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Module 8 Stereochemistry
Lecture 20 Stereochemistry I
Stereochemistry is the study of the relative arrangement of atoms or groups in a molecule
in three dimensional space. Stereochemical isomers are molecules, which have the same
chemical formula and bond connectivity but different relative arrangement in three-
dimensional space. In contrast, constitutional isomers have same molecular formula but
different bond connectivity. Thus, n-butane and isobutane are structural isomers while the
isomers of limonene, the compound which gives different taste to lemon and orange are
examples of stereochemical isomers (Figure 1).
CH3 CH3

CH3
CH3
H3C H3C CH3

n-butane isobutane H3C H3C

structural isomers (+)-limonene (-)- limonene

"orangy taste" "lemony taste"
Stereoch i l isomers
em ca

Figure 1

To understand the difference between the two isomers of limonene, introduction to some
new terms and concepts are required. The most important being the concept of chirality.
A chiral object is one that cannot be superposed on its mirror image. The term originates
from the greek term for “hand”. As it is with human hands, the left hand cannot be
superimposed on the right hand. It is the same with chiral molecules. They are non-
superimposable mirror images of each other. Achiral objects, on the other hand, are easily
superimposable on each other. A tennis racquet and a spoon are examples of achiral
objects.

The next question that comes to the mind is how to determine whether a molecule is
chiral or achiral. At times, it becomes extremely difficult to determine with increasing
molecular complexity, to determine the non superimposibity of a compound with its
mirror image. Thus, a mathemathical concept known as group theory can be applied to
determine the symmetry elements in a molecule. There are four symmetry elements
which needs to be considered for this purpose:

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• Centre of symmetry(i): The center of symmetry i is a point in space such that if a

line is drawn from any part (atom) of the molecule to that point and extended an
equal distance beyond it, an analogous part (atom) will be encountered. Thus the
molecule 3,6-dimethylpiperazine-2,5-dione has centre of symmetry (sometimes
referred to as centre of inversion) running through the centre of the molecule.

H
O N CH3

H3C N O
H

• Plane of symmetry (σ): A plane of symmetry is a reflection plane which brings

into coincidence one point of the molecule with another one through the mirror
reflection. Thus, glyoxal has a plane of symmetry running through the molecular
plane.
σ
H O

O H

• Axis of symmetry (Cn): Symmetry axis Cn, also called n-fold axis, is an axis
which rotates the object (molecule) around by 360°/n, such that the new position
of an object is superimposable with the original one. For example, (1Z,4E,8E)-
3,7,11-trimethylcyclo-dodeca-1,4,8-triene has 3-fold rotation axis.
H3C

CH3
C3

CH3

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• Rotary reflection axis (Sn): Rotary reflection axis is an axis which rotates the
object (molecule) around by 360°/n, followed by rotation in a plane perpendicular
to the axis, such that the new position of an object is superimposable with the
original one. All odd values of Sn are identical with Cn. Thus, in 1, there is a 4-
fold rotary reflection axis.
H3C CH3

H3C CH3
(1)

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If a molecule has only either centre of symmetry or plane of symmetry then it is achiral.
However, in most cases, molecules have more than one element of symmetry. In such
cases, it becomes important to know the point group to which the molecule belongs. A
point group reflects the combination of symmetry elements present in the structure. The
point group of a molecule can be determined by following the algorithm given below.
The point groups of high symmetry are usually not important in simple organic
molecules. The point groups C1, Cn and Dn are chiral groups and they contain chiral
molecules while all other groups are achiral (Figure 2).

Yes
Group of Low Symmetry C1,Cs,Ci

No

Group of High Yes

Td, Oh, Ih, C∞v, D∞h
Symmetry

No

Highest Order
Rotational Axis

Cn

Yes Perpendicular No
D groups C or S groups Cn
C2 Axes

No

σh No No σh No σv No
σd Dn S2n

Yes Yes Yes

Yes

Dnh Dnd Cnh Cnv Cnv

Figure 2

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Enantiomers

If a molecule is non-superimposable on its mirror image, then the molecule is said to

have enantiomeric relationship with its mirror image molecule. For example, in 2-
chloropropane, the molecule is superimposable with its mirror image, so they are
identical molecules, but in 2-chlobutane, the molecule is not superimposable with its
mirror image and the two molecules are called enantiomers (Figure 3). Thus, enantiomers
are stereoisomers since they differ only in the relative arrangement of the different groups
in space but not in bond connectivity. Enantiomers are identical in all physical properties
(except optical rotation) and chemical properties and reactivity compared to an achiral
reagent in reactivity
mirror

Cl Cl Cl
Cl all groups align
theref ore, molecules are
Me Me Me Me Me Me superimposable
H H Me H Me
H
2-Chloropropane

Cl
Cl Cl Cl
two groups f ail to align
Me Et theref ore, molecules are
Me Et Et Me Et H Me nonsuperimposable
H H H

2-Chlorobutane

Figure 3

Obviously, the next issue is how to detect and analyse the enantiomers physically. In this
respect, in 1801, Haüy, a French mineralogist observed that some quartz crystals rotate
polarized light clockwise, while other crystals rotate polarized light to the left. Haüy also
noticed that quartz crystals exhibit the phenomenon of hemihedrism (externally, some
crystals are non-identical mirror images of other crystals). This is referred to as optical
activity. Followed by this, J. B. Biot observed the optical activity in certain organic
compounds and was able to conclude that it is a molecular property. In 1884, Louis
Pasteur in an ingenius experiment crystallized and physically separated two types of
crystals of tartaric acid –one of which was hemihedral to the left while the other was

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hemihedral to the right. When he dissolved the two forms separately and measured their
optical rotation, he observed that the crystals having the hemihedral to the left rotated the
plane of polarized light to the left and vice-versa. Louis Pasteur thus proposed that the
two forms of tartaric acid are mirror image of each other (enantiomers).
The optical activity of a compound was found to be proportional to
• The concentration of the compound in solution (c)
• The length through light traverses through the solution (l)
• The wavelength used for the measurement (λ) and the temperature at which the
measurement is made (t). Usually, the sodium D-line is used for polarimetric
measurement.
Mathematically,
α = [α]Dlc at temperature t
where [α] is the constant of proportionality
The constant of proportionality [α] is called specific rotation and is defined as
the optical rotation in degrees of the plane of polarization of a ray of
monochromatic light that passes through a tube 1 decimeter long containing the
substance in solution at a concentration of 1 gram per millimeter in a
polarimeter.

An enantiomer will thus rotate the plane of polarized light either clockwise or
anticlockwise. The clockwise rotation is usually denoted by either of the prefix dextro or
(+). Similarly anticlockwise rotation is denoted by laevo or (-). Thus, an equimolar
mixture will not give any optical rotation at all. Such a mixture is referred to as a racemic
mixture.

Whether a particular sample consists of a single enantiomer or a mixture of enantiomers

can be determined by its observed specific rotation. For example, an enantiomerically
pure sample-meaning only one enantiomer is present-of (S)-(+)-2-bromobutane will have
an observed specific rotation of +23.1° because the specific rotation of (S)-(+)-2-
bromobutane is +23.1°. If, however, the sample of 2-bromobutane has an observed
specific rotation of 0°, we will know that the compound is a racemic mixture. If the
observed specific rotation is positive but less than +23.1°, we will know that we have a

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mixture of enantiomers and the mixture contains more of the enantiomer with the S
configuration than the enantiomer with the R configuration. From the observed specific
rotation, we can calculate the optical purity of the mixture.

observed specif ic rotation

optical purity = x 100
specif ic rotation of the pure enantiomer

For example, if a sample of 2-bromobutane has an observed specific rotation of +9.2°, its
optical purity is 0.40. In other words, it is 40% optically pure-40% of the mixture consists
of an excess of a single enantiomer.

+9.2°
optical purity = x 100 = 40%
+23.1°

Because the observed specific rotation is positive, we know that the solution contains
excess (S)-(+)-2-bromobutane. The enantiomeric excess (ee) tells us how much excess
(S)-(+)-2-bromobutane is in the mixture. As long as the compound is chemically pure,
enantiomeric excess and optical purity will be the same.

excess of a single enantiomer

enantiomeric excess = x 100%
entire mixture
40%
= x 100% = 40%
100%

If the mixture has a 40% enantiomeric excess, 40% of the mixture is excess S enantiomer
and 60% is a racemic mixture. Half of the racemic mixture plus the amount of excess S
enantiomer equals the amount of the S enantiomer present in the mixture. Thus, 70% of
the mixture is the S enantiomer and 30% is the R enantiomer.

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Another class of stereoisomers is the so called diastereomers which have different

chemical and physical properties. Such compounds may include geometrical isomers- the
cis and trans isomers (Figutre 4).

H H H CH3

H3C CH3 H3C H

cis-but-2-ene trans-but-2-ene

Figure 4

A different type of isomerism may exist in disubstituted cyclic compounds. Thus, in 4-

tert-butylcyclohexanol, two isomers-cis and trans exist (Fig 5).

OH OH
H3C
≡ OH ≡ H3C
H3C H3C H3C
H3C
CH3 CH3
H3C CH H3C CH OH
3 3
ci s-4-t er t -butylcyclohexanol t rans-4-t er t -butylcyclohexanol
Figure 5

Diastereomeric compounds may or may not be chiral. The above two examples are both
achiral, each having a plane running through them. However, when cis and trans
epoxides are compared, it can be easily seen that they may be chiral compounds. As an
example, the comparison of cis and trans isomers of 2,3-dimethyloxirane, the cis-isomer
is achiral having a plane of symmetry in the molecule. However, the trans isomer does
not have any plane of symmetry through the molecule and as such it is a chiral molecule
(Figure 6).

O O O
H3C σ CH3 H3C CH3 H3C CH3

ci s-2,3-dimethyloxirane t rans-2,3-dimethyloxirane
Achiral compound Chiral compound

Figure 6

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A similar observation can be made for 3-methyloxirane-2-carboxylic acid but here both
the cis and trans isomers are chiral compounds each of which exist as a pair of
enantiomers (Figure 7).

O O O O
H3C COOH H3C COOH H3C COOH H3C COOH

ci s-3-methyloxirane-2-carboxylic acid t rans-3-methyloxirane-2-carboxylic acid

Figure 7

The term chiral centre used so far is actually a subset of the term stereogenic centre. A
stereogenic centre is defined as an element where the interchange of two substituents will
lead to a stereoisomer. Not all stereogenic centres are chiral centres and even achiral
molecules may have stereogenic centres.

The actual arrangement of the atoms or groups in a molecule about a stereocentre is

called absolute configuration. It is mostly determined by X-ray crystallography or by
inference based on chemical reactions of specific stereochemistry involving a compound
whose absolute configuration is known, whereas the relative configuration is defined as
the correlation between the different stereogenic centres within the molecule.

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Though, here, the enantiomers are represented in the flying wedge form where two of the
groups around the chiral centre are depicted in the plane of the paper and groups towards
us in bold bonds and groups away from us in broken bonds, there are other forms of
depictions of chiral compounds. These are discussed below.

• Fischer projection formula. It is a representation of a 3D molecule as a flat

structure where a tetrahedral carbon is represented as two crossed lines. The two
vertical bonds about the stereocentre are above the plane of paper (towards the
viewer) while the horizontal bonds are below the plane of the paper (away from
the viewer) (Figure 8).

Bo ndss beeloow
on w thee
annee oof paape
p lla err

erre
sste ennicc cceen
eoog e ntrree
≡≡
onndss a aboovve
e
≡≡
Bo
anne
hee p lla
tth eoof paapeerr

err prro
Fisscche onn
ojeecctio

Figure 8

A few examples of depiction of molecules in Fischer projection formula is given

below. It must be noted that when bonds are rotated by 180°, they result in the
same identical molecule (Figure 9).

HO H COOH
Ph H
Ph COOH
OH

NHCH3 H
Ph H3C NHCH3
CH3
H Ph
OH
OH

Figure 9

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• Sawhorse projection formula. Sawhorse projection formulas are used to denote

two principal stereocentres. It is a view of a molecule down a particular carbon-
carbon bond, with the groups connected to both the front and back carbons are
drawn using sticks at 120° angles. Sawhorse Projections can also be drawn so
that the groups on the front carbon are staggered (60 ° apart) or eclipsed (directly
overlapping) with the groups on the back carbon. The overall representation is
given below (Figure 10).
NHCH3 H3C 2 H
NHCH3
2 60° rotation
Ph 2 ≡ CH3 NHCH3
CH3 H OH
1 OH
OH 1 H 1 Ph
H Ph
Eclipsed Staggered

Figure 10

• Newmann projection formula. In this notion, the molecule is again viewed by

looking down a particular carbon-carbon bond. The front carbon of this bond is
represented by a dot, and the back carbon is represented by a large circle. The
three remaining bonds are drawn as sticks coming off the dot (or circle),
separated by one another by 120°. Just like Sawhorse projection formula,
Newman Projection can be drawn such that the groups on the front carbon are
staggered (60 ° apart) or eclipsed (directly overlapping) with the groups on the
back carbon (Fig 11).

OH HO OC O H HOOC
OHH
OH
6 0° rroota
atio
onn
C OO H OHH
H3 C
H H CH 3 H C H3
HH H
H
OH
ecclipsse
e ed ssta erre
ag ge ed

Figure 11

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Module 8 Stereochemistry
Lecture 21 Stereochemistry II
Keywords: Enantiomer, Configuration, Racemic, Diastereisomer, Purification
In order to convert from one depiction to another certain rules have to be followed.
Firstly, it must be noted that Fischer projection always depicts the molecule in eclipsed
form. Thus, whenever, a Fischer projection is converted to Newman or Sawhorse
projection, it results in an eclipsed form of the molecule which is then converted to the
more stable staggered form. Similarly, while converting a Newmann or a Sawhorse
projection to Fischer projection, the molecule must be first depicted in eclipsed form
before conversion.

For example, to convert a flying wedge projection to Fischer projection, firstly, the bonds
which are supposed to be on the plane are to be decided which must be two bonds, one
vertical and horizontal connected to a carbon (Figure 1). If the vertical bond to the right is
choosen, and the other horizontal bond is bent to the right, the remaining vertical bond
group is depicted above the plane.

OH OH OH OH
HOOC CH3 ≡ HOOC CH3 HOOC CH3 ≡ H3C COOH
H H H H

Figure 1

If on the other hand, if the vertical bond to the left is choosen, and the other horizontal
bond is bent to the right, the remaining vertical bond group is depicted below the plane
(Figure 2).

head
H Br CH3
H 1
1
H3C Br H3C 1 Br H
2 ≡ H H
H3C OH
H H3C 2 OH H3C 2 OH tails
Fischer projection eclipsed staggered

Figure 2

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Step1: Put the groups at the vertical bonds on the tails of the “Y” of sawhorse projection.

Step 2: Put the other groups on the head of “Y”.

In other words, imagine that C1-C2 bond is in plane of the paper and look across the C1-
C2 bond, the groups which are coming out of the plane of paper form the tails of “Y”
while the groups below the plane of the paper form the heads of “Y”.

In order to convert a molecule from Fischer projection to sawhorse projection, the

molecule has to be first depicted in eclipsed form. Then the steps outlined above are to
be carried out in a reverse manner (Figure 3).

C2H5 2 CH3 Br Br
180° rotation of C2 H3C C2H5
Br Br ≡
H3C C2H5 H3C C2H5
Br
C2H5 1 CH3 Br
C2H5 CH3
Sawhorse projection Fischer projection

Figure 3

In other words, again look along the C1-C2 bond as being the plane of paper, then the
groups lying above the paper form the vertical line while the groups below the paper
form the horizontal bonds in Fischer projection.

To convert a Sawhorse projection to Newmann projection look along the C1-C2 bond
through C1 such that C2 is not visible. Now the groups on C1 are same for both sawhorse
and Newmann projection. The C2 carbon is replaced by a circle and the bonds emanating
from C2 being retained in their actual spatial location (Figure 3).

COOH H OH H
2 H COOH
H OH
HO H ≡
H H H COOH ≡
1
H H H H
H H H COOH
H H

Line of sight
f rom C1 to C2
through C1-C2

Figure 3

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Now coming back to the issue to assign the relative configurations of a stereocentre,
several approaches were used. The first one being the stereochemical descriptor D/L
which relies on the chemical correlation of the configuration of the chiral center to D-
glyceraldehyde. The compounds which can be correlated without inverting the chiral
center are named D, those correlated to its enantiomer are designated as L. It is worth a
while to note that though D-glyceraldehyde is dextrorotatory (rotates the plane of
polarized light to the right), the compounds correlated to D-glyceraldehyde do not have to
be dextrorotatory and vice versa (Figure 4).

CHO CHO
H OH HO H
CH2OH CH2OH
D-glyceraldehyde L-glyceraldehyde

Figure 4

This system is not much in use today. However, traditionally it is still used for sugars and
amino acids. In cases of carbohydrates, only the carbon at the end of carbon chain is
considered for assigning D/L after writing the molecule in Fischer projection with the
anomeric carbon on the top. Now if the carbon at the end of chain (farthest from
anomeric carbon) has a hydroxyl group to the left, it is denoted as an L-sugar and it has a
hydroxyl group to the right, it is called a D-sugar (Figure 19).

CHO CHO CHO CHO

H OH H OH H OH HO H
HO H HO H HO H HO H
H OH HO H H OH H OH
CH2OH CH2OH H OH H OH
CH2OH CH2OH
D-Xylose L-arabinose D-glucose D-Mannose

Figure 5

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All naturally occurring amino acids are L-amino acids since they can be correlated with
L-glyceraldehyde with the most oxidized group at the top and amino group at left in
Fischer projection (Figure 6).

COOH COOH COOH

H2N H H2N H H2N H
CH3 CH2Ph CH2COOH
L-alanine L-phenylalanine L-aspartic acid

Figure 6

The Cahn-Ingold-Prelog convention is the most widely accepted system for naming the
configurations of chirality centers. Each asymmetric carbon atom is assigned a letter (R)
or (S) based on its three-dimensional configuration. To determine the name, we follow a
two-step procedure that assigns "priorities" to the four substituents and then assigns the
name based on the relative positions of these substituents. The procedure follows:

• Rank the groups (or atoms) bonded to the asymmetric carbon in order of
priority. The atomic numbers of the atoms directly attached to the asymmetric
carbon determine the relative priorities. The higher the atomic number, the
higher the priority.

Examples of priority for atoms bonded to an asymmetric carbon:

I > Br > Cl > S > F > O > N > 13C > 12C > Li > 3H > 2H > 1H

3
CH3
2
1 F NH2
H
4

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• In case of ties, use the next atoms along the chain of each group as tiebreak-
ers. For example, we assign a higher priority to isopropyl -CH(CH3)2 than to
ethyl -CH2CH3 or bromoethyl -CH2CH2Br. The first carbon in the isopropyl
group is bonded to two carbons, while the first carbon in the ethyl group (or
the bromoethyl group) is bonded to only one carbon. An ethyl group and a -
CH2CH2Br have identical first atoms and second atoms, but the bromine atom
in the third position gives -CH2CH2Br a higher priority than -CH2CH3. One
high-priority atom takes priority over any number of lower-priority atoms.

2
CH2CH2Br
3 4
H3CH2C H
CH(CH3)2
1

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• Treat double and triple bonds as if each were a bond to a separate atom. For
this method, imagine that each pi bond is broken and the atoms at bothends
duplicated. Note that when you break a bond, you always add two imaginary
atoms. (Imaginary atoms are circled below.)

H H H H
R C C becomes R C C H
H C C
break and duplicate
H H H H
R C N becomes R C N
N C
break and duplicate

C C
R C C H becomes R C C H
C C
break and duplicate

OH OH

R C O becomes R C O
O C
break and duplicate

• Using a three-dimensional drawing or a model, put the fourth-priority group

away from you and view the molecule along the bond from the asymmetric
carbon to the fourth-priority group. Draw an arrow from the first-priority
group, through the second, to the third. If the arrow points clockwise, the
asymmetric carbon atom is called (R). If the arrow points counter-clockwise,
the chiral carbon carbon atom is called (S).

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A few examples are given to clarify the assignment of priority and configuration.

O OH
COOH COOH
C counterclockwise 2 2 clockwise
2 4 4
4 C C
C H H
H H3C CH3
H3C NH2 H2N
NH2 3 3
3 1 1
1
alanine natural (S)-alanine unnatural (R)-alanine

Here, the order of priority is assigned as follows:

Following rule 1, amino group gets first priority.

Following rule 3, carboxylate group gets second priority as shown below.

O (C) O (O)
becomes
OH OH

Following rule 2, methyl group gets third priority over hydrogen.

3
CH3 CH
anticlockwise 3
H H4
Br C3H7 B r C3H7
2-bromopentane 1 2
S-2-bromopentane

Here, the order of priority is assigned as follows:

Following rule 1, bromo group gets first priority.

Following rule 2, propyl group gets second priority ahead of methyl group.

Following rule 2, methyl group gets priority over hydrogen.

1
H3C Br 4 H3C Br
O O
3 2

2-bromo-2-methylcyclohexanone (S)-2-bromo-2-methylcyclohexanone

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Here, the order of priority is assigned as follows:

Following rule 1, bromo group gets first priority.

Following rule 3, carbonyl group gets second priority.

O
becomes (C) O (O)

H H
Following rule 2, group gets third priority over methyl.

CH3 CH3 CH3 CH3

2 1 ≡ 1
R=
Br R Br
H OH OH

Here, for C1, the priority order is set to be as follows.

Following rule 1, hydroxyl group gets first priority.

Following rule 3, ethenyl group gets second priority ahead of R and methyl groups.

becomes (C)
(C)

Following rule 2, R group gets priority over methyl.

4 1
CH3 OH CH3
2 3 S
≡ R=
Br
3 R R CH3
OH
4
1
2

Since, in this case, the lowest priority group is on the plane and not below it, so, it is
converted to an identical form by keeping one of the groups on plane constant and
rotating the other 3 groups clockwise. Now, it can be seen that the configuration is S.

CH3 CH3 CH3

2 1 ≡ 2
Br Br R
H OH H

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Here, the priority order is decided as follows:

Following rule 1 bromo gets first priority

Following rule 2, R gets second priority

Following rule 2, methyl gets third priority.

3
CH3 CH3
1 S
Br 2 R 2 R=
H OH
4

Hence the molecule is

CH3 CH3
2 1
Br
H OH
(3S,7S)-7-bromo-3-methyloct-1-en-3-ol

Sometimes, the determination of configuration of a compound drawn as a Fischer

projection is necessary. The rules are given below.

• Rank the groups (or atoms) that are bonded to the asymmetric carbon in order
of priority.

• Draw an arrow from the group (or atom) with the highest priority (1) to the
group (or atom) with the next highest priority (2). If the arrow points
clockwise, the enantiomer has the R configuration; if it points anti-clockwise,
the enantiomer has the S configuration, provided that the group with the
lowest priority (4) is on a vertical bond.

1 1
3 Cl Cl 3
H3CH2C CH2CH2CH3 H3CH2CH2C CH2CH3
H 2 2 H
4 4
(R)-3-chlorohexane S
( )-3-chlorohexane

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• If the group (or atom) with the lowest priority is on a horizontal bond, the
answer you get from the direction of the arrow will be the opposite of the
correct answer. For example, if the arrow points clockwise, suggesting that the
asymmetric carbon has the R configuration, it actually has the S configuration;
if the arrow points counter clockwise, suggesting that the asymmetric carbon
has the S configuration, it actually has the R configuration. In the following
example, the group with the lowest priority is on a horizontal bond, so
clockwise signifies the S configuration, not the R configuration.

3 3
CH3 CH3
4H OH 1 1 HO H4
2 CH2CH3 2 CH2CH3

(S)-2-butanol (R)-2-butanol

An example for finding configuration of a compound using Fischer projection formal is

provided below.

D-Mannose
CHO 2 2 2 CHO
1 R1 4 1
H OH CHO 1 R1 1 H OH
4 ≡ ≡
HO 2 H ≡ H 1 OH ≡ HO 2
H HO 3 H HO 2
H
HO 3 H
R1 1 R2 CH2OH HO 3 H

CH2OH 3 3 3 CH2OH
R S S
L-arabinose (2R,3S,4S)-arabinose

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In case of nomenclature of unsaturated diastereomeric compounds which are geometric

isomers, a different nomenclature is allowed. However, the CIP rules for determining
priority are still used. Then the groups on each carbon of the double bond are marked
according to priority. Now if the groups having higher priority are on the same side, then
the group is labelled Z (Zusamenn- german for together) while if the groups of higher
priority are not on the same side of the double bond then the compound is labelled as E
(Entgegen –german for opposite)This system may be understood from the examples
below.

a b If priority order is a>b, c>d then copmound is Z-compound

c d If priority order is a>b, c<d then copmound is E-compound

1 1 1 2
H3C CH3 H3C H

H H H CH3
2 2 2 1
cis-butane trans-butane
( )-but-2-ene
Z (E)-but-2-ene

Br Br
≡ ≡
H3C H3C R R1 I
I
4-bromo-1-iodopent-1-ene

For the chiral centre,

Following rule 1, bromo group gets first priority

I
Following rule 3, group gets second priority.

I
I ≡
(I) (C)

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Following rule 2, methyl group gets third priority.

1
Br
3 2 I
H3C R R≡
S

For the alkene part, priority order is as follows.

Following rule 1, iodo group gets first priority on C1.

Following rule 3, R1 gets first priority on C2.

2 2
H H
2 1
R1 I
1 1
Z

Br

H3C
I
(R,Z)-4-bromo-1-iodopent-1-ene

The discussion so far concerns the enantiomers only on paper, but to separate them
experimentally is altogether new ball game. The process of separating a racemic mixture
into its component enantiomers is called resolution. Historically, Louis Pasteur had
resolved tartaric acid by crystallization and then separating the enantiomers by tweezers
on the basis of hemihedral faces. However, as Pasteur said “Chance favours the prepared
mind”, he was indeed fortuitous in this case. As it happened, he prepared the solution of
racemic tartaric acid below 23 °C. Had the temperature been any higher, he would have
got crystals having both the enantiomers i.e.; racemic crystals. If the enantiomers in
racemic mixture crystallize out of solution as pure enantiomers, then the enantiomers are
said to form a conglomerate. It is usually rare and also depends on temperature and
therefore the process is mainly of historical interest only. Sometimes seeding by the
optically pure crystals of one enantiomer causes it to preferentially come out of solution.

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A method that can be used practically is the based on the fact that enantiomers same
physical and chemical properties but not diastereomers. This process involves the
conversion of an enantiomer to a diastereomer by treating with a chiral reagent. The
diastereomers are then separated by the usual methods. The separated diastereomers are
then treated with appropriate reagents to regenerate the original enantiomers. An example
of this method is the resolution of a racemic mixture of chiral acids by treatment with an
optically pure base (Figure 7).

N
COOH COOH H COO- B+ COO-B+
O H
OH OH H3C (B:) OH OH
+ H H
H3C N
O O
(±)-2-hydroxy-2-phenylacetic acid O
Mixture of diastereomeric salts
(-)-brucine

COO-B+ COO- B+

OH + OH

Separated by crytallization

H+ H+

COOH COOH

OH OH

Figure 7

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Module 8 Stereochemistry
Lecture 22 Stereochemistry III
Beside the formation of diastereomeric salts, enantiomers can be separated by resolution.
Here, enantiomers react with chiral inclusion hosts to form diastereomeric inclusion
complexes. This is called chiral recognition. So, if a particular host is employed, only one
enantiomer forms inclusion complex while other remains in solution. However, mostly,
both of the enantiomers form complexes but vary in the rate of formation of inclusion
complexes. An example of this technique is the use of crown ether for the resolution of 1-
phenylethanaminium hexafluorophosphate in chloroform (Figure 1).

O
O O Me
PF6-
O O
Ph NH3
O
(±)-1-phenylethanaminium hexafluorophosphate(V)
(1)

CHCl3

O Me O Me
PF6- PF6-
O O O O
Ph NH3 Ph NH3
O O O O
O (R) O (S)

(2) R:S = 2:1 (3)

Figure 1

Similarly, enantiomers react at the same rate only with achiral reagents, but react
differently with chiral reagents can be used to separate the enantiomers in a process
called Kinetic Resolution. An example of application of this technique is the resolution of
allylic alcohols with an enantiomer of chiral epoxidizing agent. In this case, only the (R)
enantiomer was converted to the epoxide while the (S) isomer was unaffected. However,
this method is sacrificial in nature as the recovery of one enantiomer often leads to the
destruction of the other (Figure 2).
Chiral epoxizing O
CH3 agent CH3 + CH3
OH OH OH
± −
( ) hept-1-en-3-ol (1R)-1-(oxiran-2-yl)pentan-1-ol (S)-hept-1-en-3-ol
Figure 2

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A variation of the sacrificial method for the resolution of a racemate involves treating it
with some bacteria which contains a chiral enzyme that reacts at different rate with the
different enantiomers. Since enzymes are very specific in their response to enantiomers,
only one enantiomers is degraded and the other enantiomer is obtained with a very high
purity (ee). This method however has only limited scope as the availability of such
organisms or enzymes cannot be met easily. Thus, the enzyme emulsion from bitter
almonds acts upon (±)-mandelonitrile to hydrolyze the (+)-form more rapidly.

With the advent of technology, column chromatography, the definitive tool for separation
of organic compounds can also be applied for separation of enantiomers. The principle
for the separation remains the same-differential adsorption-one enantiomer binds with the
chiral stationary phase more strongly than the other thereby causing them to have
different retention time in the column. Chiral stationary phase can consist of starch,
which for instance allows almost complete resolution of mandelic acid (2-hydroxy-2-
pheylethanoic acid), PhCH(OH)COOH. Synthetic stationary phases such as A, derived
from the enantiomerically pure amino acid alanine, and B, likewise from valine, are
effective in resolution of alcohols, amines and amino acids (both α and β) ( Figure 3).

Et Et
Me O iPr O
H O H O
N O Si N O Si
O 11
O
H 11 H
O O

A B

Figure 3

So far, all stereoisomers discussed differ in configuration but a separate class of

stereoisomers also exist which are called conformational isomers. The difference between
them being that in a set of conformational isomers, the isomers can be converted from
one isomer to the other by mere rotation of bonds. On the other hand, configurational
isomers cannot be achieved in this fashion. A bond needs to be broken and reconnected at
the same stereocentre in a different spatial arrangement to obtain a configurational isomer
from another.

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As an example, the molecule of ethane is to be considered. Now, it cannot possibly have

any configurational isomers since none of the carbons are dissymmetric. However, it may
have conformational isomers. The atoms remain connected in the same order during
conformational change. If the C1-C2-bond is considered in ethane, then it is possible to
draw two structures, one in which the hydrogen atoms on one of carbon atoms eclipse the
other and another where they are as far away from each other as possible. There is a
difference in energy between the two structures. The eclipsed form has a higher potential
energy than the staggered form (12 kJ mol-1) (Figure 4).

staggered eclipsed
f urther C atom
H HH
H H

H
H H H H
nearer C atom H
H

Figure 4

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The rotational barrier in this case is said to be 12 kJ mol-1. This is the energy required to
convert the stable staggered form to the unstable eclipsed form (Figure 5). The change in
energy on going from staggered form to eclipsed form and vice versa is plotted in with
respect to the dihedral angle. The angle between two intersecting planes on a third plane
normal to the intersection of the two planes is called dihedral angle. In this case the
dihedral angle is angle between the planes containing the atoms 1 and 2 and the plane
containing the atoms 3 and 4.

H 2 H

1H H
3H 4 H

eclipsed eclipsed eclipsed

12
relative energy /KJmol-1

0
staggered staggered staggered

0 60 120 180 240 300 360

dihedral angle θ

Figure 5

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The conformational analysis of ethane is given below. Thus, between these two extremes,
there are lots of other conformations and energy change is gradual is nature. However,
this does not mean that the ethane spends equal time in all conformations. In fact it
mostly stays at the bottom of the potential well (staggered conformation). Obviously, it
comes to mind whether the hydrogen atoms are bulky enough to cause a change in the
energy states of the eclipsed and staggered conformation. As a matter of fact, this occurs
due to the fact that the electrons in the bonds repel each other and this repulsion is at a
maximum in the eclipsed conformation. There

eclipsed: ered:
staggσ∗

H H
σ H
H H and empty C-H σ*
H antibonding orbital
H H
H H
H H stabilizing interaction
filled orbital repel between filled C-H σ bond

Figure 6

may be some stabilizing interaction between the C–H σ-bonding orbital on one carbon
and the C-H σ* anti-bonding orbital on the other carbon, which is greatest when the two
orbitals are exactly parallel: this only happens in the staggered conformation (Figure 6).

As the hydrocarbon chain size increases, more complex effects seem to effect the energy
considerations of the conformations (Figure 7). In the conformational study of propane,
the conformational analysis can be done either along the C1-C2 bond or the C2-C3 bond-
both being identical. In this case, the rotational barrier being 14 kJmol-1 is only slightly
more than that of ethane. Thus the conformational analysis diagram is almost similar to
ethane.

H Me Me
Me H H H Me H
H
H H
H H H H H H
H H H H H
H
the staggered conf ormation of propane the eclipsed conf ormation of propane

Figure 7

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With butane, there are two methyl groups if we consider the C2-C3 bond as the pivotal
bond for rotation. Here, the two methyl groups could eclipse each other in a conformation
and since the steric hindrance due to this should be significant enough, so the potential
energy will be highest for this conformation. The other eclipsed conformations will have
a methyl group eclipsed by hydrogen which will be lower in energy than the former.
Similarly, for the staggered conformations, there will two types of staggered
conformations differing in energy. Hence the terms eclipsed and staggered are
insufficient to describe the conformations.

A new system of naming the conformational isomers is thus devised (Figure 8). The term
torsion angle is defined as the angle (having an absolute value between 0° and 180°)
between bonds to two specified groups, one from the atom nearer (proximal) to the
observer and the other from the further (distal) atom in a Newman projection. The torsion
angle between groups A and D is then considered to be positive if the bond A-B is rotated
in a clockwise direction through less than 180° in order that it may eclipse the bond C-D:
a negative torsion angle requires rotation in the opposite sense. Stereochemical
arrangements corresponding to torsion angles between 0° and ±90° are called syn (s),
those corresponding to torsion angles between ±90° and 180° anti (a). Similarly, the
arrangements corresponding to torsion angles between 30° and 150° or between -30° and
-150° are called clinal (c) and those between 0° and 30° or 150° and 180° are called
periplanar (p). The two types of terms can be combined so as to define four ranges of
torsion angle; 0° to 30° synperiplanar (sp); 30° to 90° and -30° to -90° synclinal (sc); 90°
to 150°, and -90° to -150° anticlinal (ac); ±150° to 180° antiperiplanar (ap). The
synperiplanar conformation is also known as the syn- or cis-conformation; antiperiplanar
as anti or trans and synclinal as gauche or skew.

synperiplanar
0°
-30° +30°

- synclinal + synclinal
-90° +90°
- anticlinal + anticlinal

-150° +150°
antiperiplanar

Figure 8

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According to this system, the conformational isomers of butane due to rotation about the
C2-C3 bond may be named as:

H3C CH3 CH3 H CH3 CH3

H CH3 H H
rotate 60° rotate 60° rotate 60°
H CH3
H H H H H H H H
H H
H CH3
synplanar (sp) +synclinal (+sc) +anticinal(+ac) antiperiplanar (ap)

rotate 60°
CH3 H CH3
H3C H
rotate 60°
H
H H H H
H3C
H
-synclinal (-sc) -anticinal(-ac)

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Thus, the conformational analysis diagram of the different conformational isomers of n-

butane due to rotation about C2-C3 bond as a function of dihedral angle is given below
(Figure 10). As expected the synperiplanar conformer having methyl groups eclipsed
with each other has the highest energy and is least stable. The other eclipsed
conformations have lower energy than the synperiplanar conformer. These are the two
anticlinal conformations. The staggered conformers also show a similar pattern. Thus,
there are two synclinal conformers (also called gauche conformers) where the two methyl
groups are at an angle of 60° to each other. If we consider angle of torsion the then the
two anticlinal conformers may be differentiated according to the sense of rotation of the
angle of torsion. Thus they may be termed as +anticlinal (P-gauche) for a positive angle
of torsion or –anticlinal (M-gauche) for a negative angle of torsion. The anticlinal
conformations may also be prefixed with + or – to denote the angle of torsion.

syn-periplanar syn-periplanar

Me Me Me Me
H anti-clinical anti-clinical
H
H H H H
H H Me H Me H
20 syn-clinical syn-clinical
relative energy /KJmol-1

H anti-periplanar Me
Me H H H H Me
15 Me H Me H H Me
Me
H H
10 H H H H
H H
H H
5 Me

0 60 120 180 240 300 360

dihedral angle θ in degrees
Figure 9

The compounds considered so far are linear compounds and thus rotation about carbon-
carbon bond is easily possible. However, it is expected that this rotation will be hindered
in cyclic compounds. Also, the hindrance will large in small rings compared to large
rings. This brings to a new concept- Bayer’s ring strain.

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In a alicyclic compounds, all the carbons are sp3 hybridized and thus the bond angle
should be 109° ideally. But in a small planar ring, like that of cyclopropane it is not
possible to achieve this bond angle. As such the actual bond angle in cyclopropane is 60°
instead of 109°. This thus introduces a strain in the molecule known as ring strain.
According to Bayer, this strain would increase as rings grow larger and smaller than
cyclopentane, they should show increasing angular strain and increasing strain energy.

In reality, a different scenario emerges as it is observed that, the cyclopropane ring is

highly strained, the ring strain decreases with ring size and reaches a minimum for
cyclohexane and not cyclopropane. The ring strain then increases but not as rapidly as is
expected by Bayer’s theory and reaches a maximum at cyclononane and then decreases
again. As the number of ring carbons increase beyond 14, the ring strain remains roughly
constant.

This apparent deviation between theory and observed fact could be explained by the
erroneous assumption that the rings are planar. In 1890 Hermann Sachse argued that,
cyclohexane exist as non-planar chair and boat conformations which could rapidly
interconvert into one other. This was experimentally observed by O. Hassel and D.
Barton, who using X-ray crystallography one half of the twelve bonds of cyclohexane in
the chair conformation of cyclohexane were arranged parallel to 3-fold rotational axis (C3
axis) while the remaining half were close to the imaginary equator plane of the ring
system. The former group of hydrogens are called axial hydrogen while the later are
called equatorial hydrogens (Figure 10).

C3 axis
equitorial plane
H H

H H
H
H H
H
H
H
H H
axial hydrogens equitorial hydrogen

Figure 10

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In the chair conformation, all the bond angles are 109° and hence there is no angle strain.
The same may be said of the boat conformation, where all the angles are also 109°.
However, it will be seen later that this conformation is higher potential energy than the
chair form. In this case, the different groups of hydrogens are shown below (Figure 11).

H H
H H
H H H H
H
H
H H H
H
H H
pseudoaxial hydrogens pseudoequitorial hydrogens flagpole hydrogens bowspirit hydrogens
Figure 11

To understand why the boat conformation has higher energy than the chair conformation,
they need to be drawn in the Newmann projection. As can be seen from the Newmann
conformational formula, in chair conformation, there is no eclipsing of the C-H bonds.
However, in boat conformations, there are several eclipsing interactions. Besides these,
there is also an interaction between the two flagstaff hydrogen atoms. These interactions
cause the boat conformation to have 25 kJ mol-1 higher energy than the chair
conformation (Figure 12).

H H
H H H H H
H
H H H
H H
H
H H
H
H H H H H
H H

H H
H H H H
H H H
H
H H
H H
H H H HH H H H
H H

Figure 12

Thus the non-planarity of the cyclohexane ring causes the ring strain to decrease. Thus, it
may be expected that the phenomena may be occurring in other smaller ring system to

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relieve the ring strain (Scheme 13). In fact, the cyclobutane and cyclopropane rings are
not planar as well. But, non-planarity alone cannot relieve ring strain because the smaller
size of ring does not allow the freedom required to twist the C-C bonds out of plane
without cleaving the ring. The high value of heat of combustion of cyclopropane is a
clue to the ring strain due to deviation from the normal bond angle of a sp3 hybridized
carbon and also the result of eclipsing of all C-H bonds. In cyclobutane, the ring bends to
adopt a so called “puckered ring” shape. This shape though alleviates the eclipsing of C-
H bonds but decreases the bond angles to 88.5°, even further to increase the ring strain.
Thus, it appears that the eclipsing effect is impotant. Thus, in cyclopentane, even when
the bond angles (108°) are close to the ideal value, there is some strain in the molecule
and this causes the cyclopentane to adopt an open enevelope form which in turn
decreases bond angle and increases angle strain.

H H

planar molecule
H
H
all C-H bonds eclipsed

H
H H
H H H
H
H H
H
H H
H H
H H

C-H bonds partially eclipsed puckered ring

H H H H
H H
H
H
H
H H H H
HH
H H
H H H
-
C H b ds eclipsed
on open envelope shaped

Scheme 13

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Module 8 Stereochemistry
Lecture 23 Stereochemistry IV
So far, all the stereogenic centres discussed involve a carbon atom with 4 different
substituents attached to it (asymmetric centre). However, in case of trivalent central
atoms having a lone pair of electrons, the lone pair of electrons may be considered as a
fourth substituent. Usually, in such cases, the enantiomers will undergo Walden inversion
from one form to other. The Walden inversion may however be prevented by locking
using bulky substituents. Here, while the trisubstituted aliphatic amines easily undergo
inversion, the same is not possible for aziridines as it would require twisting of the 3-
membered ring. Similarly, in Troger’s base, the trivalent nitrogen is present on bridge
head and cannot undergo inversion (Figure 1).

Walden Inversion No Walden Inversion

CH3
CH3 H3C CH3 N
H3C CH3 N
N N N N
H3C CH3
CH3 H H
H3C
Troger's base
Aziridines exist as enantiomers
Figure 1

It is also to be remembered that for a compound to have enantiomers, it must be non-

superimposable on its mirror image. This condition can also be satisfied by certain other
compounds which do not have asymmetric centre. As an example, cis-octahedral
complexes may exhibit enantiomers even though they lack an asymmetric centre (Figure
2).

3+ 3+

O O

O O O O
O O
Fe Fe
O O O
O O O O O

O O O
O

Figure 2

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Some compounds which do not have asymmetrically substituted carbon atoms (no
stereogenic centre) may still be chiral if they feature two perpendicular planes which are
not symmetry planes. If these disymmetric (chiral) planes cannot freely rotate against
each other, the corresponding compounds are chiral. Compounds of this type are said to
be axially chiral. Some examples of this type involve unsymmetrically substituted
allenes, biphenyl derivatives and spiro compounds (Figure 3).

H3C H3C H3C CH3

• H • H • H H •
H CH3 H CH3 H3C
H3C H3C H
achiral achiral

H3C CH3
NO2 O2N
H3C CH3 H3C CH3
H H H H CH3 H3C
O2N NO2
chiral chiral
Figure 3

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In case of biphenyl derivatives, if both aromatic ring systems are asymmetrically

substituted, the compounds are chiral. As the chirality of these structures originates not
from an asymmetrically substituted atom center, but from an asymmetric axis around
which rotation is hindered, these enantiomers are also called atropisomers. In the
biphenyls, the ortho-substitutents must be large enough to prevent rotation around the
central single bond. Since only the hindered rotation about the central C-C single bond
leads to the stereoisomerism of these compounds. Therefore, biphenyl- and binaphtyl-
derivatives are conformational stereoisomers (not configurational stereoisomers).
Planar chirality may arise if an appropriately substituted planar group of atoms or ring
system is bridged by a linker-chain extending into the space above or below of this plane.
Some common examples are the planar chirality of cyclophanes or alkenes as shown
below (Figure 4).

CH3 H3C O O

Fe CH3 H3C Fe
H3C CH3

[2,2]-paracyclophane 1-acetylf errocene

Figure 4

Helices are also chiral as they can exist in enantiomeric left- or right-handed forms.
Typical examples for helical strutures are provided by the helicenes (benzologues of
phenanthrene). With four or more rings, steric hinderance at both ends of these molecule
prevents the formation of planar conformations, and helicenes rather adopt non-planar,
but helical and enantiomeric structures with C2 symmetry (Figure 5).

H3C H3C CH3 CH3

CH3 H3C

H3COOC COOCH3
H3COOC H3C CH3 COOCH3

[8]-helicene enantiomers
dimethyl 5,6,8,10-tetramethylheptalene-1,2-dicarboxylate
Figure 5

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The stereochemistry of a substrate may have profound effect on the rate of a reaction or
the composition of the products of a particular reaction. With respect to the composition
of products obtained by a reaction two terms are important.
• Stereoselective reactions are those reactions which give one predominant product of
the two or more products possible because the reaction pathway has a choice. Either
the pathway of lower activation energy is preferred (kinetic control) or the more
stable product (thermodynamic control). Thus, E1 dehydration of 1-phenylpropan-1-
ol provides (E)-prop-1-enylbenzene as the major product (Scheme 1).
Ph H3O+/H2SO4 Ph
CH3 CH3 Ph +
CH3 Ph CH3
OH E1
1-phenylpropan-1-ol (E )-prop-1-en-1-ylbenzene (Z)-prop-1-en-1-ylbenzene
racemate major minor
Scheme 1

• On the other hand, stereospecific reactions lead to the production of a single isomer
as a direct result of the mechanism of the reaction and the stereochemistry of the
starting material. There is no choice. The reaction gives a different diastereoisomer of
the product from each stereoisomer of the starting material. In case of E2 elimination
of ((1S,2R)-1-bromopropane-1,2-diyl)dibenzene, only the E-alkene is formed as the
product (Scheme 2).

H3C Ph H3C Ph
CH3
NaOCH3 Ph H
Ph H H Br
Ph Br - -HBr
CH3OH B
Br Ph H H3C Ph
Ph H
((1S,2R)-1-bromopropane-1,2-diyl)dibenzene (E )-prop-1-ene-1,2-diyldibenzene
Scheme 2

These two classes of reactions may further be subdivided into enantioselective or

diastereoselective reactions and enantiospecific or enantiospecific reactions based on the
product formed.

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In some reactions, an achiral centre may be converted to a chiral centre. Similarly, a

double bond may be converted into chiral centres. To understand the relationship
between an achirl substate and chiral product, two new terms need to be introduced.

Prochirality is the geometric property of an achiral object (or spatial arrangement of

points or atoms) which is capable of becoming chiral in a single desymmetrization step
(Figure . An achiral molecular entity, or a part of it considered on its own, is thus called
prochiral if it can be made chiral by the replacement of an existing atom (or achiral
group) by a different one. An achiral object which is capable of becoming chiral in two
desymmetrization steps is sometimes described as proprochiral (Scheme 3).

H H H D T D
H COOH H COOH H COOH
proprochiral centre prochiral centre chiral centre

Scheme 3

In the case of addition reactions, multiple bonds may be reduced to single bonds giving
rise to chiral centres (Scheme 4). In these cases, there are no prochiral centres but rather
prochiral faces. Thus, the term prochirality also applies to an achiral molecule or entity
which contains a trigonal system and which can be made chiral by the addition to the
trigonal system of a new atom or achiral group. The addition of hydrogen to one of the
faces of the prochiral ketone methyl ethyl ketone gives one of the enantiomers of the
chiral alcohol. Since the addition of hydrogen generates an enantiomer and not a
diastereomeric alcohol, so the faces in this case are referred to as enantiotopic faces.
However, the same faces may regarded as diastereotopic if the addition of a nucleophile
generates a diastereomic species. Thus, addition of cyanide anion to one of the
diastereotopic faces of the chiral aldehyde shown below converts it into one of the
diastereoisomers of the cyanohydrin. The two faces of the trigonal system may be
described as Re and Si. The allotment of the descriptor follows a rule similar to the
allotment of R and descriptors. First, the substituents are assigned priority according to
the CIP rules. Next, consider the molecule in the plane of paper. Then, looking from the
top, an arrow from the first-priority group, through the second, to the third. If the arrow

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points clockwise, the face is called (Re). If the arrow points counter-clockwise, the face is
called (Si).

H H H H H H CN H H
H3C H- H3C CN- H3C H + H3C CN
H3C
Ph O Ph OH Ph O Ph OH Ph OH
enantiotopic diastereotopic
f aces f aces

1 view f rom view f rom 1

O this side O this side O
2 3 3 2
Ph H Ph H H Ph
Si f ace Re f ace

Scheme 4

In the next few pages, some of the reactions discussed in various chapters will be
discussed from a perspective of stereochemistry (Scheme 5). SN2 reactions of
cyclohexane derivatives present a nice case. If the conformation of the molecule is fixed
by a locking group, the inversion mechanism of the SN2 reaction, means that, if the
leaving group is axial, then the incoming nucleophile will end up equatorial and vice
versa.

δ-
X X H H
H Nu- δ- Nu
t Bu t Bu t Bu
Nu

leaving group is axial Nucleophile occupies

equitorial position

δ-
H Nu H Nu
X Nu- δ- H
t Bu t Bu t Bu
X

leaving group is equitorial

Nucleophile occupies
axial position

Scheme 5

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It is, however, found that the substitution of an axial substituent proceeds faster than the
substitution of an equatorial substituent. This is because, in the formation of the transition
state, the nucleophile attacks the σ*-molecular orbital of the carbon-leaving group (C-X)
bond. In the case of an axial attack, this line of attack is hindered by the axial groups at 3
and 5 positions. For an equatorial attack the direction of attack is parallel with the axial
groups antiperiplanar to the leaving group and hence much less hindered (Figure 6).

Nucleophile's path is hindered

by the hydrogen atoms X
Nu-
H H
H t Bu H
t Bu X HH
Nu-
Nucleophile is parallel
to the hydrogen atoms

Figure 6

Similarly, the ring closing to form epoxides occurs only in the trans isomer. The cis
isomer adopts a conformation where one of the groups is axial (less bulky one), while the
other is equatorial. In this conformation the two groups are not antiperiplanar as required
for a SN2 reaction. The trans isomer, on the other hand adopts a conformation where both
the groups are equatorial to each other. Though, it still seems not suited for a SN2 attack
but the attack can take place in the diaxial conformation which may be generated from
the diequitorial conformation by ring flipping. Though the former is less stable than the
latter, a small amount of the molecule in diaxial conformation may drive the reaction
forward (Le Chatelier’s principle) (Scheme 6).

OH OH RO- O-
Cl
Cl Cl O-
Cl
both conf ormations donot
have proper geometry f or SN2

OH O-
OH RO- O- O
Cl Cl
Cl Cl

Scheme 6

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As with substitution, the elimination reaction in cyclohexane derivatives is also

dependent on the conformation. Since E2 reactions can occur only through an
antiperiplanar transition state so they must be stereospecific in nature. Thus, in the
elimination of trans-1-chloro-2-methyl cyclohexane, the elimination takes place from the
diaxial isomer (Scheme 7).

CH3 CH3 CH3

H
CH3
Cl CH3
Cl Cl

Scheme 7

One of the most profilic stereoselective reactions is the nucleophillic attack on carbonyl
compounds. These compounds have two stereogenic faces and, thus, it is a question on
which face will the attack preferentially take place. In this respect two empirical rules
have been developed which predict the same result.

• Cram’s rule: According to this rule, if the molecule is observed along the axis,
(represented as shown below), where S, M and L stand for small, medium and
large, respectively. The oxygen of the carbonyl orients itself between the small
and the medium sized groups. The rule is that the incoming group preferentially
attacks on the side of the plane containing the small group (Scheme 8).
Y-
O Y
M M S
S
HO R
LR L
major product
Y
X
O L O Y
M XY S L
S M
R OH
LR Y- S R M
L is capable of chelation major product

Scheme 8

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But, when chelation may occur between the carbonyl oxygen and the
counteraction of the incoming nucleophile, then the result of Cram’s rule may be
reversed. In this case the large group chelates counter cation of attacking
nucleophile and carbonyl oxygen.
• Felkin Ahn model: The statement of the rule is same as that of Cram’s rule but
the objective is achieved by reasoning from a different angle. Assuming that
there isn’t an unusually electronegative atom on the carbon next to the carbonyl,
the largest group (L) prefers a conformation where it is perpendicular to the
carbonyl C=O. This gives two relatively competitive lowest energy
conformations, with the medium (M) and smallest (S) groups differing in their
proximity to the carbonyl oxygen.
O O
S S
L L

MR R M

It is further determined that the nucleophile prefers to attack away from the large
group at an angle of 107°. Thus, it attacks nearer to the small (S) group giving
rise to only one diastereomer.

M O OH
-
Y M L
Y- L
Y R
S R S

If, however, there is an electronegative atom or group at the site α- to the

carbonyl, there is a slight change. This ‘slight change’ is that this electronegative
group(X) becomes the equivalent of the ‘large’ group in the Felkin-Ahn model.
The reason for this that the energy of the C-X σ* antibonding orbital is rather
low, and so it overlaps with the π*of the carbonyl to make a new, lower energy
LUMO (lowest unoccupied molecular orbital). This really means is that this
conformational arrangement is more reactive than any other.

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A few examples will clarify the case of application of these rules. The major product for
reduction of (R)-2-phenylpropanal can be predicted according to the Cram’s rule
(Scheme 9).

H AlH3
(M) (S) O H
H3C H H3C H3C H CH3
LiAlH4
H H
Ph HO H HO Ph
(L) O Ph
PhH
(R)-2-phenylpropanal (S)-2-phenylpropan-1-ol

Scheme 9

However, to determine the configuration of the product of the reaction between (R)-2-
methoxypropanal and dimethyl zinc, the Cram’s chelate rule needs to be applied. In this
case a chelate is formed between methoxy group’s oxygen and carbonyl group with zinc
(Scheme 10).

Zn2+ HO OCH3
O H3C O H3CO O H3C CH3
CH3 H3C CH3 H H
H OCH3 CH3 H3CO OH
OCH3 HH CH3- H H
HH
R -2-methoxypropanal
( ) (2R,3S)-3-methoxybutan-2-ol
Scheme 10

Similarly Felkin Anh model is applied for the following example. Here, the large,
medium and small groups are phenyl, ethyl and methyl groups, respectively. The attack
of hydride (R)-2-phenylpentan-3-one takes from the side of the smallest group (Scheme
11).

H3C O H3C OH
CH3 H C2H5 CH3
LiAlH4
C2H5 Ph H Ph Ph H
Ph Ph CH3
H3C OH
O H C2H5 H C2H5 OH
H3Al H
(R)-2-phenylpentan-3-one (2R,3R)-2-phenylpentan-3-ol

Scheme 11

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In this case, there is an electronegative atom containing a lone pair of electrons. Here,
also classification of the groups into large, medium and small group. As a result of the
overlap between C-N σ* antibonding orbital π*of the carbonyl makes this conformation
shown below even more important. This results in great increase in the degree of
diastereoselectivity (Scheme 12).

NBn2
H
H3C
CH3 O
=

H3C O O CH
3 HO CH3
-
NBn2 Bn2N O
Bn2N
OCH3 COOCH3
H H H
H3C CH3 CH3 CH3 CH3
H3C

=
NBn2 H3C CH3
OH
H3C COOCH3 = H3C COOCH3
CH3 OH Bn2N H
Scheme 12

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In case of cyclohexanone derivatives, a cyclic system, the addition of a nucleophile

generates either a conformation with the nucleophile at an equatorial or an axial position.
However, unless the molecule is locked in a particular conformation, it does not matter
whether the nucleophile is attacking a line to the equatorial or axial position since a ring
inversion can put the molecule in a favourable conformation. However, in 4-
t
butylcyclohexanone, the t-butyl group always occupies equatorial conformation. Now,
with the increase in steric bulk of the attacking nucleophile, there will be tendency to
attack at the equatorial position as compared to the axial position. Thus, the reduction of
4-tbutylcyclohexanone with LiAlH4 results in mostly in trans alcohol while Grignard
addition of C2H5MgBr results in mostly cis-alcohol (Scheme 13).

H OH
CH3 O CH3 CH3
H3C LiAlH4 H3C + H3C
OH H
H3C H3C H3C
90% 10%

C2H5 OH
CH3 CH3
CH3 O H3C
EtMgBr H3C C2H5
H3C OH H3C
H3C
H3C
29% 79%
Scheme 13

Steric hindrance often slows down a reaction. Similarly, sometimes steric assistance
increases the rate of a reaction. The phenomena can be seen in the ester hydrolysis of
conformationally locked cyclohexane deivatives. In the ester hydrolysis the rate
limimting slow step is the formation of sp3 hybrid intermediate by the nucleophilic
addition on the trigonal carbonyl group. This imparts some steric bulk to the intermediate
as well as decreases its degree of solvation as the species is now negatively charged.
Thus, on going from the ester to the intermediate, the steric requirement of the ester
group increases as it passes through the transition state. As a result, the difference in free
energies of the axial and equatorial isomers is enhanced in the transition state than in the
ground states and the axial isomer reacts at a slower rate. This is an example of steric
hindrance. However, in the chromic acid oxidation of cyclohexyl alcohols a different
scenario. This reaction is supposed to consist of two steps, the rapid formation of a
chromate ester followed by its rate determining decomposition into a ketone. In this case

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the axial alcohols are oxidized faster than their equatorial isomers. This occurs because
the difference in free energies between the axial and the equatorial chromate esters in the
ground state exceeds that between the respective transition states due to more ketone like
structure of the latter.

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