MF111 Study Guide 7
Stereochemistry
Learning outcomes

Differentiate between different classes of stereoisomers

Identify stereocenters within molecules

Understand the biological significance of stereoisomers

Identify diastereomers and mesocompounds

Correctly draw stereocenters using the Fischer projection

Correctly name stereocenters using R and S nomenclature

Name molecules based on optical rotation and calculate their
specific rotation
Overview
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial
arrangement of atoms that form the structure of molecules and their manipulation.
Stereochemistry is also known as 3D chemistry because the prefix "stereo-" means "threedimensionality". An important branch of stereochemistry is the study of chiral molecules.
Isomers
Figure 7.1 Different classification of isomers
Isomers (From Greek, isos = "equal", méros = "part") are compounds with the same molecular
formula but different structural formulas. Figure 7.1 shows the different classification of isomers.
Constitutional isomers are compounds with the same molecular formula and different bonding
connectivity. Ethanol and dimethyl ether, for example, are constitutional isomers.
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Figure 7.2 Two constitutional isomers
Stereoisomers are compounds that have the same molecular formula and the same atom-to-atom
connectivity, but have a different arrangement of atoms in space and cannot be interconverted by
rotation about a single bond
Figure 7.3 Two stereoisomers of alanine
Figure 7.3 shows the two stereoisomers of alanine. The stereoisomer shown on the left-hand side
of this figure, called L-alanine, which is found in virtually all proteins, in all forms of life on
earth. The D-alanine isomer is quite rare. Stereochemistry is a branch of chemistry that deals
with these isomers.
Chirality
Louis Pasteur could rightly be described as the first stereochemist, having observed in 1849 that
salts of tartaric acid collected from wine production vessels could rotate plane polarized light,
but that salts from other sources did not. In 1874, Jacobus Henricus van 't Hoff and Joseph Le
Bel explained optical activity in terms of the tetrahedral arrangement of the atoms bound to
carbon. Chiral carbons have with four different substituent groups are the most common
stereocenters in organic molecules (Figure 7.4).
Figure 7.4 Two mirror images of a chiral carbon.
The term chiral is derived from the Greek word for “handedness” – ie. right-handedness or lefthandedness. Your hands are chiral: your right hand is a mirror image of your left hand, but if
you place one hand on top of the other, both palms down, you see that they are not
superimposable (Figure 7.5).
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Figure 7.5 Chirality of hands
Enantiomers
Enantiomers (From Greek, enantios = “opposite”, méros = "part") are stereoisomers that are
mirror images of each other and are non-superposable (not identical). Figure 7.6 shows some
examples of chiral molecules that exist as pairs of enantiomers. In each of these examples,
there is a single stereocenter, indicated with an arrow. Many molecules have more than one
stereocenters and these are classified differently.
A racemic mixture is one that has equal amounts of left- and right-handed enantiomers of a
chiral molecule.
Figure 7.6 Common enantiomers
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Biological significance
Drug safety
Thalidomide is a drug, first prepared in 1957 in Germany, prescribed for treating morning
sickness in pregnant women. Thalidomide had previously been used in other countries as an
antidepressant, and was believed to be safe and effective for both purposes. The effective isomer
is (R)-thalidomide while (S)-thalidomide was found to be a teratogen i.e. causes malformations
of an embryo or fetus (Figure 7.7).
(S)-thalidomide
(R)-thalidomide
Figure 7.7 (R)-thalidomide and (S)-thalidomide. Both
have chiral carbons and cannot be super imposed.
However, it is incorrect to say that (R)-thalidomide is safe for pregnant women but
(S)-thalidomide is not. It was discovered (too late) that the the drug undergoes racemisation in
the human body i.e. even if only one of the two enantiomers is administered as a drug, the other
enantiomer is produced as a result of metabolism. The thalidomide scandal led to enactment of
much stricter laws requiring tests for safety during pregnancy.
Drug patents
Pharmaceutical companies regularly patent potential drugs to ensure exclusive rights to the drug
for a limited period of time in exchange for public disclosure of the drug formulation. Advances
in industrial chemical processes have made it possible for pharmaceutical companies to extend
the patents of drugs originally marketed as a racemic mixture by patenting individual
enantiomers (Figure 7.8). In some cases, the enantiomers have genuinely different effects. In
other cases, there may be no clinical benefit to the patient, except to extends the drug's
patentability.
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Figure 7.8 Patenting of racemic Ibuprofen and S-Ibuprofen
Diastereomers
Diastereomers (sometimes called diastereoisomers) are stereoisomers that are not enantiomers
(Figure 7.9). Diastereomerism occurs when there are two or more possible stereoisomers of a
compound. Each stereocenter gives rise to two different configurations and thus increases the
number of stereoisomers by a factor of two (2n). We will mainly concentrate on smaller
compounds with two to three stereocenters.
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Enantiomers
Diastereomers
Diastereomers
Enantiomers
Figure 7.9 Enantiomers and diastereomers of erythrose
Mesocompounds are rare exceptions which have
or more stereocenters but the compound itself is
chiral i.e. no enantiomers. A meso compound has
enantiomers because it is superimposable on its
mirror image despite having chiral carbons
(Figure 7.10). Mesocompounds are optically
inactive and there are very few naturally
occurring examples. Meso-tartaric acid is one
such example.
one
not
no
Figure 7.10 Mesocompound of tartaric
acid and its diastereomers
Figure 7.11 Cyclic mesocompound
Cyclic compounds can also be meso. One of many such examples is cis-1,2dihydroxycyclohexane (Figure 7.11). However, if the hydroxyl groups are trans to each other,
the molecule is chiral.
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Cis-trans isomers of alkenes occur because the double bonds in molecules do not allow rotation.
Therefore, the isomers cannot interconvert without breaking any bonds. These isomers are
sometimes classified as diastereomers i.e. stereoisomers that are not enantiomers. When there are
only two substituent groups, the nomenclature for these isomers are straight forward i.e. cis when
substituent groups are on the same side, trans when the stubstituent groups are on different sides.
Cis and trans isomers can have a very different shape Figure 7.12. You may want to read up the
E/Z nomenclature for alkenes with more than two substituent groups.
Figure 7.12 Cis and trans fatty acids. Trans fatty acids have a much
straighter carbon chain and tend to have higher boiling points.
Stereoisomer nomenclature
Drawing stereocenters
Fischer projection is a simplified way to depict the stereochemistry around a stereocenter. The
simpler hashed-wedged line perspective drawings are effective, but can be troublesome when
applied to compounds having multiple chiral centers. As part of his Nobel Prize-winning
research on carbohydrates, the great German chemist Emil Fischer, devised a simple notation
that is still widely used. In a Fischer projection drawing, the four bonds to a chiral carbon make a
cross with the carbon atom at the intersection of the horizontal and vertical lines. The two
horizontal bonds are directed toward the viewer (forward of the stereogenic carbon).
Naming stereocenters
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Chemists need to have a convenient way to distinguish between stereoisomers. The Cahn-IngoldPrelog system is a set of rules that allows us to unambiguously define the stereochemical
configuration of any stereocenter, using the designations ‘R’ (from the Latin “rectus”, meaning
right-handed) or ‘S’ (from the Latin “sinister”, meaning left-handed). Trivia: Sinister also means
“unlucky” in latin and this led to the negative associations with the word “left”.
Using the system, substituents bound to a chiral carbon can be assigned priorities based on
their atomic number. Substituent groups with a higher atomic number are assigned a higher
priority. Figure 7.13 shows how the priority of each substituent group of the chiral carbon in
glyceraldehyde is assigned. Priorities of the substituent groups are:
1. O (atomic number 8; hydroxyl)
2. C (atomic number 6; aldehyde)
3. C (atomic number 6; CH2OH)
4. H (atomic number 1),
Figure 7.13 Priorities for substituent groups in chiral carbon of glyceraldehyde
The priority of the H and O groups are easily assigned based on their atomic numbers. The
priorities of the C groups require more deliberation. When this occurs, we have to look at
atoms bonded to the C groups and determine which has the largest atomic numbers. However,
in the case of glyceraldehyde, both C groups are bonded to O. In such cases, a double bond is
assigned a higher priority than a single bond.
Figure 7.14 Determining the “handedness” of the chiral carbon.
To determine the handedness of the molecule, we have to flip the molecule so that the group
with the lowest priority (usually H) is facing away from us. Then we have to trace a circle
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around the groups assigned priority 1, 2 and 3 and determine if the circle is turning clockwise
or counter clockwise. Figure 7.14 shows that the glyceraldehydes molecule in Figure 7.13 is
of the R configuration i.e. (R)-glyceraldehyde. For (S)-glyceraldehyde, the circle around the
1, 2, and 3 priority groups is counter-clockwise (Figure 7.15). Again, remember to flip the
molecule so that the group with priority 4 is pointing to the back.
Figure 7.15 “Handedness” of (S)-glyceraldehyde
Optical Activity
Electromagnetic waves, such as light waves exhibit polarization because they can oscillate with
more than one orientation (Figure 7.16).
Figure 7.16 Oscillation of unpolarized light
Light passing through a polarizer produces plane polarize light i.e. oscillates on a single plane.
Optically active substances are able to rotate the plane of polarised light and this rotation is
detected and measured in a polarimeter (Figure 7.17).
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Figure 7.17 Schematic diagram of polarimeter
After polarised light is generated it passes through the sample cell (Figure 7.18). After emerging
from the cell, the light passes through a second polarising filter (analyser) and finally the detector
(often your eyes). If the sample is optically inactive, the plane is unchanged and no rotation is
detected. If the sample is optically active, the plane of polarisation is rotated. The polarimeter is
used to determine both the direction and magnitude of the rotation
Figure 7.18 Polarimeter and sample cell
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Compounds are classified based on how the rotate polarized light:
 Dextrorotatory (d) or (+): Clockwise rotation is assigned a positive value
 Levorotatory (L) or (-): Anticlockwise rotation is assigned a negative
However, the magnitude of the rotation varies depending on the length of the sample cell and
concentration. Therefore the specific rotation as calculated below is required for comparison
between different experiments:
[ ] 

c
α is observed rotation
[α] is specific rotation
ℓ is path length in dm
c is concentration in g/mL
It is important to note that (+) and (-), and (d) and (l) assignments tell us nothing about the
structure of the molecule. It is important to not confuse them with (R) and (S) assignments which
can be assigned simply by looking at the structure. The way to assign (+) or (-) to a molecule is
to place it in a polarimeter!
However, assignments based on optical rotation e.g. (d)-glucose is convenient for substances
with multiple stereocenters (Figure 7.19).
Figure 7.19
(d)-glucose can also be classified
as (2R, 3S, 4R, 5S)-glucose
Question: How many stereoisomers does glucose have?
Reading Material

Chapters 15.2
Silberberg, M.S. (2006). Chemistry: The Molecular Nature of Matter and Change. 4th Ed.
McGraw Hill.
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