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Stereochemistry
Paderborn, May 2005
Founding Fathers of Stereochemistry
Biot

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Biot: The solutions of
many naturally occurring
compounds rotate the
plane of polarization of
polarized light (18151817)
Pasteur recognized in
1850 that this optical
activity was caused by an
asymmetric arrangement
of atoms in a molecule
van’t Hoff and Le Bel
described in 1874 how the
atoms of a molecule are
actually arranged in space
Pasteur
Van’t Hoff
Subdisciplines of Stereochemistry

Static stereochemistry
• Studies the three-dimensional
arrangement of the atoms of a molecule in
the ground state

Dynamic stereochemistry
• Description of the steric relationships in
molecules as they change from one state
to another, for example during a chemical
reaction
Preview
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Introduction
Conformational analysis
• Cyclohexane
• Bicyclic compounds, steroids
• Heterocyclic compounds

Optical activity and stereoisomerism
• Symmetry and chirality
• Molecular asymmetry
• Prochirality

Chiroptical properties of chiral molecules
• Optical rotatory dispersion
Introduction
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Structure: Includes both constitution and configuration.
Constitution: Describes the kinds and order of the
bonds and atoms or atom groups in a compound.
Configuration: Describes the different spatial
arrangements of atoms or atom groups of a compound
with a given constitution.
• Stereoisomerism
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Enantiomers: Image and mirror image are not identical
Diastereomers: Stereoisomers that are not mirror images
Conformation:
Describes the different spatial
arrangements of atoms or groups in a molecule that
arise due to rotation (torsion) around single bonds.
Examples

Structure and Constitution:
H
CH3
H
H
have the same constitution, but differ
in the spatial arrangement of their
substituents -> Stereoisomers
and
H3C

H
H3C
CH3
Configuration:
Lactic acid
H3C
H
C
has two stereoisomers:
CO2H
OH
H
H3C
CO2H
CO2H
C
C
OH
Muscle lactic acid:
(+) rotation
HO
H
CH3
Fermentation lactic acid:
(-) rotation
Physical and chemical properties are identical,
only optical rotation differs
Examples

Configuration:
• Stereoisomerism
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Enantiomers: Image and mirror image are not identical
Diastereomers: Stereoisomers that are not mirror images
H
HO
OH
OH
CO2H
HO
H
CO2H
H
Mirror plane
OH
CO2H
HO
meso-Tartaric acid
o
o
mp. 174 C
mp. 151 C
Enantiomers
Identical!
Diastereomers
OH
CO2H
Mirror plane
(-)-Tartaric acid
(+)-Tartaric acid
H
H
CO2H
CO2H
CO2H
H
HO
H
H
CO2H
Conformation: Ethane
60
H
H
H
HH
o
H
H
H
HH
H
H
Eclipsed
Staggered
H
H
H
H
H
H
H
H
H
H
H
H
Conformation: Ethane
H
H
H
H
H
H
H
H
HH
HH
HH
HH
HH
H
H
H
H
HH
H
H
H
HH
H
H
H
H
H
H
H
H
H
H
H
HH
Conformational Analysis
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Cyclohexane
Bicyclic systems and steroids
Heterocyclic systems
Optical activity and Stereoisomerism
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Symmetry und chirality
•
•
•
•
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Symmetry axis Cn
Symmetry plane σ
Symmetry centre i
Rotation/reflection axis Sn
Molecular asymmetry
• Chiral axis
• Chiral plane
• Chiral centre
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Prochirality
Symmetry and Chirality
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n–Fold axis of symmetry Cn
Cl
Br
Cl
Cl
F
I

H
Cl
Plane of symmetry σ

H


H
H
H
H
Cl
O
H
H
Symmetry and Chirality

Centre of symmetry i
O2H
C
HO
H
i
H

C
O2H
OH
n-Fold rotation-reflection axis Sn
OH HO 2C
H
CO2H
HO 2C
H
OH
OH
OH HO 2C
H
H
OH
H
CO2H
H
CO2H
OH
Symmetry and Chirality
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Molecules with no reflection symmetry are chiral
A molecule with only a Cn axis is chiral
Molecular Asymmetry
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Chiral axis
Chiral plane
Chiral centre
Chiral Axis
a
b
a
b
C
C
n(H2C)
C
C
C
a
Allene
(CH2)n
C
b
a
b
Alkylidenecycloalkane
Chiral Plane
(CH2)n
1
H2C
a
O
CH2
O
b
c
2
Br
3 R
1.
2.
3.
Lead atom: atom with highest priority directly
linked to the plane
Determine the atom sequence in the plane
Determine chirality, starting from the lead atom
Chiral Centre
CH3
CH3
Br
H
CN
Br
CN
H
Prochirality
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Enantiotopos
Enantiofaces
Diastereotopos
Diastereofaces
Heterotopy
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Homotopic
Heterotopic
• Constitutopic
• Stereoheterotopic
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Enantiotopic
Diastereotopic
Substitution Test
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Identical molecules
• Homotopic (equivalent)
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Isomers
• Heterotopic
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Constitutional isomers
• Constitutopic
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Stereoisomers
• Stereoheterotopic
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Enantiomers
• Enantiotopic
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Diastereomers
• Diastereotopic
Optical Activity and Stereoisomerism
Chiroptical Properties of Chiral
Molecules
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A linearly polarized wave may be described as
the result of a left polarized wave superimposed
on a right polarized wave
Left and right polarized waves are absorbed
differently by an optically active compound
When the two components are recombined after
passing through an optically active medium, the
result is an elliptically polarized wave with
ellipticity θ:
Optical Activity

Optically active compounds are circularly
birefringent – the refractive indices of the
left and right polarized waves differ:
• v = c/n , therefore, if vL ‡ vR , then nL ‡ nR
• There is a phase difference, resulting in
optical rotation:
•  = .d(nL - nR)/ = 180d(nL - nR)/
• The optical rotation is dependent on the
wavelength – Optical rotatory dispersion
Anomalous curve
Chiroptical Properties of Chiral
Molecules
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Optical rotatory dispersion
• Plain curves
• Anomalous curves
Chiroptical Properties of Chiral
Molecules
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Optical rotatory dispersion
• Achiral chromophores
• Chiral chromophores
Achiral Chromophores
Achiral disturbance
NO 2
O
H
CH2
CH3
H NO
CH3
2
O
H
H
CH2
Chiral disturbance
Chiral Chromophores
H
H
H
H
O
+
Chiroptical Properties of Chiral
Molecules
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Optical rotatory dispersion
• Constitution
• Configuration
• Conformation
Plain Curves
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With small amounts of substance, one can
measure at shorter wavelengths
To determine whether a substance is really
optically active and not racemic
Example
O
N
N
NH
O
OH MeO
MeO
CO2H
O
N
H
Both not active at 589 nm
Inactive
Racemic
Active, [M] = -165o at 365 nm
Not racemic
ORD of Steroids: Constitution
Me
O
A
Me
B
H
C
H
Chiroptical Properties of Chiral
Molecules
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Optical rotatory dispersion
• Constitution
• Configuration and conformation
Cis/trans-Isomerism in Steroids:
Configuration
Me
OH
Me
Me
H
O
H
Me
H
O
H
Me
Me
H
O
H
OH
OH
Unsaturated Ketones and Diketones
The Octant Rule for Ketones
5
4
6
O
O
C
1
C
2
3
Octant Rule
Chiroptical Properties of Chiral
Molecules
• Octant rule:
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Configuration
Conformation
• Absolute configuration
Summary
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Introduction
Conformational analysis
• Cyclohexane
• Bicyclic compounds, steroids
• Heterocyclic compounds

Optical activity and stereoisomerism
• Symmetry and chirality
• Molecular asymmetry
• Prochirality

Chiroptical properties of chiral molecules
• Optical rotatory dispersion
Questions/Remarks ?