9. Stereochemistry II
Based on
McMurry’s Organic Chemistry, 6th edition
Stereochemistry: review
isomers
no
Do they have the same structure?
yes
structural
CH3CH2OH
stereoisomers
no
CH3OCH3
configurational
H
H
C C
Cl
Cl
yes
Can be converted eachother by rotation around
single bonds?
conformational
H
Cl
C C
Cl
H
2
Stereochemistry
 Some objects are not the same as their mirror images (technically,
they have no plane of symmetry)
 A right-hand glove is different than a left-hand glove
 The property is commonly called “handedness” (or “chirality”)
 Organic molecules (including many drugs) have handedness that
results from substitution patterns on sp3 hybridized carbon
3
Enantiomers – Mirror Images
 Molecules exist as three-dimensional objects
 Some molecules are the same as their mirror image
 Some molecules are not the same as their mirror image

These are stereoisomers called enantiomers

They are the “same” if the positions of the atoms can
coincide on a one-to-one basis (we test if they are
superimposable, which is imaginary)
 This is illustrated by enantiomers of lactic acid
4
 Enantiomers of lactic acid
5
Examples of Enantiomers
 Molecules that have one carbon with 4 different substituents
have a nonsuperimposable mirror image – enantiomers
 Build molecular models to see this
6
The Reason for Handedness: Chirality
 Molecules that are not superimposable with their mirror images are
chiral (have handedness)
 A plane of symmetry divides an entire molecule into two pieces
that are exact mirror images
 A molecule with a plane of symmetry is the same as its mirror image
and is said to be achiral
 The lack of a plane of symmetry is called “handedness” or chirality
7
Plane of Symmetry
 The plane has the same
thing on both sides for the
flask
 There is no mirror plane for a
hand
 Hands, gloves are prime
examples of chiral object
 They have a “left” and a
“right” version
8
Stereocenters
 A point in a molecule where four different groups (or atoms) are
attached to carbon is called a stereocenter
 There are two nonsuperimposable ways that 4 different groups
(or atoms) can be attached to one carbon atom
 If two groups are the same, then there is only one way
 A chiral molecule usually has at least one stereocenter
9
Stereocenters in Chiral Molecules
 Groups are considered “different” if there is any structural
variation (if the groups could not be superimposed if detached,
they are different)
 In cyclic molecules, we compare by following in each direction
in a ring
10
Review of steroechemistry classification
isomers
structural
stereoisomers
configurational
enantiomers
conformational
diastereoisomers
11
Pasteur’s Discovery of Enantiomers (1849)
 Louis Pasteur discovered that sodium ammonium salts of
tartaric acid crystallize into right handed and left handed forms
 The optical rotations of equal concentrations of these forms
were equal in amount but opposite in sign
 The solutions contain mirror image isomers, called enantiomers
and they crystallized in distinctly different shapes – such an
event is rare
12
Sequence Rules for Specification of Configuration
 A general method applies to the configuration at each
stereocenter (instead of to the whole molecule)
 The configuration is specified by the relative positions of all the
groups with respect to each other at the stereocenter
 The groups are ranked in an established priority sequence and
compared
 The relationship of the groups in priority order in space determines
the label applied to the configuration, according to a rule
13
Sequence Rules (IUPAC)
 Assign each group priority according to the Cahn-Ingold-Prelog scheme
with the lowest priority group pointing away, look at remaining 3 groups in
a plane
 Clockwise is designated R (from Latin word for “right”)
 Counterclockwise is designated S (from Latin word for “left”)
14
Examples of Applying Sequence Rules
 If lowest priority is back,
clockwise is R and
counterclockwise is S
 R = Rectus
 S = Sinister
3
2
4
1
(R)-3-methylhexane
15
Priority rules
 Priority rules of Cahn, Ingold, and Prelog
 Rank atoms that are connected at comparison point
 Higher atomic number gets higher priority
Br > Cl > O > N > C > H
 If atomic numbers are the same, compare at next connection point
at same distance
 Compare until something has higher atomic number

Dealing With Multiple Bonds
 Substituent is drawn with connections shown and no double or
triple bonds
 Added atoms are valued with 0 ligands themselves
16
Examples
17
Examples
18
Examples
O 2 OH
C
3 C
4
H
H3C
1NH2
natural alanine
S
Cl
H
S
4
H3
*
2
Cl
1
3
C C
C
H C CH2
Corresponds to
O
*C
H C * C CH(CH3)2
CH(CH3)2
C
CH
OH
2
CH2OH
1
H
O
S
O
2
C
H
CH2
19
Enantiomers are different
CH3
CH3
N
CH3
OCOCH2CH3
CH3
N
H3C
CH3CH2OCO
HO
(2S,3R)-(+)-propoxyphen
analgesic
(S)-(-)-limonene
lemon smell
(R)-(+)-limonene
orange smell
CH3
(2R,3S)-(-)-propoxyphen
anticough
NH2
COOH
HO
OH
NH2
HOOC
H
OH
H
(S)-(-)-3-(3,4-dihydroxyphenyl)alanine (R)-(+)-3-(3,4-dihydroxyphenyl)alanine
L-DOPA
inactive
anti-Parkinson
N
N
N
CH3
H
H5C2OOC
H3C
H
O
N
COOC2H5
O
N
O
O
N
N
N
O
(R)-(+)-etomidate
anaesthetic
(S)-(-)-etomidate
inactive
O
H
(S)-(-)-thalidomide
teratogen
H
O
O
20
(R)-(+)-thalidomide
sedative
Optical Activity
 Light restricted to pass through a plane is plane-polarized
 Plane-polarized light that passes through solutions of achiral
compounds remains in that plane
 Solutions of chiral compounds rotate plane-polarized light
and the molecules are said to be optically active
 Phenomenon discovered by Biot in the early 19th century
 Measured with polarimeter
 Rotation, in degrees, is []


Clockwise rotation is called dextrorotatory
Anti-clockwise is levorotatory
21
Measurement of Optical Rotation
 A polarimeter measures the rotation of plane-polarized that has
passed through a solution
 The source passes through a polarizer and then is detected at a
second polarizer (analyzer)
 The angle between the entrance and exit planes is the optical
rotation.
22
Specific Rotation
 The degree of rotation observed depends on the number of
molecules encountered (so on sample concentration and
sample path length).
 To have a basis for comparison, define specific rotation, []D
for an optically active compound (standard conditions)
 []D = observed rotation/(pathlength x concentration)
= /(l x C) = degrees/(dm x g/mL)
 Specific rotation is that observed for 1 g/mL in solution in cell
with a 10 cm path using light from sodium metal vapor (589
nanometers)
23
Specific Rotation and Molecules
 Characteristic property of a compound that is optically active –
the compound must be chiral
 The specific rotation of the enantiomers is equal in magnitude
but opposite in sign
24
Diastereomers
 Molecules with more than
one stereocenter have mirror
image stereoisomers that
are enantiomers
 In addition they can have
stereoisomeric forms that are
not mirror images, called
diastereomers
2R,3R
2R,3S
2S,3S
2S,3R
25
Diastereomers
CH3CH2CHCH
Cl OH
diastereoisomers
R
C
H
Cl
enantiomers
H
OH
H
HO
C
R
R
C
H3CH2C
H
HO
H
S
CH2CH3
S
H
Cl
S
C
C
C
Cl
C
C
CH2CH3
H
OH
S
H3CH2C
R
Cl
H
26
Meso Compounds
 Tartaric acid has two stereocenters and two diastereomeric forms
 One form is chiral and the other is achiral, but both have two
stereocenters
 An achiral compound with stereocenters is called a meso
compound – it has a plane of symmetry
 The two structures on the right in the figure are identical so the
compound (2R, 3S) is achiral
27
Meso Compounds
28
Molecules with More Than Two Stereocenters
 Molecules can have very many stereocenters
 Each point has two possible permanent arrangements (R or S),
generating two possible stereoisomers
 So the maximum number of possible stereoisomers with n
stereocenters is 2n (2n -1 pairs of enantiomers)
29
Physical Properties of Stereoisomers
 Enantiomeric molecules differ in the direction in which
they rotate plane polarized light but their other common
physical properties are the same
 Diastereomers have a complete set of different physical
properties
30
Racemic Mixtures and Their Resolution
 A 50:50 mixture of two chiral compounds that are mirror images
does not rotate light – called a racemic mixture (named for
“racemic acid” that was the double salt of (+) and (-) tartaric acid)
 The pure compounds need to be separated or resolved from the
mixture (called a racemate)
 To separate components of a racemate (reversibly) we make a
derivative of each with a chiral substance that is free of its
enantiomer (resolving agent)
 This gives diastereomers that are separated by their differing
solubility
 The resolving agent is then removed
31
Chirality in Nature
 Stereoisomers are readily distinguished by chiral receptors in
nature
 Properties of drugs depend on stereochemistry
 Think of biological recognition as equivalent to 3-point interaction
32
Chirality at Atoms Other Than Carbon
 Trivalent nitrogen is tetrahedral
 Does not form a stereocenter since it rapidly flips
 Also applies to phosphorus but it flips more slowly
33
Exercises
Give the absolute configuration of the chirality centers in the
following molecules
3
R CH3
C
H
2
Cl
CH3
R
H 2 C
H 4
HO C
Cl
R
1
4
3
1
4
2
3
1
1
Br
3
R
CH3CH
CH3
2
CH3 CH2CH3
3
4
CH3 S
4 H
2 Cl 1
2
1 Cl
CH3
H R
4
3
34
Exercises
Which relationships do correlate the following couples of compounds?
OH
H
OH
CH3
H
CH3
H3C
CH3
H
H
H
H
H
CH3
identical
CH3
C
H
Cl
H
CH3
H
H
conformers
CH3
C
Cl
H
CH3
H
C
H
HO C
Cl
CH3
HO C
H
H C
Cl
enantiomers
diastereoisomers
35
End of chapter 9
36