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Chapter 4: Stereochemistry
Introduction To Stereochemistry
Consider two of the compounds we produced while finding all the isomers of C7H16:
2-methylhexame is superimposable with its mirror image
CH3
CH3
2-methylhexane 3-methylhexane
Me
C
Me
2-methylhexane
Me
Me
H
Bu
Me
Me
H
Bu
mirror
rotateMe
Me
H
Bu
H
Introduction To Stereochemistry
CH3
CH3
2-methylhexane 3-methylhexane
Et
Me
H
Pr
Et
Me
H
Pr
mirror
rotate
C
Me
3-methylhexane
H
Et
Me
Pr
H
Consider two of the compounds we produced while finding all the isomers of C7H16:
2-methylhexame is superimposable with its mirror image
Introduction To Stereochemistry
Compounds that are not superimposable with their mirror image are called chiral (in Greek, chiral means"handed") 3-methylhexane is a chiral molecule.
Compounds that are superimposable with their mirror image are called achiral. 2-methylhexane is anachiral molecule.
An atom (usually carbon) with 4 different substituents is called a stereogenic center or stereocenter.
CH3
CH3
2-methylhexane 3-methylhexane
Consider two of the compounds we produced while finding all the isomers of C7H16:
Enantiomers
Two compounds that are non-superimposable mirror images (the two "hands") are called enantiomers.
CH3
Et
Me
H
Pr
Et
Me
H
Pr
mirror
3-methylhexane
Et
Me
H
Pr
Et
Me
H
Pr
Me H H Me
enantiomers
Introduction To StereochemistryStructural (constitutional) Isomers - Compounds of the same molecular formula with different connectivity(structure, constitution)
Conformational Isomers - Compounds of the same structure that differ in rotation around one or moresingle bonds
Configurational Isomers or Stereoisomers - Compounds of the same structure that differ in one or moreaspects of stereochemistry (how groups are oriented in space - enantiomers or diastereomers)
2-methylpentane 3-methylpentane
Me
HH
HH
Me
Me
HH
MeH
H
Me H H Me
3-methylhexane 3-methylhexane
We need a a way to describe the stereochemistry!
The CIP System Revisited
Me H
H Me
12
3 4
12
34
1. Rank each substituent attached to the stereocenter according to the CIP priority system (1 = highest, 4 = lowest)
2. "View" the compound with the lowest priority substituent pointing away from you
Et Pr
Me
H
12
3
4
Pr Et
Me
H
1 2
3
4Me H
12
3 4
3. Draw a circular arrow from connecting substituents 1–3 from highest to lowest priority. If the arrow moves clockwise, the sterocenter is labeled (R) [this stands for rectus]. If the arrow moves counterclockwise, then the stereocenter is labeled (S) [this stands for sinister].
Et Pr
Me
H
12
3
4Me H H Me
Pr Et
Me
H
1 2
3
4
H Me
12
34
counterclockwise clockwise(S)-3-methylhexane (R)-3-methylhexane
The CIP System Revisited
H3C CH3
Br H
H3C
CH3
F H
H CH3
O
HO CH3
H
H3C
CH3
CH3
The CIP System Revisited
H3C CH3
Br H
H3C
CH3
F H
H CH3
O
HO CH3
H
H3C
CH3
(R)-2-fluorobutane
(S)-4-bromo-2-methyl-1-pentene
(S)-3-tert-butylcyclohexene
(R)-2-hydroxy-2-methyl-butanal
H3C
CH3
F H
1
23
4
1
2
3
4
1
23
4
CH3
1
2 3
4
H
CH3
H3C
1
2 3
4
H3C
Properties of Chiral Molecules
Chiral objects can only be "recognized" as chiral by another chiral object
O
H
O
H
Carvone
Which is (S) and which is (R)? [Your nose can tell!]
O
H
O
H
Carvone
1
2 3
4
1
23
4
(S)(R)
Properties of Chiral Molecules
Chiral objects can only be "recognized" as chiral by another chiral object
O
H
O
H
Carvone
Which is (S) and which is (R)? [Your nose can tell!]
O
H
O
H
Carvone
1
2 3
4
1
23
4
(S)(R)
Properties of Chiral Molecules
Chiral objects can only be "recognized" as chiral by another chiral object
O
H
O
H
(R)-carvone [odor of spearmint] (S)-carvone [odor of caraway seed]
Multiple Stereocenters
Me H H Me
(S)-3-methylhexane (R)-3-methylhexane
Me H
Me
Cl
Cl H
Me H
Cl H
Me H
Cl H
Me H
Cl H
3(S), 4(R)-3-chloro-4-methylhexane3(S), 4(S)-3-chloro-4-methylhexane 3(R), 4(R)-3-chloro-4-methylhexane3(R), 4(S)-3-chloro-4-methylhexane
1 stereocenter: 2 stereoisomers
2 stereocenter: 4 stereoisomers
Multiple Stereocenters
Stereoisomers that are not enantiomers (non-superimposable mirror images) are called diastereomers
Me H
Cl H
Me H
Cl H
Me H
Cl H
Me H
Cl H
3(S), 4(R)-3-chloro-4-methylhexane
3(S), 4(S)-3-chloro-4-methylhexane 3(R), 4(R)-3-chloro-4-methylhexane
3(R), 4(S)-3-chloro-4-methylhexane
What about these relationships?
enantiomers
enantiomers
Multiple Stereocenters
8 stereoisomers
3 stereocenters
(R), (R), (R)
(S), (R), (R)
(R), (S), (R)
(R), (R), (S)
(S), (S), (S)
(R), (S), (S)
(S), (R), (S)
(S), (S), (R)
For any compound, the maximum number of stereoisomers is 2n where n is the number of stereocenters.
!
!
!
Br
ClCH3
Multiple Stereocenters
Me
Me
How many stereoisomers for 3,4-dimethylhexane?
Me
H
Me
HH
Me
H
Me
H
Me
Me
H
Me
H
H
Me
enantiomersThe same compound!
(superimposable)
Me H
MeH
H Me
HMe
Me H
HMe
(3S,4S)-3,4-dimethylhexane
H Me
MeH
(3R,4R)-3,4-dimethylhexane??-3,4-dimethylhexane??-3,4-dimethylhexane
Meso Compounds
Me
Me
3,4-dimethylhexane has 3 stereoisomers!
Me
H
Me
HH
Me
H
Me
H
Me
Me
H
Me
H
H
Me
Enantiomers (chiral)A Meso Compound (achiral)
Me H
MeH
H Me
HMe
Me H
HMe
(3S,4S)-3,4-dimethylhexane
H Me
MeH
(3R,4R)-3,4-dimethylhexanemeso-3,4-dimethylhexanemeso-3,4-dimethylhexane
Meso Compounds
The best way to identify a meso compound is to prove that it is superimposable with its mirrorimage. However, a quick test is to see if it contains a plane of symmetry:
Compounds containing a planeof symmetry are achiral!
No plane of symmetry
(3S,4S)-3,4-dimethylhexane (3R,4R)-3,4-dimethylhexanemeso-3,4-dimethylhexane
Me
H
Me
H
plane of symmetry
H
Me
Me
H
Me
H
H
Me
The Isomers of C3H4Cl2, Revisited
CH3
Cl
CH2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3
Cl
Cl
Cl Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
The Isomers of C3H4Cl2, Revisited
CH3
Cl
CH2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3
Cl
Cl
Cl Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Racemic Mixtures
A 50:50 mixture of 2 enantiomers is called a racemic mixture or a racemate.
H3C
(E)-2-butene
HBr
2-bromobutane
achiral chiral
But do we get (R) or (S)?
We get both!
CH3H3C
50% (S)-2-bromobutane (R)-2-bromobutane
H Br
CH3H3C
Br H
50%
addition reactionCH3
H
H
H3C
CH3
H
H
H
Br
Racemic Mixtures In Medicine
CH3
CH3
CH3
O
HO
CH3
CH3
CH3
O
HO
(R)-ibuprofen(inactive)
(S)-ibuprofen(active)
N
NH
O
O
O
O
H
N
NH
O
O
O
O
H
(S)-Thalidomide(teratogenic)
(R)-Thalidomide(analgesic)
Prescribed worldwide from 1957-1961 for morning sickness and as a sleep aid
Optical Rotation and Polarimetry
Chiral molecules will rotate polarized light:
monochromatic light source
randomly oriented light
optical polarizer - only allows "vertical" light to pass through
optical polarizer - only allows "horizontal" light to pass through
No light emitted
monochromatic light source
randomly oriented light
optical polarizer - only allows "vertical" light to pass through optical polarizer - only allows "horizontal" light to pass through
chiral materialdetector
monochromatic light source
randomly oriented light
optical polarizer - only allows "vertical" light to pass through optical polarizer - only allows "horizontal" light to pass through
chiral materialdetector
monochromatic light source
randomly oriented light
optical polarizer - only allows "vertical" light to pass through
optical polarizer
chiral material
detector
The maximum signal will be optained if the second polarizer is rotated to match the light rotation:
maximum signal
Optical Rotation and Polarimetry
monochromatic light source
randomly oriented light
optical polarizer - only allows "vertical" light to pass through
optical polarizer
chiral material
detector
maximum signal
The amount (in degrees) that a chiral material will rotate light is called the optical rotation. Different chiralmolecules will have optical rotations that vary in direction and size of the optical rotation. Enantiomers willalways have equal optical rotations but in opposite directions.
The optical purity of a substance can be measured by comparing the optical rotation of the sample to theknown optical rotation of a single entantiomer of that compound. Optical purity is usually reported in percententantiomeric excess (%ee).
Enantiomeric excess is the % of the sample that is non-racemic. For example, 80% ee means that there is90% of one enantiomer and 10% of the other.
%ee =single enantiomer rotation
sample rotation
X 100
Optical Rotation and Polarimetry
Vocabulary
•(R) or (S): identifies the configuration of a stereocenter using the CIP priority system
•d- or (+): indicates that a (chiral) compound rotates light in a clockwise direction (thishas no correlation with S or R)
•l or (-): indicates that a (chiral) compound rotates light in a counterclockwise direction(this has no correlation with S or R)
•dl or (+/-) or rac-: indicates a racemate
Resolution of Enantiomers
(R)-compound X
(S)-compound X
react or somehow associate with:
(R)-compound Y
(R)-compound X (R)-compound Y(R)-compound Y(S)-compound X
Separate by some technique (chromatography, crystallization, distillation, etc.)
(R)-compound X (R)-compound Y
(R)-compound Y(S)-compound X
somehow remove compound Y
(R)-compound X(S)-compound X
racemic mixture of enantiomers
Single enantiomer
mixture of 2 diastereomers
single diastereomer
single diastereomer
single enantiomer
single enantiomer
Reaction Using Diastereomers to Separate Enantiomers
O
OH
Cl
Me
O
OH
Cl
Me
this hydrogen is acidic
(S)-2-chloroproprionic acid
(R)-2-chloroproprionic acid
H2N
Me(R)-!-methylbenzylamine
this hydrogen is acidic
H3N
Me
O
O
Cl
Me
O
O
Cl
Me
H3N
Me
this nitrogen lone pair is basic
(R)-!-methylbenzylamine
The R,S-diastereomer of the salt
The R,R-diastereomer of the salt
separate
O
OH
Cl
Me
H2N
Me
this nitrogen lone pair is basic
O
O
Cl
Me
H3N
Me
acidify
(R)-2-chloroproprionic acid
H3N
MeO
O
Cl
Me
acidifyO
OH
Cl
Me
(S)-2-chloroproprionic acid
Resolution of Enantiomers
Chiral Compounds Without Stereogenic Centers
H
H H
H
mirror plane
NO2
Me
O2N
Me
mirror plane
O2N
Me
NO2
Me
mirror plane
There is hindered rotation around this bond!
Chirality Without Stereocenters
Chirality Without Stereocenters
C
Me
Me H
H
Why is 1,3-dimethylallane (1,3-dimethyl-2,3-pentadiene) chiral?
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