Introduction and concept of stereochemistry

1. STEREOCHEMISTRY
(FROM A TEXTBOOK OF ORGANIC CHEMISTRY
BY ARUN BAHL.
&
ORGANIC CHEMISTRY, FRANCIS A. CAREY) 1

2. LEARNING OBJECTIVES
By the end of this session, learners would be able to:
Compare different types of isomers along with
examples
Draw different conformational isomers and indicate
their stability

3. ISOMERS
Compounds with the same molecular formula but different
structures are called isomers.
For example, 1-butene and 2-butene have the same molecular
formula, C4H8, but structurally they are different because of
the different positions of the double bond. There are two types
of isomer:
Constitutional (structural) isomers
Stereoisomers
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4. STEREOCHEMISTRY
Stereochemistry is the chemistry of molecules in three
dimensions.
The stereoisomers have the same structural formulas but differ
in arrangement of atom in space.
A clear understanding of stereochemistry is crucial for the study
of complex molecules that are biologically important, e.g.
proteins, carbohydrates and nucleic acids, and also drug
molecules, especially in relation to their behaviour and
pharmacological actions.
Before we go into further detail, let us have a look at different
types of isomerism that may exist in organic molecules.
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5. 5

6. 1.CONSTITUTIONAL ISOMERS
(STRUCTURAL)
When two different compounds have the same molecular formula but
differ in the structural formula i.e nature or sequence of bonding,
they are called constitutional isomers.
For example, ethanol and dimethylether have same molecular
formula, C2H6O, but they differ in the sequence of bonding.
Similarly, butane and isobutane are two constitutional isomers.
Constitutional isomers generally have different physical and chemical
properties.
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7. 1.CHAIN ISOMERISM
Same molecular formula but Differ in the order in which carbon atoms
are bonded to each other.
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8. 2.POSITION ISOMERISM
Same molecular formula but Differ in the position of functional
group.
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9. 3.FUNCTIONAL ISOMERISM
Same molecular formula but Different functional group.
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10. 4.METAMERISM
Due to unequal distribution of carbon atoms on either side of
functional group.
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11. 5.TAUTOMERISM
Special type of functional isomerism in which the isomers are in
dynamic equilibrium with each other.
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12. 5.TAUTOMERISM
The equilibrium between tautomers is not only rapid under normal
conditions, but it often strongly favors one of the isomers (acetone,
for example, is 99.999% keto tautomer).
Even in such one-sided equilibrium, evidence for the presence of the
minor tautomer comes from the chemical behavior of the compound.
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13. MECHANISM FOR ENOL
FORMATION
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15. 2.STEREOISOMERS
Stereoisomers are compounds where the atoms are connected
in the same order but with different geometries, i.e. they differ
in the three-dimensional arrangements of groups or atoms in
space.
For example, in a-glucose and b-glucose, the atoms are
connected in the same order, but the three dimensional
orientation of the hydroxyl group at C–1 is different in each
case.
Similarly, cis- and trans-cinnamic acid only differ in the three
dimensional orientation of the atoms or groups.
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16. STEREOISOMERS
There are two major types of stereoisomer:
Conformational isomers and
Configurational isomers.
Configurational isomers include optical isomers, geometrical
isomers, enantiomers and diastereomers.
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17. 1.CONFORMATIONAL ISOMERS
Atoms within a molecule move relative to one another by rotation
around single bonds.
Such rotation of covalent bonds gives rise to different conformations
of a compound. Each structure is called a conformer or
conformational isomer.
Generally, conformers rapidly interconvert at room temperature.
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18. 1.CONFORMATIONAL ISOMERS
Conformational isomerism can be presented with the simplest
example, ethane (C2H6), which can exist as an infinite number of
conformers by the rotation of the C–C sigma bond.
Ethane has two sp3-hybridized carbon atoms, and the tetrahedral
angle about each is 109.5.
The most significant conformers of ethane are the staggered and
eclipsed conformers.
The staggered conformation is the most stable as it has the lowest
energy.
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19. VISUALIZATION OF CONFORMERS
There are four conventional methods for visualization of three-
dimensional structures on paper.
These are:
the ball and stick method,
the sawhorse method,
the wedge and broken line method
and the Newman projection method.
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20. VISUALIZATION OF CONFORMERS
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21. VISUALIZATION OF CONFORMERS
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22. STAGGERED AND ECLIPSED
CONFORMERS
In the staggered conformation, the H atoms are as far apart as
possible.
This reduces repulsive forces between them. This is why staggered
conformers are stable.
In the eclipsed conformation, H atoms are closest together. This gives
higher repulsive forces between them. As a result, eclipsed
conformers are unstable.
At any moment, more molecules will be in staggered form than any
other conformation.
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23. VISUALIZATION OF CONFORMERS
When two bulky groups are staggered we get the anti conformation,
and when they are at 60˚ to each other, we have the gauche
conformer.
The order of stability (from the highest to the lowest) among the
following conformers is anti > gauche > another eclipsed > eclipsed.
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24. TELL THE CONFORMATION OF
EACH EXAMPLE
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25. 25

26. 2.CONFIGURATIONAL ISOMERS
Configurational isomers differ from each other only in the
arrangement of their atoms in space, and cannot be converted from
one into another by rotations about single bonds within the
molecules.
Before we look into the details of various configurational isomers, we
need to understand the concept of chirality.
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27. CHIRALITY
Many objects around us are handed. For example, our left and right
hands are mirror images of each other, and cannot be superimposed
on each other.
Other chiral objects include shoes, gloves and printed pages.
Many molecules are also handed, i.e. they cannot be superimposed
on their mirror images.
Such molecules are called chiral molecules.
Many compounds that occur in living organisms, e.g. carbohydrates
and proteins, are chiral
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28. CHIRALITY
The most common feature in chiral molecules is a tetrahedral (i.e.
sp3- hybridized) carbon atom with four different atoms or groups
attached.
Such a carbon atom is called a chiral carbon or an asymmetric carbon.
Chiral molecules do not have a plane of symmetry.
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29. GEOMETRICAL ISOMERS
The restriction of rotation about the carbon-carbon double bond is
responsible for the geometrical isomerism.
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30. These isomers differ in physical properties such as melting point,
dipole moment.
The trans-isomer has no dipole.
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31. 31

32. THE EFFECT OF GEOMETRIC
ISOMERISM ON PHYSICAL
PROPERTIES
The table shows the melting point and boiling point of the cis and
trans isomers of 1,2-dichloroethene.
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33. WHY IS THE BOILING POINT
OF THE CIS ISOMERS HIGHER?
There must be stronger intermolecular forces between the molecules
of the cis isomers than between trans isomers.
Taking 1,2-dichloroethene as an example:
Both of the isomers have exactly the same atoms joined up in exactly
the same order. That means that the van der Waals dispersion forces
between the molecules will be identical in both cases.
The difference between the two is that the cis isomer is a polar
molecule whereas the trans isomer is non-polar.
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34. Both molecules contain polar chlorine-carbon bonds, but in the cis
isomer they are both on the same side of the molecule. That means
that one side of the molecule will have a slight negative charge while
the other is slightly positive. The molecule is therefore polar.
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35. Because of this, there will be dipole-dipole interactions as well as
dispersion forces - needing extra energy to break. That will raise the
boiling point.
By contrast, although there will still be polar bonds in the trans
isomers, overall the molecules are non-polar.
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36. The slight charge on the top of the molecule (as drawn) is exactly
balanced by an equivalent charge on the bottom. The slight charge on
the left of the molecule is exactly balanced by the same charge on the
right.
This lack of overall polarity means that the only intermolecular
attractions these molecules experience are van der Waals dispersion
forces. Less energy is needed to separate them, and so their boiling
points are lower.
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37. WHY IS THE MELTING POINT
OF THE CIS ISOMERS LOWER?
You might have thought that the same argument would lead to a
higher melting point for cis isomers as well, but there is another
important factor operating.
In order for the intermolecular forces to work well, the molecules
must be able to pack together efficiently in the solid.
Trans isomers pack better than cis isomers. The "U" shape of the cis
isomer doesn't pack as well as the straighter shape of the trans
isomer.
The poorer packing in the cis isomers means that the intermolecular
forces aren't as effective as they should be and so less energy is
needed to melt the molecule - a lower melting point.
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38. OPTICAL ISOMERISM
The outstanding feature of optical isomers is that they have the
ability to rotate plane-polarized light.
The compound which rotates the plane of polarized light to the right
(clockwise) is said to be dextrorotatory. Indicated by the sign (+).
The compound which rotates the plane of polarized light to the left
(anticlockwise) is said to be levorotatory. Indicated by the sign (-).
An equimolar mixture of two isomers, therefore, will not rotate the
plane of polarized light at all and is said to be racemic mixture
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39. 39

40. ENANTIOMERS
The Greek word enantio means ‘opposite’.
A chiral molecule and its mirror image are called enantiomers or an
enantiomeric pair.
They are nonsuperimposable.
The actual arrangement or orientation (in space) of atoms/groups
attached to the chiral carbon (stereogenic centre or stereocentre) is
called the configuration of a compound.
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41. 41

42. PROPERTIES OF ENANTIOMERS
Enantiomers share same physical properties, e.g. melting points,
boiling points and solubilities.
They also have same chemical properties.
However, they differ in their activities with plane polarized light,
which gives rise to optical isomerism, and also in their biological/
pharmacological actions.
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43. Enantiomers can have striking differences, however, in properties that
depend on the arrangement of atoms in space.
Take, for example, the enantiomeric forms of carvone.
( R )-(-)-Carvone is the principal component of spearmint oil.
Its enantiomer, ( S )-(+)-carvone, is the principal component of
caraway seed oil.
The two enantiomers do not smell the same; each has its own
characteristic odor.
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44. The difference in odor between ( R )- and ( S )-carvone results from their
different behavior toward receptor sites in the nose. It is believed that
volatile molecules occupy only those odor receptors that have the proper
shape to accommodate them.
Because the receptor sites are themselves chiral, one enantiomer may fit one
kind of receptor while the other enantiomer fits a different kind.
An analogy that can be drawn is to hands and gloves. Your left hand and
your right hand are enantiomers. You can place your left hand into a left
glove but not into a right one.
The receptor (the glove) can accommodate one enantiomer of a chiral object
(your hand) but not the other.
The term chiral recognition refers to a process in which some chiral receptor
or reagent interacts selectively with one of the enantiomers of a chiral
molecule
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45. THE CAHN–INGOLD–PRELOG R – S
NOTATIONAL SYSTEM
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47. 47

48. FISCHER PROJECTIONS
Fischer projections are always generated the same way:
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.
A projection of the bonds onto the page is a cross. The chirality
center lies at the center of the cross but is not explicitly shown.
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49. It is customary to orient the molecule so that the carbon chain is
vertical with the
lowest numbered carbon at the top as shown for the Fischer
projection of ( R )-2-butanol.
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50. To verify that the Fischer projection has the R configuration at its
chirality center, rotate the three-dimensional representation so that
the lowest-ranked atom (H) points away from you.
Be careful to maintain the proper stereochemical relationships during
the operation.
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51. 51

52. D AND L SYSTEM
D-glucose is a lot faster to write and say
than (2R,3S,4R,5R)2,3,4,5,6-pentahydroxyhexanal. The L-/D-
system allows for the configuration of a molecule with
multiple chiral centers to be summarized with a single letter.
It turns out that most naturally occurring sugars are D-, and most
naturally occurring amino acids are L- . There is a tremendous amount
of information compressed in that statement, and there is no
competing system (R/S, +/–) which could replace the L- and D- with a
single character.
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53. 53

54. CHIRAL MOLECULES WITH TWO
CHIRALITY CENTERS
When a molecule contains two chirality centers, as does 2,3-
dihydroxybutanoic acid, how many stereoisomers are possible?
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55. Stereoisomers I and II are enantiomers of each other; the enantiomer
of ( R,R ) is ( S,S).
Likewise stereoisomers III and IV are enantiomers of each other, the
enantiomer of (R,S ) being ( S,R ).
Stereoisomer I is not a mirror image of III or IV, so it is not an
enantiomer of either one.
Stereoisomers that are not related as an object and its mirror image
are called diastereomers; diastereomers are stereoisomers that are
not mirror images.
Thus, stereoisomer I is a diastereomer of III and a diastereomer of IV.
Similarly, II is a diastereomer of III and IV.
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57. Because diastereomers are not mirror images of each other, they can
have quite different physical and chemical properties.
For example, the (2 R, 3 R ) stereoisomer of 3-amino-2-butanol is a
liquid, but the (2 R, 3 S ) diastereomer is a crystalline solid.
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