Block

7
O
S M
UNIT
L
R

ASYMMETRIC INDUCTION

Structure
7.1 Introduction 7.4 Qualitative Correlation between
Conformation and Reactivity
Expected Learning Outcomes
7.5 Curtin-Hammett Principle
7.2 Cram’s, Prelog’s and Felkin-
Ahn Model 7.6 Summary

7.3 Dynamic Stereochemistry – 7.7 Terminal Questions

Acylic and Cyclic
7.8 Answers

7.1 INTRODUCTION
After having the basic understanding about the topicity, stereogenicity and
prochiral centres from Unit 6, you are now well equipped to have a deeper
knowledge about how the stereochemistry in different types of reactions
governs the course of the reaction and the products formed in them.

We will begin this unit with a discussion on asymmetric induction. Asymmetric

induction means the formation of one enantiomer or diastereomer in
preference to the other under the chiral influence which may be a chiral centre
in the substrate or a chiral reagent or a chiral catalyst. We will describe here
Cram, Prelog and Felkin-Ahn models which explain how the presence of a
chiral centre near the carbonyl carbon directs the incoming nucleophile in the
nucleophilic addition reactions.

Then, dynamic stereochemistry of both acyctic and cyctic systems will be

explained by taking the examples of different types of chemical reactions. It
would be interesting for you to know that even different conformations of a
compound can have different reactivities. This will be illustrated by correlating
the conformations of some substrates with their reactivities.

Finally, Curtin-Hammett principle will be discussed which explains about the

composition of products when conformational isomers in equilibrium undergo a
particular reaction. 151
Block 2 Stereochemistry II

Expected Learning Outcomes

After studying this unit, you should be able to:

 define asymmetric induction;

 explain Cram’s rule and predict the major product of a reaction using this
rule;

 describe Felkin-Ahn model and use it for predicting the stereochemistry

of the product obtained;

 explain Burgi-Duritz angle;

 discuss Prelog’s rule and its use in determining the configuration of

alcohols;

 differentiate between stereospecific and stereoselective reactions and

give their examples;

 illustrate conformationally rigid and conformationally labile systems;

 appreciate how different conformations of a compound can yield different

products and predict the major and minor products; and

 describe Curtin-Hammett principle.

7.2 CRAM’S, PRELOG’S AND FELKIN-AHN

MODEL
Asymmetric Synthesis

You have already studied about resolution of racemic mixtures to obtain

optically pure (active) compounds. Another method to get optically pure
compounds is asymmetric synthesis which yields one enantiomer or a
diastereomer in preference to the other.

Asymmetric synthesis could be partial or absolute depending upon whether

optically active compounds available in nature are used or not.

One example of partial asymmetric synthesis involving carbonyl compounds is

the conversion of unsymmetrical keto compounds either by (i) reduction to
secondary alcohols or by (ii) reaction with Grigrard reagents to yield tertiary
alcohols.

OH O OH
reduction R"MgX
R C R' R C R' R C R'
[H]
unsymmetrical
H ketone R"
a secondary alcohol a tertiary alcohol
(chiral) (chiral)

If a chiral centre is already present in the substrate, it causes asymmetric

induction to yield two diastereomers in different amounts. Several empirical
152 rules/models were proposed in 1950’s which correlate the configuration of the
Unit 7 Asymmetric Induction
newly created chiral centre (in the predominant diastereomer) to the one
already present in such a substrate. The rules or models took into
consideration steric and electronic factors.

These rules are Cram’s rule, Prelog’s rule and Felkin-Ahn models. Let us
study them one by one.

(i) Cram’s Rule

After studying a large number of known reactions , D. Cram in 1952 proposed

this rule based on steric considerations. According to this rule, for nucleophilic
addition reactions of ketones having a chiral carbon attached at  position to
the carbonyl group, three groups attached to the chiral centre can be labeled
as S, M and L for small, medium and large sized groups.

The preferred conformation for attack by nucleophile will be the one which is of
least energy. In this conformation, the carbonyl group would be positioned in
such a way to occupy a place between small and medium groups, as shown
below:
O
S M

L
R

Then, the attacking nucleophile would prefer to come for addition to the
carbonyl carbon from the side of small group (S) because of lesser steric
hindrance. Therefore, two products would be formed out of which one would
be major. Thus, for the addition of C6H5MgBr to the aldehyde, I, threo product
would be the major product,
H O H C 6 H5 H OH
H3C + C 6H5MgBr H 3C OH + H3C C 6 H5
C6H5 H C6H5 H C6H5 H
I
major product minor product
(S) O 80% 20%
H CH3
(M)
(threo) (erythro)
Nu
(C6H5) H (L)
C6 H5
preferred direction of
attack from the side of
small group

But, when ketone II was taken as the starting material and reduced with

LiAlH4; the nucleophile, H , attacks from backside, i.e. the side of the small
group, H and we get the erthyro product as the major product.
H O H H H OH
(i) LiAlH4
H3C H3C OH + H3C H
(ii) dil. H2SO4
C6H5 C6H5 C6H5 C6H5 C6H5 C6H5
II (erythro 80%) (threo 20%)
153
Block 2 Stereochemistry II
Now, though the major product has changed in case of ketone II, but the
Cram’s rule is still followed because the nucleophile attacked from the side of
the small group. This model was also called open-chain model.

The reason argued for this model was the complexing of metal ion (Mg of
RMgX and Al of LiAlH4) with oxygen of carbonyl carbon, to make it the bulkiest
group resulting in its placement between small and medium groups as shown
below:

Br
Mg AlH3
C6H5
H
O O
H CH3 H
CH3
small small
group group
C 6H5 C 6H5
R
C 6H5

SAQ 1
Show the attack of nucleophile (LiAlH4) on ketone II and the formation of
products thereof.

SAQ 2
Do you notice any unfavourable situation in the nucleophilic attack of LiAlH 4
on ketone II?

A rigid model was proposed by Cram when the compounds contained a

hydroxyl or an amino group attached to the chiral centre  to the carbonyl
group. In such a situation, the organometallic reagent coordinates with both
the oxygen of the carbonyl group and that of the OH (or N of NH 2) group.
R
Mg
X
O
S OH

Nu
L
R

This fixes the conformation and again the Nu adds from the side of the small
group. The resultant products are explained well by open chain and rigid
models in case the –OH /or –NH2 groups are medium sized as compared to
the other two groups. But if these groups are the smallest groups, then rigid
154 model correctly gives configuration of the major product.
Unit 7 Asymmetric Induction
A dipolar model was suggested by Cram for compounds in which a strongly
electronegative group such as a halogen group is present at the carbon  to
the carbonyl carbon. The C–X and C=O are placed anti to each other in such a
situation as shown below to minimise the repulsions between them. Here,
again the nucleophile adds from the side of the small group to yield the
product.

M
O R' L
L S HO R'

X S
X
R R

But Cram’s model could not satisfactory explain the reduction of

cyclohexanones and also the following trend in the product ratio when R group
was made more and more bulky in the ketone, as pointed out by Felkin in
1968.
O
C LiAlH4 reduction The syn and anti
H5 C6 R Product respectively, denote
H Ratio that the two groups are
CH3
anti : syn present on the same
side and on the
R = CH3 2.8 : 74:26
opposite side.
= C2H5 32 : 76:24
= iC3H7 5.0 : 83:17
= tert-butyl 49 : 98:12

O
S M
H CH3
attack of Nu
Product
from the side of
C 6H 5 small group
RL

Cram's model

According to the Cram’s model, the increase in the bulk of the R would lead to
increased repulsions between R and C6H5 group which is the large group;
hence, stereoselectivity of the reaction should decrease. But, as you can see
in the data, the ratio of anti product increased with the bulk of R.

To explain the above observations, Felkin proposed a model called Felkin

model. Let us understand it in a little more detail.

(ii) Felkin Model

Felkin proposed that the conformation having the large group should be
perpendicular to the carbonyl group and not in anti-periplanar position as was
the case with Cram’s model. This would avoid the ecliptising of R with L group.

Thus, the following two major or reactive conformations will arise when L is
perpendicular to the carbonyl group.
155
Block 2 Stereochemistry II
L
Nu
S M
O R or
R O
M S
Nu L
L

HO R

M S
Nu

Another way of looking at the molecule is shown below by its rotation by 900.
O Interconvertible by O
M rotation of S, M, L S
groups
L L Nu

Nu S M
R R

Which side will the Nu attack? Here, again the attack from the side of the small
group is favoured. And, first possibility gives the major product.
M OH

Nu L

S R
major product

Clearly, in the second situation, M group and Nu will have repulsive

interactions and this would not be a preferred arrangement.

Felkin model was also not satisfactory when R=H i.e., in case of aldehydes.

An improvement over the above is known as Felkin-Ngugen (Felkin-Ahn)

model which suggests that the attack of the nucleophile takes place at 109
angle with respect to the plane of the carbonyl carbon and this is known as
Burgi-Dunitz trajectory.

Nu Burgi-Dunitz
trajectory
109o
O

(iii) Prelog’s Rule

It is an extension of Cram’s rule. It correlates the configurations of chiral

alcohols and -hydroxy acids.

Consider the -keto ester shown below in which the alcohol portion contains
three groups-small, medium and large, denoted as S, M and L, respectively.
156 The two carbonyl groups are anti- periplanar.
Unit 7 Asymmetric Induction

C O L
R C C
O S M

alcohol part
-keto ester

If Grignard reagent, RMgX reacts with -keto ester, then in the conformation
having
O

C O L
C C
O

porition of the molecule in a plane, R would have a choice of attack on the

carbonyl carbon, i.e., either from side of M (from backside) or from side of S
(from front side).

You already know that there are two diastereotopic faces present in a carbonyl
compound. But, similar to Cram’s rule, the approach of R from the side of
small group, S, would be sterically less hindered and hence, preferred to give
the product which on hydrolysis gives -hydroxy acid as shown below:
O R' OH
O L O L
R R'MgX R
R' O S M O S M

hydrolysis

COOH
R' OH
HC CH HO R'
R COOH R
-hydroxy acid

As the asymmetric centre, inducing asymmetry in case of -keto esters, is at a

large distance from the carbonyl group; the induction could be poor, i.e., the
preferred product, though formed as a major product, would not be having
great difference in amounts as compared to the minor product.

Thus, we can conclude that the configuration of the -keto ester (or the
-hydroxy acid formed as the product) is correlated with the alcohol moiety
present in the ester. Hence, configurations of various alcohols (secondary and
tertiary) could be assigned using this rule. Generally, PhMgBr is used as the
Grignard reagent and pyruvate ester of the alcohol is used for configuration
determination.
157
Block 2 Stereochemistry II

7.3 DYNAMIC STEREOCHEMISTRY-ACYCLIC

AND CYCLIC
After discussing different models which help us in understanding the preferred
direction of the attack by the nucleophile, we will focus our attention on
dynamic stereochemistry in this section. Dynamic stereochemistry mainly
deals with the influence of spatial structures of molecules on the reaction rates
and on the direction of reactions. It also includes reactions which are
specifically directed to synthesise the molecules with a particular
stereochemistry.

To appreciate the dynamic stereochemistry, you should have the basic

knowledge about various types of reactions which you have studied in your
earlier classes. You may be already familiar with stereochemical aspects of
some of these reactions. Here, we will briefly describe different types of
reactions and their stereochemical aspects. We will consider examples from
substitution and addition reactions .

But before we actually take up this discussion, you must also be familiar with
two more terms with reference to the product formation when we start with
specific steroisomers. These are stereospecific reactions and
stereoselective reactions.

(i) Stereospecific Reactions: These reactions yield a single isomer as the

product; and the two different stereoisomeric starting materials, say
diaseteromers ,give two different products. For example, if we have two
diastereoisomers A and B and do a reaction separately on them; then A
gives X as the product while B gives Y as the product.

A X

Diastereoisomers

B Y

Then, such a reaction is called stereospecific reaction. In such

reactions the mechanism of the reaction controls the stereochemistry of
the product formed and there is no choice or option for A x Y or
B x X reaction.

We will also illustrate such reactions when we will consider different

types of reactions in this section.

(ii) Stereoselective Reactions: In such reactions, two products are formed

from a single starting material and one product is a major product and
the other one is minor product or may form in trace amount also. For
example,

A P + Q
(major) (minor)

The basis of formation of two products in the different amounts is that

there is an option in the reaction pathway or the mechanism, i.e.,
158 the reaction pathway could be either-
Unit 7 Asymmetric Induction
(i) kinetically controlled in which case the pathway of lower
activation is preferred and this leads to that product as the major
product which is formed faster;

or

(ii) thermodynamically controlled in which case the more stable

product is formed as the major product.

Under stereoselective reactions, we can further have -

 susbstrate selectivity, and

 product selectivity.

When two substrates, say, two enantiomers (or diastereomers) are present in
the starting material and only one such substrate reacts with the reagent; then
there is substrate selectivity. For example, in reactions involving enzymes, the
reaction takes place between the enzyme and only one of the stereoisomers.

On the other hand, the product selectivity occurs when the substrate reacts
with the reagents, solvent or catalyst in different ways to give two different
products which could be diastereoisomers or enantiomers. When two different
products formed are diastereomers, the reaction is called diastereoselective
and in case they are enantiomers, the reaction is called enantioselective.

With this background in mind, we will now analyse different reactions for their
stereochemistry involved in the context of the products obtained.

Let us start with the nucleophilic substitution reactions which are very
familiar to you. From your knowledge of such reactions from the earlier
classes, you know that

 SN1 reactions proceed with racemisation, and

 SN2 reactions proceed with the inversion of configuration at the

stereocentre or chiral centre.

In the SN1 reaction, in step 1, the intermediate formed is a carbocation as

shown below:

Step 1
H
H L +
C
H3C C2 H5 H3C C 2H 5
reactant carbocation

Step 2
H Nu H H Nu
 
Nu: C
+ Nu: C
+ C
H3C C 2H 5 H3C C2 H5 H3C C2 H5

products

enantiomers
159
Block 2 Stereochemistry II

As there is equal probability of attack by the nucleophile, Nu from both the
sides of the carbocation; in Step 2, the nucleophile attacks the carbocation
from both the sides and two enantiomers are formed in equal amounts leading
to a racemic mixture as the product.

But, in SN2 reactions the Nu and the leaving group form a five membered
transition state (by backside attack of Nu with respect to the leaving group)
which yields inversion of configuration in the product as shown below.

H H
_
H

Nu: C L Nu C H2 Nu C
C 2 H5
C2H5 C2H5 Me CH3
Me

reactant/substrate five-membered product

transition state

Such an example of an SN2 reaction is shown below:

H OTs  + AcO H
OAc, Bu4N
CH3CH2 CH3 DMF CH3CH2 CH3
(S) (R)

And, if we start with the reactant having R configuration as shown below, we

get the product having S configuration.
Remember that SN1 OTs H  + H OAc
reactions happen in OAc, Bu4N
two steps while SN2 CH3 DMF CH3
reactions occur in a CH 3CH2 CH 3CH2
single step. (R) (S)

Thus, we can say that SN2 reactions are stereospecific in nature.

Now what about SN1 reactions? Since, both enantiomers were formed in equal
amounts and there is no stereochemical preference observed in the product;
we can say that in the SN1 reactions, there is no stereochemical control.

Let us now take the example of addition reactions.

A simple case is that of addition of Br2 to cis-2-butene and trans-2-butene.

In case of cis-2-butene, the cyclic bromonium is obtained by addition of Br2 on

either of the faces, i.e., the top face or the bottom face since both the faces
are the same in this case.

This is followed by nucleophilic attack of Br to the cyclic bromonium ion. The
two options- (i) and (ii) are available for the attack from the bottom, since the
addition is an anti- periplanar.

In case of (i) when the Br attacks from bottom face, the product obtained after
opening of the ring is A. You can see that the two Br atoms are trans in the
product. What would happen if Br attacks on the other carbon of the cyclic
bromonium ion as shown by path (ii)? Again, the anti addition would lead to
trans position of two Br atoms with respect to each other as shown in product
160 B. Therefore, both products are formed in equal amounts.
Unit 7 Asymmetric Induction
Br

H
Br H H
+
Br CH 3 CH 3
H (i)
Br H
CH 3 Br
H A
CH 3
CH 3 (i) (ii) +
(ii)
CH3 H
CH3
cis-2-butene Br Br

Br
H
CH3
B
Can you now see any relation between A and B?

These are enantiomers.

Similarly, in case of trans-2-butene, the addition of Br 2, via the cyclic

bromonium ion yields products C and D, as shown below:
Br

H
Br H CH3 CH3
+
Br H
H (i)
Br CH3
CH3 Br
CH3 C
CH3
H (ii) +
(i) (ii)
H H
CH3
trans-2-butene Br Br

Br
CH3
H
D
But, in this case, the products C and D are not two different compounds. They
are the same and it is meso-2,3-dibromobutane.

Thus, the addition of Br2 to 2-butene is stereospecific as the two different

diastereomers have led to specific products which are as follows:

 cis-2-butene gives a racemic mixture of 2,3-dibromobutane, and

 trans-2-butene gives the meso compound,i.e. meso-2,3-dibromobutane.

Similarly, we can explore for elimination and other reactions.

7.4 QUALITATIVE CORRELATION BETWEEN

CONFORMATION AND REACTIVITY
Having studied some aspects of dynamic stereochemistry for different types of
reactions in the last section, you may be curious to know what will happen in
case different conformations of a compound are possible. Will different
conformations react differently and lead to same or different products, and if
different products are formed -which will be the major product? We will find the
answers to such questions in this section.

The knowledge of these aspects of reactions is very important as we will be

able to use such knowledge in carrying out different reactions to obtain the 161
Block 2 Stereochemistry II
desired product(s) as the major product(s). Thus, the effect of conformations
on reactivity is a very important aspect in the stereochemistry of the reactions.

You have already studied about the conformations of cyclohexanes, decalins

and related systems in Unit 3 of Block 1 of this course.

The correlation of conformations and reactivity can be understood in a simpler

way if we classify substrates or the reactants into the following three types:

Substrates or
Reactants

Conformationally Conformationally Substrates with

rigid mobile two or more
diastereomers diastereomers conformers

Let us understand each of these systems in detail.

1. Conformationally Rigid Diastereomers

One such example of conformationally rigid diastereomers is that of trans-

2-decalol and trans-2-decalol. You can see in their structures shown
below that in -decalol, the OH group occupies the equatorial
H OH

OH H

trans-2 -decalol trans-2 -decalol

position while in -decalol, it occupies the axial position. Such

stereoisomers are clearly diastereomers. As the two cyclohexane rings
are joined together in trans fashion, the above two diastereomeric
decalols cannot interconvert and such systems are conformationally
rigid systems.

Now, we can study the rates of reactions of the OH group in such a
system and analyse which diastereomer reacts faster and why?

When acelylation of OH group was done in the two diastereomers,

it was found that trans-2-decalol reacts much faster than
As the tert-butyl trans-2-decalol.
group preferably
occupies the Another such system in which the axial and equatorial groups are locked
equatorial position, in rigid fashion is a cyclohexane system in which a tert-butyl or any other
this isomer is present
in 10,000:1 ratio as bulky group is present at 4-position. Two such 4-tert-butylcyclohexanols
compared with the are shown below:
axial tert-butyl isomer.
Such systems are H
OH
called H3C
conformationally OH H3C
H
biased anancomeric C
H3C H3C C
systems. H3C H H3C
H
trans-isomer
(OH and tert-butyl groups are cis-isomer (OH and tert-butyl
162 trans to each other) groups are cis to each other)
Unit 7 Asymmetric Induction
Again, if acetylation of the above two compounds is done at the OH
groups, the first compound, the trans isomer which has OH group at
equatorial position reacts much faster than the second one in which the
OH group occupies the axial position.

So definitely, there is a relationship between the conformations of the

compounds and their reactivities. Similarly, other reactions of the OH
group also proceed faster for the diastereomer with the equatorial OH
group.

Let us next consider the second type of substrates.

2. Conformationally Mobile Diastereomers

For such systems, the relative specific rates of the reactions of the two
diastereomers depend on the corresponding rates of the conformers and
their population in the equilibrium mixture.

Let us consider the two diastereoisomers of 2,3,4-triphenylbutyric acid,

shown below as threo and erythro isomers.

1 1
COOH COOH
2 2
C 6H5 H C 6H5 H

3 3
H C6H5 C 6H5 H
4 4
CH2C6H5 CH2C6H5
threo erythro

The preferred conformations of these two diastereomers on cyclisation

with HF yield two different products as shown below.
O
COOH
H CH2C6H5 C6H5
HF

C6H5 H
C6H5
C6H5
threo tetralone

O
COOH
H C 6 H5 C6H5
HF
C6H5 H
C6H5CH 2
CH2C6H5
erythro inadnone

3. Substrates with two or more conformers

For such substrates, the overall specific reaction rate (k) depends upon
the specific reaction rates of the conformers and the ground state
population of the conformers, i.e. 163
Block 2 Stereochemistry II

k   ni ki 
 specific reaction of conformers
i
th
mole fraction of the i conformer

This equation is applicable when interconversion of conformers is much

faster than the reaction.

Further, conformers could be

i) homomeric – behave identically with respect to the rate of the

reaction and product formed.

ii) enantiomeric – behave identically under achiral conditions but

differently under chiral conditions.

iii) diaseteromeric – behave differently always.

Thus, when the products obtained from equilibrating conformers are non-
equilibrating, then the products could be related to the reacting
conformers. The enantiomeric and diastereomeric conformers need to be
considered.

The achiral 4-methylcyclohexanone, on reaction with optically active

2-isooctyl nitrite yields 2-oxyimino derivative which has one enantiomer
present in the predominant form.

O O

1
NOH
6 2
*
+ C6H13 CH CH3
5 3

4
O NO
H3C H H3C H

achiral chiral enantiomer

obtained in
larger amount

This is so because the methylene groups at C–2 and C–6 are enantiotopic
and these react with the chiral compounds at different rates leading to the
formation of one enanitomer in larger amount than the other.

SAQ 3
Write the structure of the other enantiomer of the 2-oxyimino derivative which
is formed in the smaller amount.

SAQ 4
Why is 4-methylcyclohexanone achiral?
164
Unit 7 Asymmetric Induction
The two conformers of malic acid are shown below which are in equilibrium.
COOH
H2 H1

HO H

COOH
malic acid
HOOC H1
HOOC H2 H1 COOH
H2 COOH
OH OH
HOOC HOOC
H1 H2
H HOOC HOOC H
H H
maleic acid fumaric acid
antiperiplanar
H and OH

On dehydration, the two diasteromers, maleic acid and fumaric acid are
formed; therefore H1 and H2 in the reactant malic acid are diastereotopic.

You will next study about Curtin-Hammett principle which gives the
quantitative aspects of such equilibrating conformers leading to two different
products which are not in equilibrium.

7.5 CURTIN-HAMMET PRINCIPLE

The quantitative aspects of conformation and the reactivity are explained by
the following:

(i) Curtin-Hammet principle and (ii) Winstein-Elliel rate equation.

Curtin-Hammett principle correlates the product distribution with the

transition state energies formed by the two conformers while Winstein-Elliel
rate equation correlates the overall specific reaction rate, k, of the given
substrate with the specific reaction rate of the individual conformers.

Here, we will discuss only the Curtin-Hammett principle as the Winstein-Elliel

rate equation is beyond the scope of discussion of this Unit.

Let us consider a substrate S, which can exist in two conformers A and B

which are in equilibrium, as shown below.

S
kC k1 kD
C A B D
k2

Now each of these conformers A and B reacts to give the products C and D,
respectively which are not interconvertible. The rate constants (k) for the
above changes are mentioned on the respective arrows. For such situations,
the product composition is not in direct proportion to the relative concentration
of starting conformers A and B but depends only on the difference in free
165
Block 2 Stereochemistry II
energies of the transition states, provided that the rates of reactions for
product formation kC and kD are much slower than the rates of conversion of
conformers, k1 and k2. Thus, we can write

[B] k1
K 
[A] k 2

And, k1 and k2 are much larger, i.e., at least 10 times more than kC and kD.

We can represent the free energy diagram as shown below:

Fig. 7.1: Free energy vs. reaction coordinate.

In case, kC and kD are
far greater than k1
and k2, this means
Thus, the product ratio, C:D will not depend upon the concentration ratio of the
that the ratio of A and starting conformers [A] : [B] but on the difference, G , i.e. difference between
B is not changing free energies  GC and  GD , of the transition states.
while the products C
and D are being Now four different possibilities will exist for which conformer will give the major
formed. This is called product. These are as follows:
kinetic quenching
since the A ⇌ B 1. More stable conformer giving the major product provided the rate of
interconversion has reaction of more stable conformation is higher.
stopped.
2. Less stable conformer giving the major product provided the rate of
reaction of less stable conformation is higher.
In another situation
when the magnitude 3. More stable conformer giving the major product when rates of
of kC and kD is same reactions of two conformers are comparable.
as k1 and k2, then the
4. When both conformers are equally stable and are present in equal
equilibrium is not
amounts; then the major product would be one having lower free energy
being maintained and
of activation.
hence Curtin-
Hammett and Let us study these situations in more detail.
Winstein-Eliel/Holmes
equation do not apply 1. The energy profile shown in Fig. 7.2 represents this situation in which the
in their usual form. transition state energy  GC of the more stable conformer, which is A in
166
Unit 7 Asymmetric Induction
this case, (because of its lower energy) is lower than that of the transition
state energy of B,  GD . So, C will be forming as a major product.

Fig. 7.2: Free energy vs. reaction coordinate.

Let us compare this figure with that for that of Case 2 as shown below in
Fig. 7.3.

Fig. 7.3: Free energy vs. reaction coordinate.

As the product D is being derived from the less stable conformer (B, which is
of higher energy than A), it is formed in major amount because its transition
state energy  GD is lower than that of A which is  GC .

Consider the dehydrohalogenation reaction of 2-bromobutane. Its two

conformations in equilibrium are given below in which the two groups to be lost
are shown anti to each other.

H CH3 Br Br
H CH3
C H CH3 H3C H C
gauche
C interactions
C
H CH3 H CH3 H CH3 H3C H
H H trans-2-butene
cis-2-butene
C A B D

If we compare the two conformers, in the first one, A, the two methyl groups
are close to each other and there are gauche interactions between them. Such 167
Block 2 Stereochemistry II
interactions are not there in the other conformer, B, as the two methyl groups
are for apart from each other. Thus, the first conformer will be having higher
energy and lower proportion as compared to the second one. Also, the
transition state would also be of higher energy for I and than for II. This is
shown in Fig. 7.4 below.

Fig. 7.4 Free energy vs. reaction coordinate.

Thus, as the transition state free energy is lower for the second conformer
which is also the more stable conformer,, the major product is the product
obtained from second conformer. Thus, trans-2-butene is formed in major
amount i.e., 80% while the cis-2-butene constitutes 20% of the product. Thus,
in this case major product is resulting from the stable conformer.

An example of situation 2 where less stable conformer leads to the formation

of the major product is that of quaternerisation of tropanes as discussed
below.

Tropane is a bicycle amine in which a pyrrolidine and a piperidine ring share

one nitrogen atom and two carbon atoms.
6 7
1 2
3 2 1 7 H
8
N CH3 3
N
5 CH3 6
4 N 5 4 N
8

tropane H
piperidine pyrrolidine

When tropane is drawn in a little different orientation,its two conformers can be

shown which are in rapid equilibrium. In the the less stable conformer of
13
CH3 CH3 CH3
: H3C H3C CH3
:

N N N
N
rapid 13
13
CH3I interconversion CH3I
fast
piperidine side
(less hindered
major product less stable more stable side) minor product
conformer conformer

Tropane, the methyl group occupies the axial position of the piperidine moiety
168 and the piperidine side is sterically more hindered and therefore it is the less
Unit 7 Asymmetric Induction
13
stable conformer. But when the reaction is carried out with CH3I, the less
stable conformer gives the major product as it reacts faster. This indicates
that the transition state in which the attacking group approaches from the less
hindered side of the piperidine side is preferred over the other possibility in
which the attack in the more stable conformer from the more hindered side
takes place.

Let us take the case of N-methyl-4-tert-butylpiperidine which can exist in the

following two conformers:

Here, the more stable conformer is the one in which the methyl group and the tert-
butyl group occupy equatorial positions.

When oxidation reaction of N-methyl-4-tert-butylpiperidine is carried out using

H2O2 in acetone, the axial N-oxide is the major product and the ratio of major
to minor products is 95:5. Note that axial N-oxide means that oxygen is
occupying the axial position which was the case in the more stable conformer.
Here, as the electrophile is less bulkier, it is assumed that the two conformers
are reacting at the comparable rates.

SAQ 5
Draw the energy profile for the conversion of N-methyl-tert-butylpiperidine to
its N-oxide.

Lastly, we shall see what happens when both conformers are equally stable.
This would lead to their equal amounts of the starting conformers. In such a
situation, the major product would be the one which would be having lower
free energy of activation. The free energy profile for such a system is shown
below.

169
Block 2 Stereochemistry II

Fig.7.5: Free energy vs. reaction coordinate.

You can easily predict that D will be the major product in this case. The
formation of epoxide from trans-2-halocyclohexanol conformer can be
explained as follows.
X
O OH
H
X
trans form (diequatorial) O
O
H
OH trans form
(diaxial)

No reaction as the geometry
OH
is not suitable in this
conformation for reaction

Both are trans-one is diequatorial (first one) and second is diaxial. Though
diequatorial is more stable, but geomtry is not favourable for the reaction. Both
the conformers do not have same population. The first one is more stable and
hence, its concentration is higher but the reaction of diaxial form shifts the
equilibrium to its side.

A discussion about the Curtin-Hammett principle given so far limits quantitative

aspects in the sense that  G which is the difference in the energy levels of
the transition states cannot be determined experimentally. Hence, more in
depth studies suggested that the better or modified form of Curtin-Hammett
principle should take into account the equilibrium constant of the starting
conformers, rates of their respective reactions in kC and kD terms and   G .

7.6 SUMMARY
In this unit, you have learnt that

 According to Cram’s rule, for nucleophilic addition reactions of ketones

having a chiral carbon attached at  position to the carbonyl group, three
groups attached to the chiral centre can be labeled as S, M and L,
respectively for small, medium and large sized groups. The preferred
conformation for attack by nucleophile will be the one which is of least
energy.

 A rigid model was proposed by Cram when the compounds contained a

170 hydroxyl or an amino group attached to the chiral centre  to the
Unit 7 Asymmetric Induction
carbonyl group. In such a situation, the organometallic reagent
coordinates with both the oxygen of the carbonyl group and that of the OH
(or N of NH2) group.

 A dipolar model was suggested by Cram for compounds in which a

strongly electronegative group such as a halogen group is present at the
carbon  to the carbonyl carbon. The C–X and C=O are placed anti to
each other in such a situation.

 Felkin model proposed that the conformation having the large group
should be perpendicular to the carbonyl group and not in anti-periplanar
position as was the case with Cram’s model. as shown below to minimise
the repulsions between them.

 Prelog’s Rule is an extension of Cram’s rule. It correlates the

configurations of chiral alcohols and -hydroxy acids.

 Dynamic stereochemistry mainly deals with the influence of spatial

structures of molecules on the reaction rates and on the direction of
reactions.

 Stereospecific reactions yield a single stereoisomer as the product, i.e.

the two different stereoisomeric starting materials give two different
products. SN2 reactions are stereospecific in nature.

 In stereoselective reactions, two products are formed from a single

starting material and one product is a major product and the other one is
minor product or forms in trace amount.

 When two substrates, say, two enantiomers (or diastereomers) are

present in the starting material and only one such substrate reacts
with the reagent; then there is substrate selectivity.

 When two different products formed are diastereomers in unequal

amounts, the reaction is called diastereoselective and in case they
are enantiomers, the reaction is called enantioselective.

 the effect of conformations on reactivity is a very important aspect in the

stereochemistry of the reactions.

 The quantitative aspects of conformation and the reactivity are explained

by :

(i) Curtin-Hammett principle and (ii) Winstein-Elliel rate equation

 Curtin-Hammett principle correlates the product distribution with the

transition state energies formed by the two conformers.

7.7 TERMINAL QUESTIONS

1. (i) Write the structure of the hydroxy acid produced when pyruvate ester
of an asymmetric alcohol reacts with C6H5MgBr and the product so
obtained is hydrolysed.
171
Block 2 Stereochemistry II
(ii) What are the common and IUPAC names of this acid?

(iii) Write the S and R configurations for the above acid.

2. (i) Predict the major product when the following ester reacts with CH 3MgX.

O H3C CH3
CH3MgX
C O
C6H5 C
H
O

CH3

(ii) Will there be any minor product? Give its structure also.

3. Which of the following will react faster in a substitution reaction with 128I?

I127
I127
or
C(CH3) 3
C(CH3)3
I II

4. Using dipolar model, predict the product of reduction of any of the

following enantiomeric compound using NaBH4.

O C 2H 5
C 3H 7 C CH
Cl

5. Draw the Newman projection for the major and minor products and also
predict the side of attack when S-3-phenylbutanone is reduced using
LiAlH4.

7.8 ANSWERS
Self-Assessment Questions
1. O
H CH3
(S) (M)


H C 6H5
(L)
C 6H5

Products formed are as follows:

172
Unit 7 Asymmetric Induction
H O H H H OH
(i) LiAlH4
H3C H3C OH + H3C H
(ii) dil. H2SO4
C6H5 C6H5 C6H5 C6H5 C6H5 C6H5
II (erythro 80%) (threo 20%)

2. Yes
O O

3. HON NOH

H3C H H CH3

4. A plane of symmetry is present in the molecule which is clearly visible in

the 3D structure of the molecule cutting the methyl group in the middle.

plane of symmetry

H3C H

5. The energy profile for the conversion of N-methyl-tert-butylpiperidine to its

N-oxide is as shown below:

Terminal Questions
1. (i) COOH COOH
HO C C 6 H5 or C 6H5 C OH

CH3 CH3

(ii) Atrolactic acid, 2-hydroxy-2-phenylpropanoic acid.

173
Block 2 Stereochemistry II
(iii) 2 2
COOH COOH
1 3 3 1
HO C 6H 5 C 6 H5 OH
CH3 CH3
4 4
R S

2. (i) Here, CH3 will attack from the backside, i.e., the side of H group of
alcohol moiety of the ester according to the Prelog rule to yield the
following major provide.
H3C CH3
HO CH3
C O
C6H5 C
H
O

CH3

(iii) OH H3C CH3

H3C
C O
C6H5 C
H
O

CH3

3. II; as the transition state in both the cases would be same and II is less
stable than I.

BH3
O H C 2H 5
4. C 2H 5 H HO H

Cl H
Cl
C 3H 7 C 3H7

O O
5. H 3C
H
- C 6H5 or
H C 6H5 -
H H
CH3 CH3
CH3
favoured not favoured

(i) LiAlH 4 (i) LiAlH 4

+
+ (ii) H 3O
(ii) H 3O

H 3C OH HO H
H C 6H5 C 6H5 H

H CH3 H 3C CH3
major product minor product
174