Stereochemistry at
Tetrahedral
Centers
McMurry,
‘Fundamentals of
Organic
Chemistry’, 7 t h Ed.
Chapter 6
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”
Organic molecules
(including many drugs) have
handedness that results
from substitution patterns
on sp3 hybridized carbon
2
Why this Chapter?
Handedness is important in organic
and biochemistry
Molecular handedness makes possible
specific interactions between enzymes
and substrates
3
6.1 Enantiomers and the Tetrahedral
Carbon
Molecules that have one carbon with 4
different substituents have a
nonsuperimposable mirror image –
enantiomers
Build molecular models to see this
Figure 6.1 Tetrahedral carbon atoms and their mirror images.
4
Enantiomers are molecules that are not the same
as their mirror image
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
Figure 6.2 Attempts at superimaging the mirror-image forms of lactic
5
6.2 The Reason for Handedness
in Molecules: Chirality
Molecules that are not superimposable with
their mirror images are chiral (have
handedness)
A point in a molecule where four different
groups (or atoms) are attached to carbon is
called a chirality center (or stereocenter)
A chiral molecule usually has at least one
chirality center
(*: chirality
center ) 6
7
Chirality
A plane of symmetry divides an entire molecule
into two pieces that are exact mirror images
If an object has a plane of symmetry it is
necessarily the same as its mirror image
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”, chirality
Hands, gloves are prime examples of
chiral object
8
Plane of Symmetry
The plane has the same thing on both sides for
the flask (figure 6.3 (a))
There is no mirror plane for a hand (figure 6.3 (b))
Figure 6.3 The meaning of symmetry plane.
9
Plane of Symmetry in Molecules
Figure 6.4 The achiral propanoic acid molecule versus the chiral lactic acid
molecule.
10
6.3 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 Jean-Baptiste Biot
in
the early 19 th century
11
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
The angle between the entrance and exit planes
is the optical rotation
Figure 6.5 Schematic representation of a polarimeter. 12
Optical Activity
Rotation, in degrees, is []
Clockwise rotation: dextrorotatory
Anti-clockwise rotation: levorotatory
To have a basis for comparison, define specific
rotation, []D for an optically active compound
Specific rotation is that observed for 1 g/cm 3 (=1
g/mL) in solution in cell with a 10 cm (=1 dm) path
using
light of 589 nm wavelength
D
Units = [(deg•cm 2 )/g]
13
Specific Rotation of Some Molecules
Characteristic property of a compound that is
optically active – the compound must be
chiral
The specific rotation of the enantiomer is equal in
magnitude but opposite in sign
(+)-lactic acid [] D = +3.82
(–)-lactic acid [] D = –3.82
14
6.4 Pasteur’s Discovery of
Enantiomers
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 have opposite optical rotations
The solutions contain mirror image isomers,
called enantiomers and they crystallized in
distinctly different shapes – such an event is rare
Figure 6.6 Drawing of
sidium ammonium
tartrate crystals taken
from Pasteur’s
original sketches.
15
6.5 Sequence Rules for
Specifying Configuration
A general method applies to the configuration
at each chirality center (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 chirality center
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
16
Sequence Rules (IUPAC)
Rule 1:
Look at the four atoms directly attached to the
chirality center, and rank them according to
atomic number (Cahn-Ingold-Prelog scheme)
Rule 2:
If decision can’t be reached by ranking the first
atoms in the substituents, look at the second,
third, or fourth atoms until difference is found
Rule 3:
Multiple-bonded atoms are equivalent to the same
number of single-bonded atoms
17
Assign R or S
With the lowest priority group pointing away, look
at remaining 3 groups in a plane
Clockwise is designated R (from Latin for “right”)
Counterclockwise is designated S (from Latin
word for “left”)
Figure 6.7 Assignment of configuration to a chirality
18
Figure 6.8 Assigning configuration to (a) (R)-(-)-lactic acid and (b) (S)-(+)-lactic
19
Figure 6.9 Assigning configuration to (a) (-)-glyceraldehyde and (b) (+)-
20
6.6
Diastereomers
A molecule with n chirality center -> maximum
2n stereoisomers
Molecules with more than one chirality center
have mirror image stereoisomers that are
enantiomers
In addition they can have stereoisomeric forms
that are not mirror images, called diastereomers
21
Threonine: 2 chirality center -> 4 possible
stereoisomers
Figure 6.10 The four stereoisomers of 2-amino-3-hydroxybutanoic acid.
22
23
6.7 Meso
Compounds
Tartaric acid has two chirality centers and
two diastereomeric forms
One form is chiral and the other is achiral, but
both have two chirality centers
24
An achiral compound with chirality centers is called
a meso compound – it has a plane of symmetry
The two structures (2R, 3S) and (2S, 3R) are
identical
so the compound is achiral
Figure 6.11 A symmetry plane
cutting through the C2-C3
bond of meso-tartaric acid
makes the molecule achiral
even though it contains two
chirality centers.
25
Tartaric acid exists in three stereoisomeric
forms: two enantiomers and one meso form
26
6.8 Racemic Mixtures and the
Resolution of Enantiomers
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
27
Figure 6.12 Reaction of racemic lactic acid with achiral methylamine leads to
racemic mixture of enantiomeric ammonium
a
salts. 28
Figure 6.13 Reaction of racemic lactic acid with (R)-1-phenylethylamine yields
a mixture of diastereomeric ammonium salts, which have different properties
and can be separated.
29
6.9 A Brief Review of
Isomerism
The flowchart summarizes the types of isomers
we have seen
Figure 6.14 A summary of the different kinds of
isomers.
30
Constitutional Isomers
Different order of connections gives different
carbon backbone and/or different functional groups
31
Stereoisomers
Same connections, different spatial arrangement of atoms
Enantiomers (nonsuperimposable mirror images)
Diastereomers (all other stereoisomers)
Includes cis, trans and configurational
32
Determining the relationship between two
nonidentical molecules
33
6.10 Chirality in Nature and
Chiral Environments
Although the different enantiomers of a chiral
molecule have the same physical properties, they
almost always have different biological
properties
34
Stereoisomers are readily distinguished by
chiral receptors in nature
Properties of drugs depend on stereochemistry
35
Think of biological recognition as equivalent to
3- point interaction
Figure 6.15 Imaging that a left hand interacts with a chiral object, much as
a biological receptor interacts with a chiral molecule.
36
Figure 6.16 What the achiral substrate molecule ethanol is held in a chiral
environment on binding to a biological receptor, the two seemingly
identical hydrogens are distinguishable. 37
The shape of molecules and the sense of smell
38
Chiral Drugs
39
