carbon-3 R S R S
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Isomers
constitutional isomers
stereoisomers
enantiomers
diastereomers
80
? -9.5
? 9.5
enantiomers
enantiomers
? -17.8
? 17.8



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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
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Fischer projections

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

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Fischer projections
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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

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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
86
Threo

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

17.8
17.8
87
Two chirality centers in a ring
S
R
S
R
trans-1-Bromo-2-chlorocyclopropane

• nonsuperposable mirror images enantiomers

88
Two chirality centers in a ring
s
S
R
R
cis-1-Bromo-2-chlorocyclopropane

• nonsuperposable mirror images enantiomers

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

• stereoisomers that are notenantiomers
  diastereomers

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7.11Achiral MoleculeswithTwo Chirality Centers

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

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2,3-Butanediol
3
2

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

92
Three stereoisomers of 2,3-butanediol
2R,3R
2S,3S
2R,3S
chiral
chiral
achiral
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Three stereoisomers of 2,3-butanediol
2R,3R
2S,3S
2R,3S
chiral
chiral
achiral
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Three stereoisomers of 2,3-butanediol
these two areenantiomers
2R,3R
2S,3S
chiral
chiral
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Three stereoisomers of 2,3-butanediol
these two areenantiomers
2R,3R
2S,3S
chiral
chiral
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Three stereoisomers of 2,3-butanediol
the third structure is superimposable on
its mirror image
2R,3S
achiral
97
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
98
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
99
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
100
Three stereoisomers of 2,3-butanediol
A line drawnthe center ofthe Fischer
projection of ameso formbisects it intotwo
mirror-image halves.
2R,3S
achiral
101
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.
102
7.12MoleculeswithMultiple Chirality Centers
103
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

104
Example

• 4 chirality centers
• 16 stereoisomers

105
Cholic acid (Figure 7.12)

• 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

106
How many stereoisomers?

• 3-Penten-2-ol

R
E
E
S
H
OH
HO
H
R
Z
Z
S
OH
H
H
HO
107
7.13 Chemical Reactions That Produce
Diastereomers
108
Stereochemistry of Addition to Alkenes

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

109
Bromine Addition to trans-2-ButeneFig. 7.12 (p
323)
S
R
Br2
S
R
meso

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

110
Bromine Addition to cis-2-ButeneFig. 7.13 (p 323)
R
S
Br2

S
R
50
50

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

111
Epoxidation of trans-2-ButeneProblem 7.21
S
R
RCO3H

R
S
50
50

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

112
Epoxidation of cis-2-ButeneProblem 7.21
R
S
RCO3H
S
R
meso

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

113
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

114
Stereospecific reaction
.
115
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
116
7.14 Resolution of Enantiomers

• separation of a racemic mixture into its two
  enantiomeric forms

117
Strategy
enantiomers
118
7.16Chirality CentersOther Than Carbon
119
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

120
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

121
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

122
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