BITS Pilani

Pilani Campus

CHEM F111 General Chemistry

Lecture 30
Dr. Ajay K. Sah
BITSPilani, Pilani Campus

Topic Discussed
Application
of
Cahn-Ingold-Prelog
convention in naming the alkenes
Atropisomers

Optical activity; Polarimeter;

polarized light; Specific rotation;

Plane

Enantiomeric excess
Resolution
Reactions involving stereoisomers
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Stereochemistry
Reactions involving stereoisomers
An axiom of stereochemistry is :

A reaction that does not involve the

breaking of a bond to a stereocenter
proceeds with retention of configuration
about that stereocenter.

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Fischer Rosanoff convention

D-L system
Correlate to D- and
L-glyceraldehyde
D-erythrose is
mirror image of
L-erythrose

the

Now only used for

sugars and amino
acids
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Stereochemistry
Relative configuration

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Stereochemistry
Relative configuration

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Stereochemistry

R,S

+,-

There is no implied relationship among the terms!

D,L
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Reactions involving stereoisomers

(c) reactions like (b) in which a second
chiral center is generated
h
*
*
*
CH3CH2CHClCH3 + Cl2
CH3CHClCHClCH3
CH3
H
Cl
CH2
CH3
(S)-

CH3
H
Cl
H
Cl
CH3
(R,S)-

CH3
H
Cl
Cl
H
CH3
(S,S)-

diastereomers in unequal amounts8

Stereochemistry

Stereochemistry
Reactions involving stereoisomers
(d) Reactions of chiral compounds with
optically active reagents.

Enantiomers differ in reaction with

optically active reagents.
Products are diastereomers.
These reactions are used for resolution
the separation of enantiomers.
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Stereochemistry
Reactions involving stereoisomers
(e) A reaction of a chiral compound in
which a bond to a chiral center is broken.
The stereochemistry depends on the
mechanism of the reaction.

*
(S)-(+)-1-chloro-2methylbutane

*
racemic-1,2-dichloro-2methylbutane
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Stereochemistry
Reactions involving stereoisomers
In a reaction of a chiral
compound in which a bond to a chiral
center is broken, the stereochemistry
depends on the mechanism of the
reaction.
This means that we can use the
stereochemistry of such a reaction to give
us information about the mechanism for
that reaction.
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Reactions:
Substitution/Elimination

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Substitution/Elimination
One group takes the place of another.

Y +

R X

R Y +

Y takes the place of X (Substitution)

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Alkyl Halides
Halogens are more electronegative
than carbon
Carbon-halogen bond is polar, so
carbon has partial positive charge.
Electrostatic potential maps of alkyl
halides illustrate this point.

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NUCLEOPHILIC SUBSTITUTION REACTION

Consider a general reaction :
R X + OH- R OH

X-

RX is called the substrate

OH- the nucleophile

X- the leaving group

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NUCLEOPHILIC SUBSTITUTION REACTION

Why nucleophilic substitution
characteristic of alkyl halides?

is

It is because, halide ion is an

extremely weak base.
Why X- is a weak base ?
Because, hydrogen halides, are
strong acids. HX can readily release a
proton to other bases.
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NUCLEOPHILIC SUBSTITUTION REACTION

As a synthetic tool, nucleophilic
substitution is one of the most useful classes
of organic reactions.

The synthesis of aliphatic compounds,

most often starts with alcohols.
But OH group being a very poor leaving
group, it is only conversion of alcohols into
alkyl halides - or other compounds with good
leaving groups - that opens the door to
nucleophilic substitution.
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THESE REACTIONS HAVE A

WIDE RANGE OF SUBSTRATES

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COMMON SUBSTRATES
( Leaving group varies )
alkyl halides alcohols
R OH

R Cl

R O H
H

R Br
R

Alcohols require acid

and then H2O leaves

ABBREVIATION

tosylates
O
R O S
O

R O Ts

CH3

alkyl p-toluenesulfonate20

The Leaving group

The CX bond is heterolytically cleaved,
and the leaving group departs with the
electron pair forming X:. The more stable the
leaving group X:, the better able it is to accept
an electron pair.
In comparing two leaving groups the
better leaving group is the weaker base.
For example, H2O is a better leaving group
than HO because H2O is a weaker base.
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The Leaving group

There are periodic trends in leaving
group ability:
Left to right across a row, basicity
decreases so leaving group ability
increases.

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The Leaving group

Down a column of the periodic
table, basicity decreases so leaving
group ability increases.

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The Leaving group

Conjugate Bases of Strong Acids are Good
leaving groups

Good leaving groups

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The Leaving group

Conjugate Bases of Weak Acids are
Poor leaving groups

Poor Leaving Group

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THERE IS ALSO A
WIDE RANGE OF NUCLEOPHILES
A WIDE VARIETY OF COMPOUNDS CAN BE MADE

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The Nucleophile
A nucleophile may be any molecule with
an unshared electron pair.
Nucleophiles in general are anions
( -CN-, -I-, -SH- etc.) or neutral molecules
(H2O, ROH, NH3 etc.)

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NUCLEOPHILES
Nucleophile
-

- -

Product

Class

R X

alkyl halides

R OH

alcohols

RO

R O R

ethers

C N

R C N

nitriles

O
R' C

esters

Cl ,Br ,I
OH

O
R' C

O-

O R

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NUCLEOPHILES
Nucleophile

Product

Class

R' C C:-

R' C C R

alkynes

SH-

R SH

thiols

R O H
R O R

alcohols
ethers

R NH2

amines

R' NH R

amines29

H O

R O

NH3
R'

NH2

The Nucleophile
Although nucleophilicity and basicity
are interrelated, they are fundamentally
different.
Basicity is a measure of how readily
an atom donates its electron pair to a
proton.
It is characterized by an equilibrium
constant, Ka in an acid-base reaction,
making it a thermodynamic property.
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The Nucleophile
Nucleophilicity is a measure of
how readily an atom donates its electron
pair to other atoms.

It is characterized by a rate
constant, k, making it a kinetic property.
1. For two nucleophiles with the
same nucleophilic atom, nucleophilicity
parallels basicity, i.e. the stronger base is
the stronger nucleophile.
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The Nucleophile
The relative nucleophilicity of HO and
CH3COO, two oxygen nucleophiles, is
determined by comparing the pKa values of
their conjugate acids (H2O = 15.7, and
CH3COOH = 4.8). HO is a stronger base and
stronger nucleophile than CH3COO.

2. A negatively charged nucleophile is

always a stronger nucleophile than its
conjugate acid.
HO is a stronger base and stronger
nucleophile than H2O.
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The Nucleophile
Nucleophilicity does not parallel
basicity when steric hindrance becomes
important.

Steric
hindrance
decreases
nucleophilicity but not basicity.
Sterically hindered bases that are
poor nucleophiles are called non
nucleophilic bases.
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The Nucleophile

Ethoxide (Stronger nucleophile)

tert. Butoxide (Stronger base)

Three CH3 groups sterically hinder the O

atom, making it a weaker nucleophile 34

General Features of Nucleophilic Substitution

Negatively charged nucleophiles like HO
and HS are used as salts with Li+, Na+, or K+
counterions to balance the charge.
Since the identity of the counterion is
usually inconsequential, it is often omitted from
the chemical equation.

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General Features of Nucleophilic Substitution

When a neutral nucleophile is used, the
substitution product bears a positive
charge.

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General Features of Nucleophilic Substitution

If +ve charge resides on electronegative atom

having hydrogen attached, it looses H+ ion and
becomes neutral

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Kinetics of Nucleophilic substitution

Let us take simplest of the alkyl halide ,
CH3X and react it with OH-.

The rate of the reaction can be

determined experimentally by measuring the
rate at which methyl halide or hydroxide ion
disappears from the solution, or the rate at
which methanol or halide ion appears in the
solution.
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Kinetics of Nucleophilic substitution

We can make any of these
measurements by withdrawing a small
sample from the reaction mixture soon
after the reaction begins and analyzing
it for the concentrations.

We
perform
several
such
experiments keeping the temperature
constant, but varying the initial
concentrations of the reactants.
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Kinetics of Nucleophilic substitution

The rate of the reaction can be determined
experimentally

By measuring the rate at which Substrate

disappears, or the rate at which Product
appears

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Kinetics of Nucleophilic substitution

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Kinetics of Nucleophilic substitution

R X + OH-

R OH

X-

This second order reaction is also

bimolecular, meaning that two species are
involved in the rate determining step.
This reaction is said to be
(Substitution Nucleophilic Bimolecular).

SN2

S = substitution
N (subscript) = nucleophilic
2 = both nucleophile and substrate in
characteristic step (bimolecular)
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Kinetics of Nucleophilic substitution

In the case of tertiary alkyl halide
substrate the rate is found to be dependent
only upon the substrate concentration.

The rate expression therefore is,

rate [(CH3)3CX]

or

rate = k [(CH3)3CX] .
This reaction is said to be first order overall.
This reaction is called as
(Substitution Nucleophilic Unimolecular).

SN1
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Nucleophilic Substitution Reactions

SN1
rate = k1 [RBr]

SN2
rate = k2 [RBr] [NaOH]

HUGHES AND INGOLD found that

Most primary compounds undergo SN2

reactions with second order kinetics.
Most tertiary compounds undergo SN1
reactions with first order kinetics.

Nucleophilic Substitution Reactions

Order of bond breaking and making
[1] Bond making and bond breaking occur at
the same time.

The mechanism comprises of one step.

In such a bimolecular reaction, the rate
depends upon the concentration of both
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reactants.

Mechanism for SN2 reaction

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Exergonic reaction

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Endergonic reaction

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Mechanism for SN2 reaction

This mechanism is very well supported by
three evidences.
(1) Kinetics
(2) Stereochemistry and
(3) Reactivity of substrates.

Stereochemistry
All SN2 reactions results in inversion
of configuration at a stereogenic center.
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Mechanism for SN2 reaction

Back side attack was proposed to
account for inversion of configuration.

Nucleophile attacks
carbon from side
opposite to the
leaving group

Three-dimensional
arrangement
of
bonds in product is
opposite to that of
reactant

Mechanism for SN2 reaction

When a substrate contains more than
one stereocenter, inversion takes place
only at the stereocenter being attacked by
the nucleophile.

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Mechanism for SN2 reaction

As the number of substituents attached
to the carbon bearing the halogen is
increased,
the
reactivity
toward
SN2
substitution decreases.

Methyl
(30)

10
(1)

20
Neopentyl
(0.03) (0.00001)
Relative Rates

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(~0)

Compare the Transition State for a

methyl RX and a 2 RX.

SN1
The mechanism has two steps and a
carbocation is formed as an intermediate.