Chirality
Chirality
A molecule is chiral if its two mirror-image forms are not
superimposable in three dimensions.
The word chiral is derived from the Greek word cheir,
meaning “hand”.
Chirality most often occurs in molecules that contain a
carbon that is attached to four different groups.
Enantiomers
Stereoisomers that are related as an object and its
nonsuperimposable mirror image are classified as
enantiomers.
Rotating Molecules in Space
To check whether the representations are superposable
first rotate the molecule around so that the H is in the
same direction.
Rotating molecules in Space
After rotation of B check if it is superposable with A. The H
and the F are superposable but the Br and Cl are not. So,
non-superposable mirror images that are enantiomers.
Chirality Center
Molecules of the general type
CWXYZ are chiral when w, x,
y, and z are different.
2-Butanol is chiral: four
different groups on C-2.
2-Propanol is achiral: two of
the groups on C-2 are the
same.
Common Chiral Molecules
Linalool, a pleasant smelling oil from oranges.
Limonene, a constituent
of lemon oil. C-4 is the
chirality center.
Chirality with Isotopes
Achiral alkanes can be transformed
into chiral molecules by replacing H
with deuterium (D) or tritium (T) as
shown in this molecule:
Isotopic labelling can be used to learn information about
the mechanism of reactions. For example:
Symmetry in Achiral Compounds
A molecule that has either a plane of symmetry or, a
center of symmetry will be superposable on its mirror
image and therefore achiral.
Plane of Symmetry
A plane of symmetry bisects a molecule so that one
half of the molecule is the mirror image of the other half.
This achiral molecule, chlorodifluoromethane, has the
plane of symmetry shown.
Center of Symmetry
A point is a center of symmetry if any line drawn from
it to some element of the structure will, when extended
an equal distance in the opposite direction, encounter
an identical element.
Optical Activity
A sample is “optically active” if it rotates the plane of
polarized light.
To be optically active, the sample must contain a chiral
substance and one enantiomer must be present in excess
of the other.
Optical Activity
The direction and magnitude of rotation are cited as α,
the observed rotation.
Mixtures of enantiomers are characterized by the
% enantiomeric excess (ee).
ee = (% major enantiomer) – (% minor enantiomer)
If ee = 100% the sample is enantiopure.
A 1:1 mixtures of enantiomers are called racemic
mixtures. Racemic mixtures are optically inactive.
All achiral substances are optically inactive.
Specific Rotation
Specific rotation [a] is the rotation adjusted for concentration
and the length of the sample cell.
[a] can be used to determine the sample purity.
Enantiomers have [a] of equal magnitude but opposite
sign.
Absolute Configuration
The exact three-dimensional spatial arrangement of
substituents at a chirality center is its absolute
configuration.
Cannot decide which is (+)-2-butanol, or (-)-2-butanol!
Relative Configuration
Compounds have the same relative configuration if the
configuration of the chirality center is the same.
In these reactions the reactant and product have the
same relative configuration because the reactions do
not affect the chirality center.
From Relative Configuration to
Absolute Configuration
Absolute configuration of a salt of (+) tartaric acid was
determined in 1951 by X-ray crystallography. The
absolute configurations of all compounds related to (+)tartaric acid were then known.
In this way the absolute configuration of the enantiomers
of 2-butanol are known.
The Cahn-Ingold-Prelog Rules
1. Rank the substituents at the chirality center
according to rules used in E-Z notation.
highest = -OH > CH2CH3 > CH3 > H = lowest
2. Orient the molecule so that lowest-ranked substituent
points away from you and ignore the lowest-ranked
substituent.
becomes
The Cahn-Ingold-Prelog Rules
3. If the order of decreasing precedence traces a clockwise
path, the absolute configuration is R. If the path is
counterclockwise, the configuration is S.
becomes
So the name is (S)-2-Butanol.
Names of Enantiomers
The pair of enantiomers differ only in the arrangement of
atoms in space so the name only differs in the R/S
assignment.
Chirality Center in a Ring
Remember a C=C double bond is treated like two bonds
to a C.
(+)-4-methylcyclohexene
and the configuration is R
Fischer Projections
For a Fischer projection the molecule is oriented so that the
vertical bonds at the chirality center are directed away from
you and the horizontal bonds point toward you.
The chirality center is at the center of a cross and not
specified.
Fischer Projections
The molecule is oriented so that the lowest numbered
carbon is at the top of the chain.
Properties of Enantiomers
Some enantiomers have different odors. Each enantiomer
reacts with the receptors in the nose differently. This is
chiral recognition which is common in nature where
receptors interact with only one enantiomer.
Chiral Drugs
Many drugs have a chirality center, two examples are
ibuprofen and thalidomide. Often only one enantiomer is
active.
(S)-Ibuprofen has pain-relieving properties while the (R)enantiomer does not.
(R)-Thalidomide was used for its anti-nausea properties.
The (S)-enantiomer caused birth defects.
Chirality Axis
A chirality axis is an axis about which a set of atoms or
groups is arranged so that the spatial arrangement is not
superposable on its mirror image.
Substituted biaryls like biphenyl may have chirality axes and
exist as two non-superposable enantiomers.
Chirality Axis
Unsubstituted biphenyl (A, B, X, Y = H) is nonplanar but can
rotate about the C-C single bond to interchange between
conformations rapidly. With substituents A, B, X, Y the
conformations are locked and cannot interchange.
Chirality Axis
The compound below was demonstrated to exist as two
enantiomers with a chirality axis in 1922!
These isomers are known as atropisomers, from the Greek
“a” meaning not and “tropos” meaning turn.
Chirality Axis
Many compounds with chiral axes are incorporated into
metal catalysts. These catalysts mediate reactions that are
enantiospecific and yield predominantly one enantiomer as
product. Binap is one example used in chiral drug synthesis.
Reactions that Create Chiral Centers
Many of the reactions we have examined so far often
form chiral centers.
The central carbon of the epoxide is a chirality center
with four different groups attached.
Reactions that Create Chiral Centers
The alkene is planar so the peroxyacid attacks the alkene
from the top or the bottom.
Reactions that Create Chiral Centers
Addition of HBr to an alkene can generate a chirality
center.
Chlorination of alkanes can generate a chirality center.
Both reactions form a 1:1 mixture of enantiomers which
is a racemic mixture.
Reactions that Create Chiral Centers
Optically inactive starting materials can give optically
active products only if they are treated with an optically
active reagent or if the reaction is catalyzed by an
optically active substance.
In nature the chiral catalyst is an enzyme.
Molecules with two Chirality Centers
Consider 2,3-dihydroxybutanoic acid.
Carbons 2 and 3 are chirality centers. Each stereocenter
could be R or S so there are four possible stereoisomers:
(2R, 3R); (2S, 3S); (2R, 3S); (2S, 3R).
Stereoisomers of 1,2-Dihydroxybutanoic acid
Stereoisomers I and II are enantiomers of each other;
Stereoisomers III and IV are enantiomers of each other;
Stereoisomers of 1,2-Dihydroxybutanoic acid
Stereoisomers I and III are diastereomers of each other.
Diastereomers are
stereoisomers that are
not enantiomers.
Pairs of diastereomers:
I and III; I and IV;
II and III; II and IV.
Stereoisomers of 1,2-Dihydroxybutanoic acid
Enantiomers:
Are mirror images of each other.
With two stereocenters in a molecule the enantiomer has
the configuration changed at both stereocenters.
Enantiomers have equal and opposite specific rotations.
Diastereomers:
Are stereoisomers that are not mirror images.
With two stereocenters in a molecule a diastereomer has
the configuration changed at only one stereocenter.
Diastereomers will have different magnitude and direction
specific rotations.
Fischer Projections of 1,2-Dihydroxybutanoic Acid
Setting up the Fischer Projection:
Draw the structure so that the lowest numbered carbon is
at the top.
Arrange horizontal bonds to be facing towards you.
Then flatten the molecule and draw it out.
Fischer Projections of 1,2-Dihydroxybutanoic Acid
Fischer Projection of compounds with multiple stereocenters
simplifies identification of enantiomers and diastereomers.
Erythreo isomers have like substituents on the same side.
Threo isomers have like substituents on opposite sides.
Physical Properties of Diastereomers
Physical properties of enantiomers are identical except for
the rotation of plane polarized light.
Diastereomers may differ in any physical property, for
example:
Stereoisomers of 1-bromo-2-chlorocyclopropane
Two stereocenters in a ring may also give rise to four
stereoisomers which can be grouped as two pairs of
enantiomers.
Symmetric Molecules with two Chirality Centers
2,3-Butanediol has two chirality centers that are
equivalently substituted.
There are only three stereoisomers not four. Why?
Stereoisomers of 2,3-Butanediol
These are the three stereoisomers.
Compound (c) has a plane of symmetry and is superposable
on its mirror image. This is a molecule with chirality centers
that is achiral (not chiral) and is named a meso form. It is
superposable on its mirror image so there are only three
stereoisomers.
Stereoisomers of 2,3-Butanediol
These stereoisomers can be shown as Fischer projections.
The dashed line represents the plane of symmetry.
Stereoisomers of 1,2-dibromocyclopropane
This molecule has three stereoisomers. The cis compound
has a plane of symmetry and is a meso compound.
Molecules with Multiple Chirality Centers
A molecule with n stereocenters can have a maximum
of 2n stereoisomers.
This carbohydrate has 4 stereocenters and no planes
of symmetry so there are 24 = 16 stereoisomers.
Molecules with Multiple Chirality Centers
Steroids also contain multiple stereocenters.
Cholic acid shown here has 11 stereocenters and
potentionally 211 or 2048 stereoisomers. Only one has
been isolated from natural sources.
Alkenes and Chirality Centers
Molecules that include both an alkene and a chirality center
may exist as 4 stereoisomers (R,E), (R,Z), (S,E) and (S,Z).
For example 3-penten-2-ol:
-enantiomers-
-enantiomers-
Reactions that Produce Diastereomers
Reaction of 2-butene with bromine yields 2,3-dibromobutane
which has two identically substituted chirality centers.
The product can therefore exist as a pair of enantiomers and
a meso compound.
The actual product formed depends on the stereochemistry
of the alkene and the anti addition of bromine.
Effect of Alkene Stereochemistry
Anti addition of bromine to the (E) stereoisomer yields the
meso product.
meso-2,3-dibromobutane
meso-2,3-dibromobutane
A single achiral product is formed!
Effect of Alkene Stereochemistry
Anti addition of bromine to the (Z) stereoisomer yields a
(1:1) racemic mixture of enatiomers.
(2R,3R)-2,3-dibromobutane
(2S,3S)-2,3-dibromobutane
A 1:1 (racemic) mixture of enantiomers is formed.
Generating a Second Chirality Center
Hydrogenation of the alkene below yields two stereoisomers.
The major product corresponds to hydrogenation from the
least hindered side of the alkene.
The reaction is stereoselective – one stereoisomer is
formed as the major product.
Resolution with Tartaric Acid
The first resolution was carried out by Louis Pasteur in 1848
using tartaric acid.
Pasteur separated a salt of a rare racemic mixture of tartaric
acid based using a micrsocope and tweezers.
Resolution of Enantiomers
Enantiomers only differ in the rotation of plane polarized
light but diastereomers may differ in other physical
properties and may be separated.
The strategy:
(1) Transform the mix of enantiomers into a mix of
diastereomers as a salt for separation.
(2) Separate the diastereomeric mixture;
(3) Reform the separated enantiomer.
Resolution of Enantiomers
Graphical representation.
Forming Diasteromeric Salts
Enantiomers are transformed into diastereomeric salts by
acid-base reactions.
The compounds used for resolution are generally derived
from natural sources, for example (S)-malic acid from
apples.
Dissociating the Diastereomeric Salts
After separation of the diastereomeric salts the separated
salts are treated with base to regenerate the enantiomer:
Kinetic Resolution
Kinetic resolution depends on the different rates of reactions
of two enantiomers with a chiral compound (enzyme).
One enantiomer of the ester is hydrolyzed preferentially.
The product of that reaction is isolated as a pure enantiomer
while the unreacted enantiomer can be isolated as well.