CHAPTER 5

Stereoisomers
We have already covered two kinds of isomerism:
•Constitutional Isomers (structural isomers)
•Stereoisomers
Examples of Constitutional Isomers:

Examples of Stereoisomers:
Another type of stereoisomerism is called mirror-image
stereoisomerism. Mirror-image related stereoisomers are said to
be left-handed and right-handed and occur when a molecule and
its mirror image are non-superimposable.
5-1 Chiral Molecules
The radical bromination of butane to form 2-bromobutane
appears to yield a single product:
Chiral molecules cannot be superimposed on their
mirror images.

The two 2-bromobutane

molecules formed by the
radical bromination of butane
are actually non-
superimposable and are
therefore not identical.
A molecule that is not
superimposible on its mirror
image is said to be chiral.
In this case each isomer is
called an enantiomer.
Compounds whose mirror images are superimposable are called
achiral.
Examples of chiral and achiral molecules:

Above all, the chiral examples contain an atom that is connected

to 4 different substituent groups. This atom is called an
asymmetric atom or a stereocenter.

Often, asymmetric atoms are marked

with an asterisk.
Molecules having one stereocenter are
always chiral.
The symmetry in molecules helps to distinguish
chiral structures from achiral ones.
For most organic molecules, a sufficient test for chirality is
absence of a plane of symmetry (mirror plane).
A mirror plane is one that bisects the molecule in such a way that
the half of the molecule on one side of the plane is the mirror
image of the half on the other side of the plane.
Methane has 6 planes of symmetry, chloromethane has 3,
dichloromethane 2, bromochloromethane 1, and
bromochlorofluoromethane none:
5-2 Optical Activity
Enantiomers cannot be distinguished on the basis of their physical
properties, such as boiling points, melting points, and densities.
Enantiomers can be distinguished by the way they interact with
plane-polarized light.
When plane-polarized light is passed through a sample of one of
the enantiomers, the plane of polarization is rotated either
clockwise or counterclockwise. When the experiment is repeated
with the other enantiomer, the plane-polarized light is rotated an
equal amount, but in the opposite direction.
If facing the light source:
•Clockwise rotation: enantiomer is dextrorotary (+)
•Counterclockwise rotation: enantiomer is levorotary (-)
This interaction with light is called optical activity and
enantiomers are often called optical isomers.
Optical rotation is measured with a polarimeter.
Light is electromagnetic radiation that oscillates perpendicular to
its direction of motion.
The oscillation of light can be resolved into two perpendicular
components.
When light is passed through a polarizer, only one of the two
perpendicular components of light is passed through. This light is
referred to as plane-polarized light.
When plane-polarized light interacts with a chiral molecule, the
plane of polarization of the light is rotated to the left or right.
This effect is called optical rotation and the molecule is said to be
optically active.
Optical activity is measured using a polarimeter. This device
contains a light source, a polarizer to produce the plane-polarized
light, a sample cell, and an analyzer to determine the amount of
rotation.
The measured rotation (in degrees) is the observed optical
rotation, , of the sample.
The value of  depends upon:
•Structure of the chiral molecule
•Concentration of the chiral molecule
•Length of the sample cell
•Wavelength of the light
•Solvent used
•Temperature
The specific rotation [] of a sample is defined for each chiral
molecule (the value is solvent dependent):

o 
[ ]  
t

lc
w here [  ] = specific rotation
t = tem perature in degrees C elsius
 = w avelength of incident light
(D = 589 nm , the yellow D line from N a)
 = observed optical rotation in degres
l = sam ple container length in dm
c = concentration (g/m l)

Specific rotation is a physical constant for a substance, as is

melting point, boiling point, density, etc.
Examples of specific rotations:
Optical rotation indicates enantiomeric
composition.
A racemic mixture is a mixture of equal amounts of the + and –
enantiomers of a chiral compound. It shows no net rotation of
plane-polarized light.
When one enantiomer equilibrates with its mirror image, the
process is called racemization.
When one of the two enantiomers of a chiral compound is present
in a mixture in excess over the other, there will be a net rotation
of plane-polarized light.
A 50% enantiomer excess would be defined as a mixture of 75%
one enantiomer and 25% of the other (50%+ with 25%+ and
25%-). The mixture would be called 50% optically pure.
The optical purity of an enantiomer is defined:

   observed 
% optical purity    100   enantiom er excess
  
 
 
5-3 Absolute Configuration: R-S Sequence Rules
X-ray diffraction can establish the absolute
configuration.
The absolute configuration of an enantiomer is the actual spatial
arrangement of the substituent groups around the chiral centers.
There is no straightforward correlation between the absolute
configuration of an enantiomer and the sign of rotation of the
molecule.
The absolute configuration of an enantiomer can be determined
through single crystal X-ray diffraction analysis or through
chemical correlation to a molecule whose absolute configuration
has already been determined.
Stereocenters are labeled R or S.
The convention for naming enantiomers unambiguously was
developed by R.S. Cahn, C. Ingold, and V. Prelog.

The four substituents around

the chiral carbon must be first
ranked in order of decreasing
priority.
•a highest priority
•b second-highest priority
•c third-highest priority
•d lowest priority

When the molecule is positioned with the lowest-priority

substituent away from the viewer, the remaining three
substituents will be arranged in either a clockwise or
counterclockwise direction.
If the progression from a to b to c is clockwise, the configuration
at the stereocenter is named S (sinister) otherwise the
configuration is named R (rectus)
The R or S is added as a prefix in parentheses to the name of the
chiral compound.
(R)-2-bromobutane
(S)-2,3-dihydroxypropanal
(R,S)-bromochlorofluoromethane (a racemic mixture)
If known, the sign of rotation of plane-polarized light may also be
added, however, there is no correlation between R,S and +,-:
(R)-(+)-2,3-dihydroxypropanal.
Sequence rules assign priorities to substituents.
Rule 1:
Look first at the atoms directly attached to the stereocenter.
Precedence is in order of highest atomic number. Hydrogen is
always the lowest precedence.
A higher-mass isotope takes precedence over a lower-mass
isotope.
Rule 2:
If two atoms are of the same precedence using rule 1,
proceed along the two respective substituent chains until you
reach a point of difference.
Verify these two examples:
Rule 3:
Double and triple bonds are treated as if they are single and
the atoms in them are duplicated or triplicated at each end by
the respective atoms at the other end of the multiple bond.

Verify these assignments:

5-4 Fischer Projections
Fischer projection formulas represent 3-D tetrahedral carbon
atoms and their substituents in two dimensions.
The molecule is drawn in the form of a cross.
•The tetrahedral carbon is in the plane of the paper at the
center of the cross.
•Atoms connected to the tetrahedral carbon by horizontal
bonds are behind the plane of the paper.
•Atoms connected to the tetrahedral carbon by vertical bonds
are in front of the plane of the paper.
There is more than one correct way to draw a Fischer projection:
Rotating a Fischer projection may or may not
change the absolute configuration.
Rotating a Fisher projection formula by 90o converts the structure
into that of the enantiomer of the molecule originally represented.
Rotating a Fisher projection formula by 180o keeps the same
enantiomer.
Exchanging substituents in a Fischer projection also
changes the absolute configuration.
To compare a Fischer projection to another in a different
orientation in order to see if they represent the same enantiomer:
•Exchange any two substituents. This turns the molecule into its
mirror image.
•Exchange another two substituents. This then turns the molecule
back into the original enantiomer.
•Using a series of exchanges, convert one Fisher formula into the
other.
•If an odd number of exchanges are required, the two projection
formulas represent different enantiomers.
•If an even number of exchanges are required, the two
projection formulas represent the same enantiomer.
Fischer projections tell us the absolute
configuration.
•Draw any correct Fischer projection formula of a chiral center.
•Assign priorities to all of the substituents.
•Using two consecutive substituent exchanges (to preserve the
chirality of the Fischer formula), place group d (lowest priority)
on the top.
•If the a,b,c groups are now arranged in a clockwise order, the
enantiomer is R: if in a counterclockwise order, the enantiomer is
S.
5-5 Molecules Incorporating Several
Stereocenters: Diastereomers
Two stereocenters can give four stereoisomers:
chlorination of 2-bromobutane at C3.

Consider the chlorination of 2-

bromobutane. Several products are
formed, but consider only the 2-
bromo-3-chlorobutane.
A second stereocenter is formed by
the addition of the chlorine atom.
The possible combinations are RR, RS, SR, and SS.
Because all of the horizontal bonds in a Fischer projection formula
point towards the viewer and all vertical bonds away from the
viewer, a Fischer projection formula represents the molecule in its
eclipsed conformation.
In order to convert a Newman or dashed-wedged representation
into a Fischer representation, first rotate the molecule to form an
eclipsed rotomer.
Treat each stereocenter separately and regard the group
containing the other stereocenter as a simple substituent.
When a chiral molecule has two stereocenters, four stereoisomers
are possible: RR, RS, SR, and SS.
The RR and SS isomers are mirror images of each other and are
therefore enantiomers.
The RS and SR isomers are also mirror images of each other and
are enantiomers.
The RR and RS stereoisomers are not mirror images of each
other; nor are the SS and SR stereoisomers.
Stereoisomers not related as object and mirror image are called
diastereomers.
Diastereomers are distinct molecules with different physical and
chemical properties.
They can be separated by fractional distillation, crystallization, or
chromatography.
They have different melting points, boiling points, densities, and
specific rotations.
Cis and trans isomers are cyclic diastereomers.
Consider 1-bromo-2-chlorocyclobutane:

There are 4 stereoisomers: RR, SS, RS, and SR. The two cis
isomers, SR and RS, are enantiomers and the two trans isomers,
RR and SS are enantiomers.
A cis isomer and a trans isomer are diastereomers of each other.
More than two stereocenters means still more
stereoisomers.
A compound containing 3 stereocenters will exist as 8
stereoisomers which can be grouped into 4 pairs of enantiomers:
RRR | SSS
SRR | RSS
RSR | SRS
RRS | SSR
In general, a compound having n stereocenters can have a
maximum of 2n stereoisomers.
5-6 Meso Compounds
Two identically substituted stereocenters give rise
to only three stereoisomers.
Consider the radical bromination of 2-bromobutane:

Since there are 2 chiral centers in the product, we might expect 4

distinct stereoisomers: RR, RS, SR, and SS.
These could then be organized into enantiomeric pairs: RR | SS
and RS | SR.
A closer look at the RS and SR pair of molecules, however, shows
that they are superimposable molecules and are therefore
identical.
A compound containing 2 or more stereocenters that is
superimposable with its mirror image is called a meso compound.
Meso compounds contain an internal mirror plane which divides
the two halves of the molecule which are mirror images of each
other.
The presence of a mirror plane in any energetically accessible
conformation of a molecule is sufficient to make it achiral.

2,3-Dibromobutane exists as three stereoisomers only: a pair of

enantiomers and an achiral meso diastereomer.
Examples of meso compounds having multiple chiral centers:
Cyclic compounds may also be meso.
1,2-Dicyclobutane exists in the cis and the trans form. The cis
form, however, contains a mirror plane and is therefore an achiral
meso compound.

For the purpose of identifying a mirror plane, cyclic compounds

can usually be treated as if the ring were planar since the out-of-
plane conformers are all generally interconvertable at room
temperature.
5-7 Stereochemistry in Chemical Reactions
The radical mechanism explains why the
bromination of butane results in a racemate.
When a hydrogen atom is extracted from butane by an attacking
bromine atom, it does not matter which hydrogen is extracted, an
achiral planar sp2 radical is formed:

The two lobes of the p orbital are

equally susceptible to attack by
bromine in the second step. The
two transition states are
energetically equivalent to each
other, so equal amounts of the
two enantiomeric products are
formed.
The formation of chiral compounds from achiral reagents yields
racemates (optically inactive reactants yield optically inactive
products).
The presence of a stereocenter affects the outcome
of the reaction: chlorination of (S)-2-bromobutane.
Chlorination of (S)-2-bromobutane at a terminal methyl group
can proceed at either C1 or at C4:

Both products are optically active. The original stereocenter remains

unchanged.
In the case of C1 chlorination, the sequence of priorities about the
stereocenter changes, which changes the configuration at C2 from S to
R.
In the case of C4 chlorination, the carbon chain must be renumbered to
maintain the lowest possible substituent numbering.
Chlorination of (S)-2-bromobutane at C2, the stereocenter, leads
to 2-bromo-2-chlorobutane. The molecule remains chiral,
however a racemic mixture is formed.
Hydrogen abstraction at C2 leads to a planar, sp2-hybridized,
achiral radical.

Chlorination occurs equally at either lobe of the p orbital leading

to equal amounts of the R and S enantiomers and thus a racemic
mixture.
Chlorination of (S)-2-bromobutane at C3, forms a second
stereocenter and gives rise to diastereomers

In this case, the two faces of the

radical transition state are not
mirror images of each other, due to
the stereocenter at C2.
Attack by chlorine at the two faces
of the radical will occur at different
rates (due to steric reasons) and
the two diastereomers are formed
at different rates.
Stereoselectivity is the preference for one
stereoisomer.
A reaction that favors the formation of one of several possible
stereoisomeric products is said to be stereoselective.
Chlorination of (S)-2-bromobutane at C3 is stereoselective,
whereas chlorination at C2 is not (a racemate is formed).
100% stereoselectivity is usually obtained in nature when
enzymes (chiral molecules themselves) convert achiral
compounds into chiral ones.
5-8 Resolution: Separation of Enantiomers
Pure enantiomers can be
obtained by first synthesizing a
racemic mixture and then
separating the enantiomers
formed by a process called
resolution.
Resolution is best carried out by
converting a racemate into a
mixture of diastereomers by
adding an enantiomerically pure
reagent. The resulting
diastereomers can then be
separated by standard
techniques.
Each pure diastereomer can then
be separated into one of the
original enantiomeric molecules
and the optically active reagent,
which can be used again to
resolve further racemic mixtures.
A popular reaction employed in the resolution of racemic mixtures is salt
formation between acids and bases.
(+) Tartaric acid can be used to resolve racemic amines.

Chiral chromatography can be used to resolve racemic mixtures

without first isolating diastereomers. In this method, an optically
active compound is attached to a solid support in a column, and
the racemic mixture is allowed to pass through it.
Each of the two enantiomeric molecules in the mixture will
interact differently with the attached chiral molecule and will have
different retention times on the column.
5 Important Concepts

1. Isomers – Same molecular formula, different

compounds:
• Constitutional – Individual atoms are connected differently
• Stereoisomers – Same connectivity, different 3D arrangement.
• Mirror-Image Stereoisomers – Related as image
2. Chiral Molecule – Not superimposable on its mirror
image
3. Stereocenter – Carbon atom bearing 4 different
substituents
4. Enantiomers – Two stereoisomers, each a non-
superimposable mirror image of the other
5 Important Concepts

5. Racemate – A one-to-one mixture of enantiomers

6. Mirror Plane – Chiral molecules cannot contain a
mirror plane.
7. Diastereomers – Stereoisomers not related to each
other as mirror images (i.e. cis/trans).
8. Two Stereocenters In A Molecule – Create up
to 4 stereoisomers: 2 diastereomerically related pairs.
If the 2 stereocenters generate a mirror plane in the
molecule, the molecule is known as a meso compound
and is achiral.
9. Physical Properties of Stereoisomers – Most
are the same except for the rotation of plane-polarized
light. One enantiometer rotates the plane of
polarization to the right, the other to the left. This
rotation is expressed as the specific rotation [].
5 Important Concepts

10. Absolute Configuration – Determined by X-ray

diffraction. Assignment of R or S, as determined by the
Cahn, Ingold, and Prelog sequence rules
11. Fischer Projections – Standard 2-D
representation of 3-D molecules containing
stereocenters
12. Radical Halogenation – Can introduce chirality
into an achiral compound. Racemic mixtures are often
produced.
13. Radical Halogenation of a Chiral Molecule
Containing 1 Stereocenter –
• Gives a racemate if the reaction occurs at the stereocenter
• Gives 2 diastereomers in unequal amounts if the reaction
occurs elsewhere
5 Important Concepts

14. Stereoselectivity – Preference for the formation of

one stereoisomer when several are possible
15. Resolution – Separation of enantiomers
• Reaction with a pure enantiomer of a second chiral
compound and separation of the diastereomers
• Chiral chromatography