Well explained many aspects of the stereochemistry.

1. Stereochemistry
Prepared by
Mr. Dharmendrasinh A Baria
Assistant professor
Department of Pharmaceutical Chemistry
Smt. S. M. Shah Pharmacy college, Amsaran

3. Introduction
• The two major classes of isomers are constitutional isomers and
stereoisomers.
Constitutional/structural isomers have different IUPAC
names, the same or different functional groups, different
physical properties and different chemical properties.
Stereoisomers compounds with the same connectivity,
different arrangement in space They have identical IUPAC
names (except for a prefix like cis or trans). They always
have the same functional group(s).

5. O Configuration the arrangement in space of the four different groups
about a chiral center. Stereoisomers differ in configuration.
O Stereochemistry: The study of the three-dimensional structure of
molecules.

6. Importance of stereochemistry
O Stereochemistry plays an important role in determining the
properties and reactions of organic compounds:
CH2
H3
C
H
O
CH3
CH2
H3
C
H
O
CH3
H2
C CH3
O
CH3
H
Caraway seed Spearmint

7. O The properties of many drugs depends on their stereochemistry:
CH3
HN
CH3
O
Cl
NH
O
Cl
NH
(S)-Ketamine
CH3
HN
CH3
O
Cl
NH
O
Cl
NH
(R)-Ketamine
Anesthetic Hallucinogen

8. O Enzymes are
capable of
distinguishing
between
stereoisomers:

9. Chirality
• Although everything has a mirror image, mirror images may or may
not be superimposable.
• Some molecules are like hands. Left and right hands are mirror
images, but they are not identical, or superimposable.

10. • Other molecules are like socks.
Two socks from a pair are
mirror images that are
superimposable. A sock and its
mirror image are identical.
• A molecule or object that is
superimposable on its mirror
image is said to be achiral.
• A molecule or object that is not
superimposable on its mirror
image is said to be chiral.

11. • We can now consider several molecules to determine whether or
not they are chiral.

12. O In general, a molecule with no stereogenic centers will not be
chiral.
O With one stereogenic center, a molecule will always be chiral.
O With two or more stereogenic centers, a molecule may or may not
be chiral.
O Achiral molecules usually contain a plane of symmetry but chiral
molecules do not.

13. Stereogenic Centers/Asymmtric
carbon/Chiral center/Chiral carbon
O The most common feature that leads to chirality in organic
compounds is the presence of an asymmetric (or chiral) carbon
atom.
O A point in a molecule where four different groups (or atoms) are
attached to carbon is called a chiral center.
O There are two non-superimposable ways that 4 different different
groups (or atoms) can be attached to one carbon atom.
O If two groups are the same, then there is only one way.
O A chiral molecule usually has at least one chiral center.

14. • Always omit from consideration all C atoms that cannot be
tetrahedral stereogenic centers. These include
CH2 and CH3 groups
Any sp or sp2 hybridized C

15. O In general:
O no asymmetric C usually achiral
O 1 asymmetric C always chiral
O > 2 asymmetric C may or may not be chiral
Example: Identify all asymmetric carbons present in the following
compounds.
C C C C
OH
H
H
H
H
H
H H
H
H
H3C
CH3
CH2CH3
H H H
BrBr Br CH3
Br
H

17. Internal Plane of Symmetry
O Cis-1,2-dichlorocyclopentane contains two asymmetric carbons but
is achiral.
O Contains an internal mirror plane of
symmetry
O Any molecule that has an internal mirror plane of symmetry is
achiral even if it contains asymmetric carbon atoms.
H H
ClCl
s

18. O Cis-1,2-dichlorocyclopentane is a meso compound:
O an achiral compound that contains chiral centers
O often contains an internal mirror plane of symmetry

19. Example: Which of the following compounds contain an internal
mirror plane of symmetry?
C C
C
C
C
O
OH
O
OH
HO
OH
H
H
H
Cl
HF
C C
CO2H
H
OH
H
HO
HO2C
C C
CO2H
OH
H
H
HO
HO2C
CH3H
H3C H
FF
C C
CH2CH3
Br
H
BrH
H3CH2C

20. Optical activity
O Optical activity – the ability to rotate the plane of plane –polarized
light.
O Plane polarized light – light that has been passed through a nicol
prism or other polarizing medium so that all of the vibrations are in
the same plane.
O Polarimeter – an instrument used to measure optical activity.
O Plane-polarized light that passes through solutions of achiral
compounds remains in that plane ([α] = 0, optically inactive)
O Solutions of chiral compounds rotate plane-polarized light and the
molecules are said to be optically active.

21. Plane-Polarized Light

22. Plane-Polarized Light through an
Achiral Compound

23. Plane-Polarized Light through a
Chiral Compound

24. Dextrorotatory – when the plane of polarized light is rotated in a
clockwise direction when viewed through a polarimeter.
(+) or (d) do not confuse with D
Levorotatory – when the plane of polarized light is rotated in a
counter-clockwise direction when viewed through a polarimeter.
(-) or (l) do not confuse with L
The angle of rotation of plane polarized light by an optically active
substance is proportional to the number of atoms in the path of the
light.

25. Specific rotation – the angle of rotation of plane polarized light by a
1.00 gram per cm-3 sample in a 1 dm tube. [α ]D (D = sodium lamp,
λ = 589 mμ).
The more molecules of a chiral sample are present the greater the
rotation of the light = concentration dependent.
O where α = observed rotation
l = length (dm)
d = concentration (g/cc)
Cl
D




g/ml)intrationdm)(conceninh(pathlengt
degrees)inrotation(observed
][

26. Enantiomers
O Enantiomers are stereoisomers that are non-
superimposable on their mirror images.
A AB B
C C
D D
mirror
CO2H
H3C NH2
H CH3
CO2H
H2N
H

29. Properties of Enantiomers
1. Enantiomers have identical physical properties such as
boiling points, melting points, refractive indices, and
solubilities in common solvents except optical rotations.
1) Many of these properties are dependent on the magnitude of
the intermolecular forces operating between the molecules,
and for molecules that are mirror images of each other these
forces will be identical.
2) Enantiomers have identical infrared spectra, ultraviolet
spectra, and NMR spectra if they are measured in achiral
solvents.

30. 2. Enantiomers show different behavior only when
they interact with other chiral substances.
1) Enantiomers show different rates of reaction toward
other chiral molecules.
3) Enantiomers have identical reaction rates with
achiral reagents.

31. 2) Enantiomers show different solubilities in chiral
solvents that consist of a single enantiomer or an
excess of a single enantiomer.
3. Enantiomers rotate the plane of plane-polarized light
in equal amounts but in opposite directions.
O Separate enantiomers are said to be optically active
compounds.

32.  Reactivity with chiral molecules …. e.g., enzymes,
receptors, ….. drug action/metabolism
CH2
Ph
CH3
HMeNH
CH2
Ph
CH3
NHMeH
I II
(R)(S)
Methamphetamine
10X more potent
CNS stimulant
Less cardiovascular
desoxyephedrine

33. Why do chiral molecules react differently with biological
molecules?

34. Diastereomers
O Diastereomers are stereoisomers that are not mirror
images of each other – they are stereoisomers that are
not enantiomers.
O Molecules with 2 or more chiral carbons.
C C
H
CH3
H
H3C
C C
CH3
H
H
H3C

35. Alkenes
O Cis-trans isomers are not mirror images, so these are
diastereomers.
C C
H H
CH3H3C
cis-2-butene trans-2-butene
C C
H
H3C
CH3
H

36. Ring Compounds
O Cis-trans isomers possible.
O May also have enantiomers.
O Example: trans-1,3-dimethylcylohexane
CH3
H
H
CH3
CH3
H
H
CH3

37. The four stereoisomers of 2,3-dibromopentane

38. Properties of Diastereomers
O Diastereomers are similar, but they aren’t mirror images.
O Enantiomers have opposite configurations at all chiral centers;
Diastereomers are opposite at some, but not all chiral centers.
O Diastereomers have different physical properties

39. O Epimers are diastereomers different at only 1 chiral center
•Diastereomers and constitutional isomers have different
physical properties, and therefore can be separated by
common physical techniques.

40. Meso Compounds
O A meso compound is one which is superimposable on its mirror
image even though it contains stereogenic centres.
O An achiral compound with chiral centers is called a meso
compound – it has a plane of symmetry.

42.  As long as any one conformer of a compound has a
plane of symmetry, the compound will be achiral.
plane of
symmetry
plane of
symmetry

43. Geometrical isomers
O Cis–trans isomers (also called geometric isomers) result from
restricted rotation.
O Restricted rotation can be caused either by a double bond or by a
cyclic structure.
O As a result of the restricted rotation about a carbon–carbon double
bond, an alkene such as 2-pentene can exist as cis and trans isomers.
The cis isomer has the hydrogens on the same side of the double
bond, whereas the trans isomer has the hydrogens on opposite
sides of the double bond.

44. CIS
Groups/atoms are on the
SAME SIDE of the double
bond
TRANS
Groups/atoms are on
OPPOSITE SIDES across
the double bond

45. RESTRICTED ROTATION OF C=C BONDS
Single covalent bonds can easily rotate. What appears to be a
different structure in an alkane is not. Due to the way structures
are written out, they are the same.
All these structures are the same because c-c bonds have ‘free’
rotation

46.  C=C bonds have restricted rotation so the groups on either
end of the bond are ‘frozen’ in one position; it isn’t easy to
flip between the two.
RESTRICTED ROTATION OF C=C BONDS
 This produces two possibilities. The two structures cannot
interchange easily so the atoms in the two molecules occupy
different positions in space.

47. ISOMERISM IN BUTENE
O There are 3 structural isomers of C4H8 that are alkenes*. Of
these ONLY ONE exhibits geometrical isomerism.
BUT-1-ENE 2-
METHYLPROPENE
trans BUT-2-
ENE
cis BUT-2-
ENE

48.  Cyclic compounds can also have cis and trans isomers.
 The cis isomer has the hydrogens on the same side of the ring, whereas
the trans isomer has the hydrogens on opposite sides of the ring.

49. Properties of Geometric Isomers
O Geometric isomers have similar chemical properties but some
different physical properties.
O Symmetrical alkenes have the same groups or atoms attached to one
of the carbon atoms in the C=C bond.

50. E and Z Based on Priority:
Cahn-Ingold-Prelong rules:
1. Atomic Number
2. Atomic weight
3. Atomic number of the next atom
O Higher priority at the opposite side of pi bond (E)
O Higher priority at the same side of pi bond (Z)

51. cis or trans?
E and Z Based on Priority:

53. Racemic mixture
O 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
O The pure compounds need to be separated or resolved from the
mixture (called a racemate).
O A racemic mixture is optically inactive. Because two enantiomers
rotate plane-polarized light to an equal extent but in opposite
directions, the rotations cancel, and no rotation is observed.

54. Physical Properties of
Stereoisomers—Racemic Mixtures

55. Resolution of Enantiomers
O Separating enantiomers is called resolution.
O A pair of enantiomers can be separated in several ways,
of which conversion to diastereomers and separation of
these by fractional crystallization is the most often used.
O In this method and in some of the others, both isomers
can be recovered, but in some methods it is necessary to
destroy one.

56. Methods of resolution
1. Conversion to Diastereomers.
2. Differential Absorption
3. Chiral Recognition.
4. Biochemical Processes
5. Mechanical Separation
6. Kinetic Resolution
7. Deracemization

57. Conversion to Diastereomers
O 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).
O This gives diastereomers that are separated by their
differential solubility.
O The resolving agent is then removed.
O Usually, fractional crystallizations must be used and the
process is long and tedious.

58. O Fortunately, naturally occurring optically active bases (mostly
alkaloids) are readily available. Among the most commonly used
are brucine, ephedrine, strychnine, and morphine.
O Once the two diastereomers have been separated, it is easy to
convert the salts back to the free acids and the recovered base can
be used again.
O Most resolution is done on carboxylic acids and often, when a
molecule does not contain a carboxyl group, it is converted to a
carboxylic acid before resolution is attempted.

59. O However, the principle of conversion to diastereomers is not
confined to carboxylic acids, and other functional groups may
be coupled to an optically active reagent.
O Racemic bases can be converted to diastereomeric salts with
active acids.
O Alcohols can be converted to diastereomeric esters, aldehydes
to diastereomeric hydrazones, and so on.

60.  Using an Achiral amine doesn’t change the relationship of the
products Still can’t separate the Enantiomeric Salts.

61.  Using a Chiral amine changes the relationship of the products
Now we can separate the Diastereomeric Salts.

62. (R)-compound X
(S)-compound X
react or somehow associate with:
(R)-compound Y
(R)-compound X (R)-compound Y(R)-compound Y(S)-compound X
Separate by some technique (chromatography,
crystallization, distillation, etc.)
(R)-compound X (R)-compound Y
(R)-compound Y(S)-compound X
somehow remove compound Y
(R)-compound X(S)-compound X
racemic mixture
of enantiomers
Single
enantiomer
mixture of 2
diastereomers
single
diastereomer
single
diastereomer
single
enantiomer
single
enantiomer
Resolution of Enantiomers

63. Differential Absorption/Chromatographic
Resolution of Enantiomers
O When a racemic mixture is placed on a hromatographic column, if
the column consists of chiral substances, then in principle the
enantiomers should move along the column at different rates and
should be separable without having to be converted to
diastereomers.
O This has been successfully accomplished with paper, column, thin-
layer, and gas and liquid chromatography.
O For example, racemic mandelic acid has been almost completely
resolved by column chromatography on starch.

64. O Columns packed with chiral materials are now commercially
available and are capable of separating the enantiomers of
certain types of compounds.

65. Chiral Recognition
 In this host forms an inclusion compound with one
enantiomer of a racemic guest, but not the other. This is
called chiral recognition.
 One enantiomer fits into the chiral host cavity, the other
does not. More often, both diastereomers are formed, but
one forms more rapidly than the other, so that if the guest
is removed it is already partially resolved.
 An example is use of the chiral crown ether partially to
resolve the racemic amine salt.

66.  When an aqueous solution of 59 was mixed with a solution of
optically active 58 in chloroform, and the layers separated, the
chloroform layer contained about twice as much of the complex
between 58 and (R)-59 as of the diastereomeric complex.
 Many other chiral crown ethers and cryptands have been used, as
have been cyclodextrins, cholic acid, and other kinds of hosts.

67. Biochemical Processes.
O Biological molcules may react at different rates with the two
enantiomers.
O For example, a certain bacterium may digest one enantiomer,
but not the other.
O Pig liver esterase has been used for the selective cleavage of
one enantiomeric ester.
O This method is limited, since it is necessary to find the proper
organism and since one of the enantiomers is destroyed in the
process.

68. O However, when the proper organism is found, the method leads to a
high extent of resolution since biological processes are usually very
stereoselective.

69. Mechanical Separation
O This is the method by which Pasteur proved that racemic acid was
actually a mixture of (+)- and (-)-tartaric acids.
O In the case of racemic sodium ammonium tartrate, the enantiomers
crystallize separately: all the (+) molecules going into one crystal
and all the (-) into another.
O Since the crystals too are non-superimposable, their appearance is
not identical and a trained crystallographer can separate them with
tweezers.

70. O However, this is seldom a practical method, since few compounds
crystallize in this manner.
O Even sodium ammonium tartrate does so only when it is crystallized
<270C. A more useful variation of the method, although still not
very common, is the seeding of a racemic solution with something
that will cause only one enantiomer to crystallize.

71. Kinetic Resolution
O Since enantiomers react with chiral compounds at different rates, it
is sometimes possible to effect a partial separation by stopping the
reaction before completion.
O A method has been developed to evaluate the enantiomeric ratio of
kinetic resolution using only the extent of substrate conversion.
O An important application of this method is the resolution of racemic
alkenes by treatment with optically active diisopinocampheylborane,
since alkenes do not easily lend themselves to conversion to
diastereomers if no other functional groups are present.

72. O One enantiomer was converted to the epoxide and the other was
not, the rate ratio (hence the selectivity factor) being >100. Of
course, in this method only one of the enantiomers of the original
racemic mixture is obtained, but there are at least two possible
ways of getting the other:
O (1) Use of the other enantiomer of the chiral reagent;
O (2) Conversion of the product to the starting compound by a
reaction that preserves the stereochemistry.

73. Deracemization.
O In this type of process, one enantiomer is converted to the other, so
that a racemic mixture is converted to a pure enantiomer, or to a
mixture enriched in one enantiomer.
O This is not quite the same as the methods of resolution previously
mentioned, although an outside optically active substance is
required.
O To effect the deracemization two conditions are necessary:
O (1) the enantiomers must complex differently with the optically
active substance;

74. (2) they must interconvert under the conditions of the experiment.
O When racemic thioesters were placed in solution with a specific
optically active amide for 28 days, the solution contained 89% of
one enantiomer and 11% of the other.
O In this case, the presence of a base (EtN) was necessary for the
interconversion to take place. Biocatalytic deracemization processes
induce deracemization of chiral secondary alcohols.

75. Enantiotopic Hydrogens, Diastereotopic
Hydrogens, and Prochiral Carbons
O If a carbon is bonded to two hydrogens and to two different groups,
the two hydrogens are called enantiotopic hydrogens.
O For example, the two hydrogens (Ha and Hb) in the group of ethanol
are enantiotopic hydrogens because the other two groups bonded to
the carbon ( CH3 and OH) are not identical.
O Replacing an enantiotopic hydrogen by a deuterium (or any other
atom or group other than or OH) forms a chiral molecule.

76. A molecule that is achiral but that can become chiral by a single
alteration is a prochiral molecule.

77. Re and Si are used to describe the faces of the prochiral sp2
reactant.

78. O An sp3 carbon with two groups the same is also a prochiral center
O The two identical groups are distinguished by considering either and
seeing if it was increased in priority in comparison with the other
O If the center becomes R the group is pro-R and pro-S if the center
becomes S

79. O Enantiotopic hydrogens have the same chemical reactivity
and cannot be distinguished by achiral agents, but they are
not chemically equivalent toward chiral reagents.
O Diastereotopic hydrogens do not have the same reactivity
with achiral reagents

81. •Enantiomeric excess (optical purity) is a measurement of how
much one enantiomer is present in excess of the racemic mixture. It
is denoted by the symbol ee.
•Consider the following example—If a mixture contains 75% of one
enantiomer and 25% of the other, the enantiomeric excess is 75% -
25% = 50%. Thus, there is a 50% excess of one enantiomer over the
racemic mixture.

82. How do we “draw” a chirality
centre?
Perspective Formula
H Cl
CH3
C2H5
Cl H
CH3
C2H5
Fischer projections

83. Naming compounds with more
than one stereocenter
O FISCHER PROJECTION
1. Convention: The carbon chain is drawn along the vertical line
of the Fischer projection, usually with the most highly oxidized
end carbon atom at the top.
1) Vertical lines: bonds going into the page.
2) Horizontal lines: bonds coming out of the page

84. Allowed motions for Fischer
Projection
1. 180° rotation (not 90° or 270°):

85. 2. 90° rotation: Rotation of a Fischer projection by 90° inverts its
meaning.

86. 3. One group hold steady and the other three can rotate:
4. Differentiate different Fischer projections:

88. Configurations
O The particular arrangement of atoms in space that is
characteristic of a given molecule is called its configuration.
O Configurations are not the same as conformations.
O Conformations are inter convertible by rotation about single
bond(s) whereas bonds must be broken to change one
configuration into another.
O Two types of configurations.
1. Relative configuration (L and D),
2. Absolute configuration (R and S)

89. Specification of configuration
(Cahn - Prelog - Ingold rules)
O Step 1: assign a priority to the 4 atoms or groups of atoms
bonded to the tetrahedral stereogenic centre:
i. If the 4 atoms are all different, priority is determined by
atomic number. The atom of higher atomic number has the
higher priority.
ii. If two atoms on a stereogenic center are the same, assign
priority based on the atomic number of the atoms bonded to
these atoms. One atom of higher atomic number determines
the higher priority.

91. iii. If two isotopes are bonded to the stereogenic center,
assign priorities in order of decreasing mass number.
Thus, in comparing the three isotopes of hydrogen, the
order of priorities is:

92. iv. To assign a priority to an atom that is part of a multiple bond, treat
a multiply bonded atom as an equivalent number of singly bonded
atoms. For example, the C of a C=O is considered to be bonded to
two O atoms.
•Other common multiple bonds are drawn below:

93. O Examples of assigning priorities to stereogenic centers

97. Orienting the lowest priority group in back

98. 2,3-Dichloropentane
CH3-CH-CH-CH2-CH3
ClCl
* *
(2S,3S) (2R,3R)
H Cl
CH3
Cl H
C2H5
Cl H
CH3
H Cl
C2H5
(2S,3R) (2R,3S)
H Cl
CH3
H Cl
C2H5
Cl H
CH3
Cl H
C2H5

99. How many stereoisomers exist?
O Look at 2,3-dichlorobutane. Are there four different
isomeric forms?
O There are two tetrahedral stereogenic carbons.......2n?
CH3-CH-CH-CH3
ClCl
* *

100. 2,3-dichlorobutane
(2S,3S) (2R,3R)
(2S,3R)?
Cl H
CH3
H Cl
CH3
H Cl
CH3
Cl H
CH3
Cl H
CH3
Cl H
CH3
H Cl
CH3
H Cl
CH3

101. O Relative configuration compares the arrangement of
atoms in space of one compound with those of another.
O Absolute configuration is the precise arrangement of
atoms in space.
O Sugars and amino acids with same relative
configuration as (+)-glyceraldehyde were assigned D
and same as (-)-glyceraldehyde were assigned L.

102. D and L Assignments
CHO
H OH
CH2OH
D-(+)-glyceraldehyde
CHO
H OH
HO H
H OH
H OH
CH2OH
D-(+)-glucose
*
COOH
H2N H
CH2CH2COOH
L-(+)-glutamic acid
*
=>

103.  Regioselective reaction: preferential
formation of one constitutional
isomer
 Stereoselective reaction: preferential
formation of a stereoisomer

104. Stereospecific reaction: each stereoisomeric reactant
produces a different stereoisomeric product or a
different set of products
 All stereospecific reactions are stereoselective.
 Not all stereoselective reactions are stereospecific.

105. Axial Chirality
O Though “optical activity due to axial chirality” was first reported
by Christie and Kenner in 1922.
O Nonplanar arrangement of four groups about an axis

106. Atropisomers - stereoisomers resulting from restricted rotation
about a single bond

107. O The term “Atropisomerism” was coined by Richard Kuhn later in
1933.
O From Greek: a – not
O tropos – to turn
O Atropisomerism is that kind of isomerism, where the conformers
(called atropisomers) can be isolated as separate chemical species
and which arise from restricted rotation about a single bond.
O Axis of Chirality: An axis about which a set of atoms/functional
groups/ligands is held so that it results in a spatial arrangement that
is not superimposable on its mirror image.

108. Conditions for Atropisomerism
1. Two necessary preconditions for axial chirality are:
i. a rotationally stable axis
ii. Presence of different substituents on both sides of the axis
2. Atropisomers are recognised as physically separable species when,
at a given temperature, they have a half life of at least 1000 s.
3. The minimum required free energy barriers at different
temperatures are as below.

109. 4. The configurational stability of axially chiral biaryl compounds is
mainly determined by three following factors:
i. The combined steric demand of the substituents in the proximity
of the axis
ii. The existence, length, and rigidity of bridges
iii. Atropsiomerization mechanism different from a merely physical
rotation about the axis, e.g. photochemically or chemically induced
processes.

110. Nomenclature of Atropisomers
1. Notations used for Atropisomers:
aR (axially Rectus) or P (plus)
aS (axially Sinister) or M (minus)
2. Priority of the substituents are determined by the CIP rule.
3. Here it is assumed that priority of A>B and A’>B’.

112. Classification of Atropisomers
The following classification is based upon the basic structure of the
“Biaryl Atropisomers”.

113. Examples of Natural Bridged
Atropisomers

114. Examples of Natural non-bridged
Atropisomers

115. Uses of Atropisomers

116. Chiral Allenes: General Information

118. Some Facts About Chiral Allenes
O The rotation barrier to stereoisomerization of chiral allenes amounts
to 195 kJ/mol for 1,3-dialkylallenes and to > 125 kJ/mol for
1,3diarylallenes, while the threshold for isolation of stereoisomers
at 20ᵒ C is 83 kJ/mol.
O Higher cumulenes - pentatetraenes and heptahexaenes - have lower
rotation barrier.
O Thus, only few enantioenriched pentatetraenes and no
heptahexaenes are known.
O Cumulated double bonds in allenes are strained. Upon undergoing
any addition reaction it experiences a relief in strain of about 40
kJ/mol.

119. O In allenes, the central carbon is sp bonded. The remaining two p
orbitals are perpendicular to each other and each overlaps with the p
orbital of one adjacent carbon atom, forcing the two remaining bonds
of each carbon into perpendicular planes. Thus allenes fall into the
category represented by Fig. 4.2: Like biphenyls, allenes are chiral
only if both sides are unsymmetrically substituted.

120. These cases are completely different from the cis–trans isomerism of
compounds with one double bond (p. 182). In the latter cases, the four
groups are all in one plane, the isomers are not enantiomers, and
neither is chiral, while in allenes the groups are in two perpendicular
planes and the isomers are a pair of optically active enantiomers.

121. O When three, five, or any odd number of cumulative double bonds
exist, orbital overlap causes the four groups to occupy one plane and
cis–trans isomerism is observed. When four, six, or any even number
of cumulative double bonds exist, the situation is analogous to that in
the allenes and optical activity is possible.

122. Conformational isomers
 ‘Different arrangements of atoms that can be converted
into one another by rotation about single bonds are called
conformations’. 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. 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 s bond.

123. O 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.

126. O 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. Using these
methods, the staggered and eclipsed conformers of ethane can be
drawn as follows.

127. 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.

128. O As a result, eclipsed conformers are unstable. At any
moment, more molecules will be in staggered form
than any other conformation.
O Torsional energy and torsional strain
O Torsional energy is the energy required for rotating
about the C–C s bond. In ethane, this is very low (only
3 kcal). Torsional strain is the strain observed when a
conformer rotates away from the most stable
conformation (i.e. the staggered form).

129. O Torsional strain is due to the slight repulsion between
electron clouds in the C–H bonds as they pass close by
each other in the eclipsed conformer. In ethane, this is
also low.

130. Conformational isomerism in
propane
O Propane is a three-carbon- (sp3- hybridized) atom-
containing linear alkane. All are tetrahedrally arranged.
When a hydrogen atom of ethane is replaced by a
methyl (CH3) group, we have propane. There is rotation
about two C–C s bonds.

131. In the eclipsed conformation of propane, we now have a
larger CH3 close to H atom. This results in increased
repulsive force or increased steric strain. The energy
difference between the eclipsed and staggered forms of
propane is greater than that of ethane.

133. Conformational isomerism in
butane
O Butane is a four-carbon- (sp3- hybridized) atom-
containing linear alkane. All are tetrahedrally arranged.
When a hydrogen atom of propane is replaced by a
methyl (CH3) group, we have butane. There is rotation
about two C–C s bonds, but the rotation about C2–C3 is
the most important.

134. Among the conformers, the least stable is the first eclipsed structure,
where two CH3 groups are totally eclipsed, and the most stable is the
first staggered conformer, where two CH3 groups are staggered, and
far apart from each other.
When two bulky groups are staggered we get the anti conformation,
and when they are at 60º to each other, we have the gauche conformer.
In butane, the torsional energy is even higher than in propane. Thus,
there is slightly restricted rotation about the C2–C3 bond in butane.

135. O The order of stability (from the highest to the lowest)
among the following conformers is anti Gauche another
eclipsed eclipsed. The most stable conformer has the
lowest steric strain and torsional strain.

137. Conformational isomerism in
Cyclopropane.
O Cyclopropane is the first member of the cycloalkane
series, and composed of three carbons and six hydrogen
atoms (C3H6). The rotation about C–C bonds is quite
restricted in cycloalkanes, especially in smaller rings,
e.g. cyclopropane.

138. O In cyclopropane, each C atom is still sp3-hybridized, so
we should have a bond angle of 109.5º, but each C
atom is at the corner of an equilateral triangle, which
has angles of 60º As a result, there is considerable
angle strain. The sp3 hybrids still overlap but only just!
This gives a very unstable and weak structure. The
angle strain can be defined as the strain induced in a
molecule when bond angle deviates from the ideal
tetrahedral value. For example, this deviation in
cyclopropane is from 109.5 to 60º.

139. Conformational isomerism in
cyclobutane
O Cyclobutane comprises four carbons and eight hydrogen
atoms (C4H8). If we consider cyclobutane to have a flat or
planar structure, the bond angles will be 90º, so the angle
strain (cf. 109.5º) will be much less than that of
cyclopropane. However, cyclobutane in its planar form will
give rise to torsional strain, since all H atoms are eclipsed.

140. Cyclobutane, in fact, is not a planar molecule. To reduce
torsional strain, this compound attains the above nonplanar
folded conformation. Hydrogen atoms are not eclipsed in this
conformation and torsional strain is much less than in the
planar structure. However, in this form angles are less than
90º, which means a slight increase in angle strain.

141. Conformational isomerism in
cyclopentane
O Cyclopentane is a five carbon cyclic alkane. If we
consider cyclopropane as a planar and regular pentagon,
the angles are 108º. Therefore, there is very little or
almost no angle strain (cf. 109.5º for sp3 hybrids).
However, in this form the torsional strain is very large,
because most of its hydrogen atoms are eclipsed.

142. O Thus, to reduce torsional strain, cyclopentane twists to adopt a
puckered or envelope shaped, nonplanar conformation that strikes
a balance between increased angle strain and decreased torsional
strain. In this conformation, most of the hydrogen atoms are almost
staggered.

143. O Conformational isomerism in cyclohexane Cyclohexane (C6H12) is
a six-carbon cyclic alkane that occurs extensively in nature. Many
pharmaceutically important compounds possess cyclohexane rings,
e.g. steroidal molecules. If we consider cyclohexane as a planar and
regular hexagon, the angles are 120º (cf. 109.5º for sp3 hybrids).

144. O Again, in reality, cyclohexane is not a planar molecule. To strike a
balance between torsional strain and angle strain, and to achieve
more stability, cyclohexane attains various conformations, among
which the chair and boat conformations are most significant. At any
one moment 99.9 per cent of cyclohexane molecules will have the
chair conformation. The chair conformation of cyclohexane is the
most stable conformer. In the chair conformation, the C–C–C angles
can reach the strain free tetrahedral value (109.5º), and all
neighbouring C–H bonds are staggered. Therefore, this
conformation does not have any angle strain or torsional strain.

145. O Another conformation of cyclohexane is the boat conformation.
Here the H atoms on C2–C3 and C5–C6 are eclipsed, which
results in an increased torsional strain. Also, the H atoms on C1
and C4 are close enough to produce steric strain.
O In the chair conformation of cyclohexane, there are two types
of position for the substituents on the ring, axial (perpendicular
to the ring, i.e. parallel to the ring axis) and equatorial (in the
plane of the ring, i.e. around the ring equator) positions.

146. O Six hydrogen atoms are in the axial positions and six others in the
equatorial positions. Each carbon atom in the cyclohexane chair
conformation has an axial hydrogen and an equatorial hydrogen
atom, and each side of the ring has three axial and three equatorial
hydrogen atoms.