Post on 22-Apr-2018
Stereochemistry at
Tetrahedral Centers
McMurry, ‘Fundamentals of
Organic Chemistry’, 7th Ed.
Chapter 6
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”
Organic molecules
(including many drugs) have
handedness that results
from substitution patterns on
sp3 hybridized carbon
3
Why this Chapter?
Handedness is important in organic and biochemistry
Molecular handedness makes possible specific interactions between enzymes and substrates
4
Molecules that have one carbon with 4 different
substituents have a nonsuperimposable mirror
image – enantiomers
Build molecular models to see this
6.1 Enantiomers and the Tetrahedral Carbon
Figure 6.1 Tetrahedral carbon atoms and their mirror images.
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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 acid.
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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 )
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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
They have a “left” and a “right” version
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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.
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Plane of Symmetry in Molecules
Figure 6.4 The achiral propanoic acid molecule versus the chiral lactic acid molecule.
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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 19th century
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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.
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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/cm3 (=1 g/mL)
in solution in cell with a 10 cm (=1 dm) path using
light of 589 nm wavelength
Units = [(deg•cm2)/g]
D
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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
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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.
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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
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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
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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”)
Assign R or S
Figure 6.7 Assignment of configuration to a chirality center.
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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
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Threonine: 2 chirality center -> 4 possible stereoisomers
Figure 6.10 The four stereoisomers of 2-amino-3-hydroxybutanoic acid.
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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
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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.
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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 by
their differing solubility
The resolving agent is then removed
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Figure 6.12 Reaction of racemic lactic acid with achiral methylamine leads to a racemic mixture of enantiomeric ammonium salts.
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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.
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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.
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Constitutional Isomers
Different order of connections gives different
carbon backbone and/or different functional groups
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Stereoisomers
Same connections, different spatial arrangement of atoms
Enantiomers (nonsuperimposable mirror images)
Diastereomers (all other stereoisomers)
Includes cis, trans and configurational
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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
35
Stereoisomers are readily distinguished by chiral
receptors in nature
Properties of drugs depend on stereochemistry
36
Figure 6.15 Imaging that a left hand interacts with a chiral object, much as a biological receptor interacts with a chiral molecule.
Think of biological recognition as equivalent to 3-
point interaction
37
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.