Molecular Orbitals o Common Functional

Groups

1
Introduction
In this module, a broad and qualitative overview of basic molecular
orbital (MO) theory is provided. The simplified picture of MO for some
standard functional groups are emphasized. The concept of node in the
context of MO and its effect on the energy levels of these MOs are also
given.
The objective of this module is to provide important molecular orbitals
of conjugated olefins, which are typically used in the discussion of
cycloaddition and other pericyclic reactions. Understanding of orbital
symmetry rules demands a prior knowledge of molecular oribtals.
In addition, molecular orbitals are very useful toward understanding
reaction mechanism, such as the direction of approach of the
nucleophiles, stereochemistry of elimination reactions and many more
situations. Conformational features, stability of reactive intermediates
etc., can also be explained by using molecular orbital theory concepts.

2
 Sigma Orbitals
σ∗
ABMO

BMO
σ Symmetric along the axis

For any bonding molecular orbital (BMO) there should be a corresponding

antibonding molecular orbital (ABMO)
The shading of the above orbitals that are overlapping shows that they are
‘in-phase’ for bonding orbital formation
In the anti-bonding orbital out-of-phase combination of participating orbital
occurs
Note: BMO is toward the internuclear direction while ABMO is away
from the internuclear direction 3
 More on sigma orbitals

σ
σ-type overlaps contain no nodes along the internuclear axis.

Symmetric along the axis

Note that the word ‘type’ refers to the symmetry relation. For example, orbital as shown
in (i) does not change its sign when it is rotated along the internuclear axis (horizontal
axis passing through both the nuclei in this picture). Similarly, (ii) and (iii) also doesn’t
change the sign. Hence, there are orbitals are exhibit similar symmetry features as that
of a pure sigma bonding molecular orbital. Hence, these are termed as sigma-type
4
orbitals
 Types of Orbitals: Ethylene

σ∗

π∗
Note: π-orbitals are formed
by the lateral overlap
π between p-orbitals centered
on two adjacent atoms
σ

Note: Nonbonding orbitals are orbitals centered on atoms, but it doesn’t interact
with other atomic orbitals. When a molecule is formed by the linear combination
of atomic orbital (LCAO), the atomic orbitals that are left free are also called
nonbonding molecular orbital. Term non-bonding is used simply because those
orbitals are not bonding
Nonbonding orbital: e.g., pz-orbital (AO) on BH3
5
 Types of Orbitals: BH3
Nonbonding orbitals are orbitals centered on atoms, but it doesn’t
interact with other atomic orbitals. When a molecule is formed by
the linear combination of atomic orbital (LCAO), the atomic orbitals
that are left free are also called nonbonding molecular orbital. Term
non-bonding is used simply because those orbitals are not bonding.
It is important to notice that these are orbitals that appear in the
frontier region (higher energy or leading (frontier) orbitals) of a
molecule. Hence the influence of these orbitals on the
properties/reactivities of these molecules are high.
For instance, the nonbonding orbital on BH3 renders Lewis acid
features to the molecule.
Non-bonding Mos are denoted by small letter n usually with a
H
subscript conveying on which atom it is located.
H
6
Nonbonding orbital: nB on BH3 H
 Types of Orbitals: Formaldehyde
z

In xy-plane C O
y
x

πCO∗ Empty levels

Frontier MOs

Nonbonding MOs nO
Hold the lone-pair Filled levels
electrons n’O

πCO
7
 Description of Orbitals
πCO∗

nO
Nonbonding MOs
Holds the lone-pair Filled levels
n’
electrons
O

πCO

Here, both no and n o are non-bonding MOs. Careful examination would reveal that
the lower lying NBMO is alligned along the C-O bond while the higher lying is
perpendicular, but in the plane of the molecule. These NBMOs are therefore not of
same energy (non-degenerate).
8
 Ethylene MOs
Ethylene shows interesting properties due to the presence of a π-
bond
The C-C π-orbital is the Highest Occupied Molecular Orbital
(HOMO) of the alkene
Linear Combination of p-orbitals, leading to C-C π-orbital can be
represented as,
Out of-phase combination of
p-orbitals to give a π-orbital

Nodal Plane (nodes)

π* orbital higher in energy
than p-orbital
Increasing 2 x
Energy of
Orbitals
π-orbital lower in energy
than p-orbital
9
 Ethylene MOs

The blue dotted-line shown in ABMO is a nodal plane. Presence of a node in a MO will
increase the energy of the corresponding MO. [The concept of node is comparable to
the meeting point of a crust and a trough, used in the representation of a wave]
10
 How about MOs for allyl system?
Allyl (three carbon conjugated system) 2
Cl
E.g., Allyl chloride 3 1

Antibonding molecular orbital

ψ3

Increasing Nonbonding molecular orbital

ψ2
Energy of LUMO
Orbitals

ψ1 Bonding molecular orbital

HOMO
Note that the LUMO of this molecule has a node passing through the second carbon atom.
The number nodes increase by one in the MOs of a linear conjugated system. There is no
11
alternative way of placing a node other than having no contribution from the second
carbon
 Can we construct butadiene MOs?

The molecular
orbitals of
butadiene is a
good example to LUMO is lower in
shown that the energy than the
energy of the MO LUMO of
increases with the ethylene
number of nodes
HOMO is higher in
energy than the
HOMO of ethylene

12
 Butadiene MOs
Total number of π-orbitals = 4 3 2

Total number of π-electrons = 4 4

1

Three nodes ψ4 A

Increasing Two nodes ψ3 S LUMO

Butadiene is more Energy of
reactive than Orbitals

ethylene ψ2 A HOMO
One node

Zero node ψ1 S

A and S are symmetry properties of Mos with respect

to the plane of symmetry present between C2 and C3 13
carbon in s-cis geometry
Extended Conjugation and Colour (E.g. 1)

If the conjugation is extended further, the gap between HOMO and LUMO
will decrease to allow the compound to absorb visible light and hence
would become COLOURED.

Lycopene, the red pigment present in tomatoes and other berries

β-carotene, the red pigment present in carrots and other vegetables

14
 Generalizations for acylic polyenes
The lowest energy orbital is always symmetric with respect to the
principal mirror plane

The number of nodes increases by ONE on going from one orbital

to the next higher energy orbital

Nodes must be symmetrically located with respect to the central

mirror plane

In systems with an odd number of atoms, the antisymmetric levels

always have a node at the central carbon atom.
15
π Molecular Orbitals of Benzene

16
16
Picture from Volhardt’s book
Terms and Terminologies in
Mechanistic Organic Chemistry

Key words: Acids, bases, nucleophiles, electrophiles,

Hardness-Softness (HSAB) concepts
Introduction

In this module, some very basic terms and terminologies are described.
Historical perspectives and origin of some of the concepts are presented.
Concepts such as electrophiles, nucleophiles, hardness and softness etc., are discussed.

These concepts are of high significance to the following modules under reaction
Mechanisms.
The term acid • It comes from the Latin root ac,
was first used in
the seventeenth meaning sharp, as in acetum i.e.
century. vinegar.

• a characteristic sour taste

Acids have long
been recognized • ability to change the color of
as a distinctive litmus from blue to red
class of
compounds • react with certain metals to
whose aqueous
solutions exhibit produce gaseous H2
the following
properties. • react with bases to form a salt
and water.

First definition • According to his definition, acids

of acid was are substances containing common
given by element which gives that
Antoine compound the acidic nature.
Lavoisier, in • And he postulated that element to
1787.
be oxygen.
In 1811, • By 1830, dozens of oxygen free
Humphrey Davy acids had been discovered.
showed that
muriatic acid • But it was only after 1840, the
(HCl) does not hydrogen theory of acid became
contain oxygen. generally accepted.

In 1890, the • According to his theory, acid is a

Swedish chemist substance containing hydrogen
Svante atom, that can dissociate or ionize,
Arrhenius
formulated the when dissolved in water,
first important producing hydrated hydrogen ion
theory of acids. and an anion.

However, there
are substances • Hence, definition of acid was
which do not modified to “a substance that
contain H, but
still yield H+ yields an excess of hydrogen ions
ions when when dissolved in water.”
dissolved in
water.
 • HCl is a strong acid, it
dissociates completely in water.

H 2O
HCl H3O+ + Cl-

• H2SO4 is a polyprotic acid, it

dissociates completely in water in
two stages.

HCl H2SO4
H2O
H3O+ + HSO4-
H2O
HSO4- H3O+ + SO42-

• Acetic acid is a weak acid, it does

not dissociate completely in water.

H2O
CH3COOH H3O+ + CH3COO-
‘Base’ , as • The word alkali is synonymous
defined by
Arrhenius, is with base. It is of Arabic origin, but
substance that the root word comes from the same
yields excess of Latin kalium i.e., potash
OH- ions when
dissolved in • Alkali more specifically used for
water. those containing OH- ions.

• a bitter taste
The name base • a soapy feeling when applied to the
has long been
associated with a skin
class of • ability to restore the original blue
compounds color of litmus that has been turned
whose aqueous
solutions are red by acids
characterized by • ability to react with acids to form
salts.

NaOH, KOH, H2O

oxides of certain NaOH Na + + OH-
metal and
hydrogen H2O
compound of CaO Ca2+ + 2OH-
certain nonmetals
are classified as H2O
Arrhenius bases. NH3 NH4+ + OH-
Although
Arrhenius gave
useful definition
of acid and base, • acidic nature of FeCl3
he could not • basic nature of NH3, Na2S
justify nature of
certain
substances.

In 1923, a • Danish chemist J.N. Bronsted

theory that is and English Chemist T.M.Lowry,
both simple and put forward, independently, the
more general
was proposed by proton donor-acceptor concept.
two chemists.

According to
this concept,
acid is a proton • Definition makes no reference to
donor whereas the environment in which proton
base is a proton transfer takes place, so that it
acceptor. applies to all kinds of reaction.
Reaction • If the acid is denoted by AH and
between acid
and base is thus the base by B, then we can write a
a proton generalized acid-base reaction as
exchange
reaction. AH + B A - + BH +

• It gives rise to a very important

concept of conjugate acid-base
In this reaction, pair.
the protonated
base formed is • Conjugate pair differ by one
capable of proton.
losing H+ ions in • Conjugate acid and base are in
the solvent. equilibrium in solution.
acid1 + base2 base1 + acid2

Some common conjugate acid-base pairs

Substance Acid Conjugate
base
Thus, the Hydrochloric acid HCl Cl-
protonated base
is another Acetic acid CH3COOH CH3COO-
potential acid Nitric acid HNO3 NO3-
and anion of
first acid is Ammonium NH4+ NH3
another potential chloride
base. Water H2O OH-
Hydronium ion H3O+ H2O
 The stronger an
acid is, the • Table showing examples of
weaker its
strong and week conjugate acid
conjugate base
will be and vice base pairs.
versa.

Many • For example water is a Bronsted-

substances can Lowry base in its reaction with
Proton Acid act as an acid in
one reaction and HCl and an acid in its reaction
as a base in with NH3.
Base another are
called HCl + H2O -----> H3O+ + Cl-
amphoteric. H2O + NH3 -----> NH4+ + OH-

Another • In fact the amino acids usually

important group of
amphoteric species exist in zwitterion form, where the
is the amino acids. proton has transferred from
Each amino acid the carboxyl to the amino group.
molecule contains
an acidic carboxyl NH2
NH 3
group and a basic
amino group. R CH COOH
R CH COO
The Bronsted- • But still it fails to explain
Lowry theory is reactions between substances that
more general show similar features but no
than any that protons are transferred in the
preceded it. reaction.

This deficiency
was overcome by
more general • According to this concept, acid is
concept
proposed by an electron pair acceptor while
American base is an electron pair donor.
chemist, G N
Lewis in 1923.

The acid-base • If acid is denoted by A and base

reaction is by B:, then acid-base reaction
sharing of between them is formation of
electrons
between the adduct A-B.
two. A + B: A B
The principal
advantage of the • Therefore the number of acid-
Lewis theory is
the way it base reactions are also in majority
expands the in relation to this theory.
number of acids.

Various
molecules, ions, • A classical example is formation
etc., can be of adduct between molecules BH3
grouped as acid and NH3.
according to this
theory. BH 3 + :NH3 H3B-NH3

Like BH3, acidic • Al3+, thus exhibits acidic

properties of
various other properties as it can accept lone pair
molecules and of electrons from water molecule
ions can be in the hydration reaction.
explained using
Lewis theory. Al3+ + 6H2O: [Al(H2O) 6]3+
The Lewis acid-
base theory can • In the course of the reaction,
also be used to water molecule acts as a base
explain why donating a pair of electrons to
nonmetal oxides
such as CO2 carbon in CO2 molecule.
dissolve in water CO2 (g) + H2 O H2 CO 3(aq)
to form acids.

The proton (H+) • Ignoring the fact that H+ is

is one of the solvated, acid-base reactions of H+
strongest but can be viewed as formation of
also one of the adduct.
most H+ + OH-
complicated H2O
Lewis acids.
H+ + NH3 NH4+

Nearly all
compounds of • Many Lewis bases are
transition metals multidentate, i.e., they can form
can be viewed several bonds to the Lewis acid.
as a collections These multidentate Lewis bases
of the Lewis
bases. are called chelating agents.
 The acid-base • Reactions like,
nomenclature FeCl3 + Cl- ------> FeCl4-
can create are a little confusing viewed as the
confusion with acid (FeCl3) being a species
Bronsted lacking an octet, (Fe3+) is a neutral
nomenclature.
species.

Molecular orbital The reactions can

• a filled atomic or molecular
be viewed as
interpretation involving the orbital on the base
interaction of
molecular orbitals • an empty atomic or molecular
on the base and the orbital on the acid.
acid.

The filled orbital • Then we refer to the reaction

would be the highest
energy occupied simply as a filled-empty
molecular orbital, interaction or a HOMO-LUMO
the HOMO, and the
empty orbital will be interaction.
the lowest energy H
unoccupied
H H B
molecular orbital,
the LUMO. H
HOMO 1s LUMO 2p
 Substance that yields H+ ACID is a proton donor. ACID is an electron pair
ARRHENIUS THEORY

LEWIS THEORY
BRONSTED-LOWRY THEORY
(H3O+) in solution is an BASE is a proton acceptor.
ACID. acceptor. BASE is an electron pair
donor.
Substance that yields OH- 1. Acid1 ----> H+ + Base1
in solution is a BASE. A + B: -----> A-B
2. Base2 + H+ -----> Acid2
Acid1 + Base2 -----> BF3 + F- -----> BF4-
AH ------> H+ + A- Base1 + Acid2 I2 + I- -----> I3-
BOH ------> B+ + OH- HCl -----> H+ + Cl-
NH3 + H+ -----> NH4+ Acid: species lacking an
HCl + NaOH These are called octet: BH3, CH3+, etc.
is actually conjugate acid-base Base: species with an
H+ + OH- -----> H2O pairs. unshared pair of
electrons: H2O, NH3, H-,
Cl-, etc.
ACID BASE
Hydrogen halides : NaOH, KOH, LiOH
HCl, HBr, HI
Halogen oxyacids : Ba(OH)2, Ca(OH)2,
HClO, HClO2, Mg(OH)2
HClO3, HClO4
H2SO4, HSO3F Al(OH)3
HNO3, H3PO4
Acetic acid,
Benzenesulfonic
acid, PTSA
Oxalic acid
In 1965, Ralph
Pearson • He introduced the hard and soft
attempted to
explain the acid-base (HSAB) principle.
differential
affinity of Lewis • He classified Lewis acids and
bases towards bases as hard, borderline or soft.
Lewis acids.

According to
him, hard acids • This statement is neither an
prefer to explanation or a theory. It is
coordinate to simply a guideline that helps one
hard bases and to qualitatively predict the relative
soft acids to soft
stability of acid-base adducts.
bases.

• The adjectives hard and soft

doesn't mean strong and weak.
Ralph G • Classification in the original
Pearson, JACS, work was mostly based on
85, 3533(1963) equilibrium constants for reaction
of two Lewis bases competing for
a Lewis acid.
In 1968, G.
Klopman • Hard acids bind to hard bases to
quantified give charge controlled ionic
Pearson's HSAB
principle using complexes.
frontier • Soft acids bind to soft bases to
molecular
orbital theory. give FMO controlled covalent
complexes.

In 1983, the
qualitative • A less polarizable atom or ion is
definition of
HSAB was hard.
converted to a
quantitative one • A more easily polarized atom or
by using the idea ion is soft.
of polarizability.

• High positive charge

With these • Small size
modifications, • Not easily polarizable
hard acid is
• High energy LUMO
supposed to be
associated with • No electron pairs in their valence
properties such shells
as • Low electron affinity
• Strongly solvated
 • Low or partial positive charge
• Large size
On the other • Easily oxidized
hand soft acids • Highly polarizable
have properties • Low energy LUMO and large
such as LUMO coefficients
• Electron pairs in their valence
shells

• Low polarizability
Hard bases have • High electronegativity
properties such • Not easily oxidized
as • Low energy HOMO
• Highly solvated

• High polarizability
• Diffuse donor orbital
Soft bases have • Low electronegativity
properties as • Easily oxidized
• High energy HOMO and large
HOMO coefficients
 Characteristic Properties of Hard and Soft acids and bases

Properties Hard Acids Soft Acids Soft Bases Hard Bases

Electronegativity 0.7 – 1.6 1.9 – 2.5 2.1 – 3.0 3.4 – 4.0

Ionic radius (pm) < 90 > 90 > 170 ~ 120

Ionic charges ≥ +3 ≤ +2

Borderline species have intermediate properties. It is not necessary for species to possess all properties.
 HARD SOFT
BORDERLINE
H+, Na+, K+, Li+ Cu+, Ag+, Au+, Tl+, Hg+, Cs+,
Bi2+, Mg2+, Ca2+, Mn2+, Sr2+ Co+
Fe2+, Co2+, Ni2+, Sn2+,
Al3+, Se3+, Ga3+, Gd3+, In3+, Ru2+, Rh3+, Cu2+, Zn2+, Pd2+, Cd2+, Pt2+, Hg2+
La3+ Pb2+, B(CH3)3, SO2, CH3Hg+
Cr3+, Co3+, Fe3+, As3+, Ir3+ NO+, C6H5+ Tl3+, Ti(CH3)3, RH3, InCl3
Si4+, Ti4+, Zr4+, Tb4+, Pu4+, RS+, RSe+, RTe+, BH3
VO2+
2+,
I+, Br+, HO+, RO+
UO2 (CH3)2Sn2+
I2, Br2, INC, etc.
BeMe2, BF3, BCl3, B(OR)3
Trinitrochlorobenzene, etc.
Al(CH3)3, Ga(CH3)3,
In(CH3)3 Chloranil, Quinones, etc.
RPO2+, ROPO2+ Tetracyanoethylene
RSO2+, ROSO2+, SO3 Carbenes

I7+, I5+, Cl7+ M0 (Metal atoms)

Bulk Metals
R3C+, RCO+, CO2, NC+ ACID
HX (Hydrogen bonding
molecules)
 BORDERLINE

Aniline, Pyridine, N3-,

HARD Br- NO2-, SO32-, N2 SOFT

H2O, HO-, F- R2S, RSH, RS-

CH3CO2-, PO43-, SO42- I-, SCN-, S2O32-
Cl-, CO32-, ClO4-, NO3- R3P, R3As, (RO)3P
ROH, RO-, R2O CN-, RNC, CO
NH3, RNH2, N2H4 Ethylene, Benzene
H-, R-

BASE
 The HSAB Principle for Organic and Main Group Chemists

For our purposes main group and organic reaction chemistry the Pearson approach is very
successful when comparing pairs of species:

 Sodium ion, Na+, is harder than the silver ion Ag+

 Copper(II) ion is harder than copper(I) ion

 Alkoxide ions, RO–, are harder than thioanions, RS–

 The nitrogen anion end of the ambidentate cyanide ion, CN–, is harder than the carbon
anion end, NC-

 The ambidentate enolate ion, has a hard oxyanion centre while the carbanion centre is
softer and more nucleophilic

This type of analysis can be very useful in explaining reaction selectivity.

For example, in ring opening reaction of β-propiolactone by nucleophilic Lewis bases, attack
can occur at two positions and nucleophiles exhibit regioselectivity.
 O

O -
Nu(soft) Nu (soft) O

O
(hard)Nu O

-O
Nu (hard)

O O
Harder nucleophiles like alkoxide
ion (RO–) attack the carbonyl carbon. - O
-
O OR
RO

O O
-
Softer nucleophiles like a cyanide NC

ion (NC–) or a thiolate (RS–), -

O NC O
attack the β-alkyl carbon.

O O
-
RS

-
O RS O
In a nucleophilic substitution reaction in which one Lewis base replaces another, for
example, if the acid site is hard, then soft nucleophile will not provide a high rate of
reaction. If the acid is soft, then a soft nucleophile will react more quickly. [Pearson R. G.
and Songstad J, JACS, 1967, 89, 1827.]

Although, it certainly does not say that soft acids do not ever complex with hard bases, or
that hard acids do not form stable complexes with any soft bases.
ELECTROPHILES
AND NUCLEOPHILES
 History
 Terminology
 Examples
 Types
 Key Facts
 • The terms nucleophile and electrophile were introduced
by Christopher Kelk Ingold in 1929, replacing the
terms cationoid and anionoid proposed earlier by A. J. Lapworth in
HISTROY 1925.
• The word nucleophile is derived from nucleus and the Greek
word phile for affinity, while electrophile is derived from electros
meaning electron.

• Electron loving
• electron deficient molecules
Electrophile • attracted to negative charge i.e. high electron density

(E / E+) • bear partial or full positive charge or an open octet

• accepts pair of electrons
• similar to Lewis acid

• deficiency in valence electron shell

Examples O

Positively charged ions H

C
N

O
 H
Polar molecules O δ-
O
valence saturated but contain an atom C δ+ Hδ+ Clδ-
O
from which bonding electron pair can C δ+ O
Brδ− H
be removed as leaving group
H

Polarizable molecules
# easily polarizable bond • Br Br Cl Cl I I
# generates electrophilic end

Neutral molecules with incomplete • Carbenes AlCl3 BF3

octet

• for same electrophilic atom, greater degree of positive charge

Key Facts gives stronger electrophile
e.g. H3C+ > H3Cδ+-Brδ─
 • Nucleus loving
• abundance of electrons i.e. electron rich molecules
Nucleophile • attracted to positive charge i.e. low electron density
• bear partial or full negative charge or pi bond or lone pair of electrons
(Nu: / Nuc)
• donates pair of electrons
• similar to Lewis base

• easily available non-bonding electron pair

Examples Br OH C N
Anions Cl OR HC C
I SR

H H H C H
pi bonds C C
H C C H
C C
H H H C H

H
 Molecules with lone pairs H O
O N
bonding electron pair that can be
H H
donated from bond involved H
H

δ- δ+
Polar molecules H 3C MgBr

• Carbon nucleophiles: alkyl metal halides such as Grignard reagent,

organolithium, organozinc reagents, and anions of a terminal alkyne.
Enolates are also carbon nucleophiles. Enolates are commonly used in
Types of nucleophiles condensation reactions such as Claisen condensation, Aldol
condensation reactions, etc.
• Nitrogen nucleophile: NH3, RNH2, RCN, H2N─, etc.

• Oxygen nucleophiles: H2O, HO─, ROH, RO─, H2O2, COO─, etc.

• Sulfur nucleophiles: hydrogen sulfide and its salts (HS), thiols (RSH),
Types of nucleophiles thiolate anion (RS─), thiocarboxylic acids (RCOSH), dithiocarbonates
(ROCSS─), dithiocarbamates (R2NCSS─), etc.
In general, sulfur is very nucleophilic. Due to its large size, it is
polarizable and its lone pair of electrons are easily accessible.
 • all nucleophiles are bases but not all bases can act as nucleophiles
e.g. lithium diisopropylamide is a very strong base but a very poor
nucleophile
Key Facts • stronger base is stronger nucleophile (same nucleophilic atom)
e.g. HO─ is better nucleophile than H2O
RO─ > HO─ > phenoxide > carboxylate >> alcohol, H2O >>> RSO3─

• nucleophile with negative charge is more powerful than its conjugate

acid
e.g. H2N─ >NH3, HO─ >H2O
Key Facts • nucleophilicity decreases with increasing electronegativity of the
attacking atom (within same period)
e.g. R3C─ > R2N─ > RO─ > F─
H2N─ > RO─ > R2HN─ > ArO─ > NH3 > Py > F─ > H2O > ClO4─

• going down in a group nucleophilicity increases

e.g. I─ >Br─ > Cl─ >> F─
RS─ > RO─
Key Facts • more free nucleophile, more nucleophilicity
e.g. NaOHDMSO >NaOHwater
In water Na+ and HO ─ both are solvated while in DMSO Na+ is
solvated preferably than HO ─, leaving HO ─ as free nucleophile.
 • Steric effect is also important in deciding strength of nucleophile. Less
basic but sterically unhindered nucleophiles have higher nucleophilicity.
e.g. RCH2O─ > R2CHO─ > R3CO─
Key Facts • Nucleophilicity is increased by attached heteroatom that possess free
electron pair (α-effect).
e.g. HO-O─ > H-O─ , H2N-NH2 > H-NH2

• Sometimes not whole molecule, but small region on large molecules

can function as nucleophile or electrophile.
• Some molecules have both electrophilic and nucleophilic regions
Key Facts within them. They often go hand-by-hand.
• More electronegative atom functions as nucleophilic region. It may be
partially negatively charged.

• Similarly, less electronegative atom functions as electrophilic region. It

may be partially positively charged.
e.g. C=O bond
Key Facts • Flow of electrons, in a reaction, is always from nucleophile to
electrophile.
Nu E+
Electrophilic moiety Nucleophilic moiety
H Cl
H Br
H I
H OSO 3H

H OH2
Cl Cl
Br Br
Cl OH
Br OH
RS Cl
Hg (OAc)2

R 2B H
KINETICS AND
THERMODYNAMICS OF
REACTIONS

Key words: Enthalpy, entropy, Gibbs free energy, heat of reaction, energy of
activation, rate of reaction, rate law, energy profiles, order and molecularity,
catalysts
INTRODUCTION

 This module offers a very preliminary detail of

basic thermodynamics. Emphasis is given on
the commonly used terms such as free energy
of a reaction, rate of a reaction, multi-step
reactions, intermediates, transition states etc.,
FIRST LAW OF THERMODYNAMICS.

o Law of conservation of energy. States that,

• Energy can be neither created nor destroyed.
• Total energy of the universe remains constant.
• Energy can be converted from one form to another form.
eg. Combustion of octane (petrol).
2 C8H18(l) + 25 O2(g) → 16 CO2(g) + 18 H2O(g) + 10.86 KJ/mol .
Conversion of potential energy into thermal energy.
ESSENTIAL FACTORS FOR
REACTION.
 For a reaction to progress.
• The equilibrium must favor the products-

• Thermodynamics(energy difference between

reactant and product) should be favorable
• Reaction rate must be fast enough to notice
product formation in a reasonable period.
• Kinetics( rate of reaction)
ESSENTIAL TERMS OF THERMODYNAMICS.

 Thermodynamics.
 Predicts whether the reaction is thermally favorable.
 The energy difference between the final products and reactants are taken as the
guiding principle.
 The equilibrium will be in favor of products when the product energy is lower.
 Molecule with lowered energy posses enhanced stability.
 Essential terms
o Free energy change (∆G) –
Overall free energy difference between the reactant and the product
o Enthalpy (∆H) –
Heat content of a system under a given pressure.
o Entropy (∆S) –
The energy of disorderness, not available for work
in a thermodynamic process of a system.
 The Gibbs free energy is the maximum amount of non-
expansion work that can be extracted from a closed system
which can be attained only in a completely reversible process.

 The Gibbs free energy change at temperature T is expressed

as,
Δ G= Δ H – T Δ S

o In terms of standard states, when reactants and products at 1 M

concentrations (or 1 atmosphere pressure), the free energy change
is expressed as,
o Δ Go = Δ Ho - T Δ So
FREE ENERGY (∆G)

 For a reaction to be spontaneous

• The overall free energy at any concentrations of reactant
and product is:
∆G = ∆G° + RT ln[product]/[reactant]
Where R(gas constant)= 8.314 Jmol-1K-1 and
T(temperature) = in oK
At equilibrium,
∆G° + RT ln[product]/[reactant] =0
∆G°= -RT ln Keq
= - 2.303 RT log Keq
For a reaction, equilibrium shifts in the direction of
lower species. Hence ,
Go (reactant ) ˃ Go (product) then,
o reaction is spontaneous since Δ Go ˂ 0.
i.e. negative and K ˃ 1
eq

Go (reactant ) < Go (product) then,

o reaction is nonspontaneous since Δ Go ˃ 0
i.e. positive and K ˂ 1
eq
 Calculation of equilibrium constant with respect to ∆G at 298
ᵒK for a reaction.

∆Gᵒ in Calculated values Amount at equilibrium

kcal mol-1 of Keq
-4.2 103 Products (99.99%)
-1.4 101 Product=(10 times of reactant)
0 1 Equal (product=reactant)
+1.4 10-1 Reactant =(10 times of reactant).
+4.2 10-3 Reactant (99.99%).

o It can be noted from the above calculation that a small change in ∆G can produce
considerable change to the value of Keq .
o The values for product concentration decreases as ∆Gᵒ becomes progressively more
+ve.
ENTHALPY (∆H)
o Enthalpy can be regarded as thermodynamic potential.
o It is a state function and an extensive quantity.
o It also refers to the difference in bond energies between the reactant and
product.
o In short enthalpy is ‘ the heat absorbed (or released) by a chemical
reaction’.
CALCULATION OF ENTHALPY

 Enthalpy is a measure of difference in bond

energy between reactants and products.
E.g. Combustion of methane.
CH4(g) + 2 O2 (g) = CO2 (g) + 2 H2O (l)
ΔHreaction = Σnp H(reactants) – Σnr H(products )
ΔHocomb = ΔHof,methane +2 ΔHof,oxygen -2 ΔHof,water - ΔHof,carbon dioxide
= 75+0-(2*286+394) (ΔHof,oxygen = 0 as oxygen is a pure element.)
= -891 KJ mol-1 .

∆Ho is +ve when reaction is endothermic (endergonic).

∆Ho is –ve when reaction is exothermic (exergonic).
SOME FACTS ABOUT ENTROPY (∆S)

 The second law of thermodynamics states that the entropy of any closed
system, not in thermal equilibrium, will almost always increases.
 Entropy is a thermodynamic property, it is the measure of energy not used
to perform work but is dependent on temperature as well as volume.
 Entropy is directly proportional to Spontaneity.
 Comparison of entropies: Gases ˃ liquids˃ solids (bromine gas has greater
entropy than when in liquid state)
 Entropy is greater for larger atoms (as we move down in groups in periodic
table) and molecules with larger number of atoms.
 Entropy is a measure of the number of ways particles as well as energy can
be arranged.
 More configurations (different geometries), more will be the entropy.
 Entropy of a irreversible system always increases.
CALCULATION OF ENTROPY.
 The standard entropy ( Sᵒ) of a substance is the value of entropy of the substance at 298 K
and 1 atm.
 CH4(g) + 2 O2 (g) = CO2 (g) + 2 H2O (l)
 From the Table of Thermodynamic Data, the Standard entropies of the substances involved in
the above reaction are:

CH4(g) 186
O2(g) 205
CO2(g) 214
H2O(l) 70
The entropy change of the reaction can be calculated as:
ΔSᵒreaction = ΣnpS(products) - ΣnrS(reactants )
ΔSᵒ = [214 + 70 * 2] - [186 + 205 * 2] = -242 J/K.
 ΔSᵒ= +ve when there is decrease in order.
 ΔSᵒ= -ve when there is increase in order.
THERMODYNAMICS
VARIATION OF ∆G IN RELATION WITH ∆ H & ∆ S

Enthalpy Change Entropy Change Spontaneous Reaction?

Exothermic (ΔH < 0) Increase (ΔS > 0) Yes, ΔG < 0
Only at low temps, if |T
Exothermic (ΔH < 0) Decrease (ΔS < 0)
ΔS| < |ΔH|
Endothermic (ΔH > Only at high temps, if |T
Increase (ΔS > 0)
0) ΔS| >|ΔH|
Endothermic (ΔH >
Decrease (ΔS < 0) No, ΔG > 0
0)
ILLUSTRATIVE EXAMPLES ON THERMODYNAMICS
PERICYCLIC REACTIONS
DIELS ALDER REACTION

 Diels Alder reaction (4+2 cycloaddition , converting two weaker π-

bonds into two stronger σ-bonds)
 Dimerization of Cyclopentadiene :-
R. T.
2
170 0c- 2000 c

 Cyclopentadiene at normal temperatures exists as a dimer with selective

endo product and exists as a monomer at 200ᵒc
 At normal temperature, the dimerization is favored due to –ve ∆G (-9.61
Kcal mol-1 ) which is +ve at 200ᵒc (0.05 Kcal mol-1 ) hence increasing
spontaneity.
CHELETROPIC ADDITION OF SO2

 Cheletropic Addition of SO2

 Reaction involving two sigma bonds directed to a single atom of a
ring are made or broken concertedly resulting in decrease or
increase of one pi bond. An example is the reversible addition of
sulfur dioxide to 1,3-butadiene shown here.

BE LOW 1 000C
SO2 SO2
A BOVE 1 000C

 ΔHº = –16.5 kcal/mole

 Below 100ᵒ C the equilibrium favors the addition product with ΔHᵒ
= –16.5 kcal/mole. Above 100ᵒ C the cyclic sulfone decomposes to
1,3-butadiene. The equilibrium constant is close to unity at
100ᵒC.The entropy change calculated is as follows:-
INFLUENCE OF ΔGᵒ IN LACTONE FORMATION REACTION
(MUKIYAMA ESTERIFICATION)

 Consider the reaction,

 CH3CO2H + C2H5OH CH3CO2C2H5 + H2O
ΔHº = –0.80 kcal/mol ΔSº = +1.6 cal/ ºK mol ΔGº = –1.28 kcal/mol
 This reaction is considerably slow, requires a good amount of catalyst, and
continuous removal of water to favor yield more than 90%.
 Exactly reverse is the condition with lactone formation
O
DABCO ,R.T.
O H2 O
HO mukiyama esterification
OH O

4-hydroxybutanoic acid cyclic 5 membered lactone.

ΔHº = +1.10 kcal/mol ΔSº = +13.9 cal/ ºK mol ΔGº = –3.1 kcal/mol
There is 1.90 kcal/mol increase in ΔHº is due to combination of angle, eclipsing and other
conformational strains contributing to overall ring strain, hence we can expect ΔGº to be
less negative.
 This lactonization is known to occur in (CH2) n when n=2,3
Below this(n=1) lactonization is unfavored as it may result in highly
strained ring increasing ΔHº so much that ΔSº cannot counterbalance it,
thus leading to a +ve ΔGº value and decrease in spontaneity.
Above this (n>3) particularly in 7 or 8 membered rings, the probability
of –OH and -COOH group coming closer is low. Hence dimerization or
polymerization can is preferred over intramolecular lactonization reaction.
 MOLECULARITY AND IT’S DETERMINATION
 It is the total count of number of atoms, molecules or ions colliding
together in the slow rate-determining step of a reaction.

 Classification of molecularity
 Molecularity is classified on basis of number of molecules taking part
in reaction, illustrated as follows
• Unimolecular :-when one reactant disintegrate to form products.
• e.g., N2O5 N2O4 +1/2O2

• Bimolecular :-when two molecules collide to form products.

 e.g., C12H22O12(sucrose) +H20(excess)
C6H12O6(Glucose)+C6H12O6(fructose)

 Termolecular :- when three molecules collide to form products.

 e.g., 2 Cl Cl 2Cl 2
2
• 2NO + O2 2NO2
KINETICS OF REACTION
 Kinetics is the study of
How fast the reactant is converted to product.
Relates to reaction rates.
Pathway for the reaction.
 Kinetics depend on following factors,
Activation energy to cross the barrier.
Concentration
Temperature of the reaction
Catalyst and co-catalyst (lowers the activation energy for
the reaction without affecting reactant or products).
RELATION OF KINETICS WITH REACTION RATES.

• As per the Arrhenius equation the rate constant(small k)

is inversely proportional to the energy of activation(Ea).
• Faster the reaction is larger will be the rate constant
• Catalyst increases the rate of reaction by forming a
different pathway which decreases the Ea and hence
increasing the rate constant k.
• The rate law and rate equation are experimentally
determined quantities (not involving theoretical
calculations). They show the relations between the
concentration of reactant with the reaction rate.
ENERGY PLOTS.
 It is a schematic plot representing the the changes in ∆Hᵒ or ∆Gᵒ of
system with respect to the reaction progresses (from reactant to
product).
 ∆Hᵒ or ∆Gᵒ are –ve when the reaction is exothermic or exergonic
respectively i.e., the products having lower energy than the
reactants.
 ∆Hᵒ or ∆Gᵒ are +ve when the reaction is endothermic or endorgenic
respectively i.e. the product having higher energy than the reactant .
 They are plotted with energy on the Y-axis and the reaction
coordinate (on simpler terms, progress of reaction) on the X-axis.
 The maxima on the energy profile is typically transition states, the
energy required to attain that level is the energy of activation
represented by Ea.
EXOTHERMIC AND ENDOTHERMIC REACTIONS
 Exothermic and endothermic reactions

E energy of activation
energy of activation
E
energy of products

energy of reactants energy absorbed

energy released
energy of products energy of reactants

course of reaction course of reaction

EXOTHERMIC REACTION
ENDOTHERMIC REACTION
 ENERGY DIAGRAM FOR A TWO STEP PROCESS
 Consider a two step process in which a nucleophile X─ attack the AB molecule giving
AX as products. R. L. S. X
A B A + B STEP II A X
STEP I

PLOT OF ENERGY FOR STEP I PLOT OF ENERGY FOR STEP II

T.S. I A X
A B
T.S. II

E E A+ B + X Ea(II)
A +B
Ea(I) dH(II) A X
d H(I)
A B
progress of reaction
progress of reaction

1. The highest transition state is for step I

(higher Ea). This will be the slowest step OVERALL PLOT OF ENERGY
and hence is the Rate Determining step . A X
T.S. I T.S. II
2. The overall reaction is endothermic
(⍙H is +ve). E A+ B + X Ea(II)
3.Each step is characterized by it’s Ea(I)
own ⍙ H & Ea values. d H(I) dH (II) A X
4.Step II is faster step having lower dH(total)
ectivation energy. A B
progress of reaction
 RATE OF REACTION (MEASURE OF HOW FAST A
REACTION PROCEED)
 It is a measure of the rate with which reactant are consumed to form
products (which may vary from a few seconds to years).
 It can be expressed as decrease of concentration as a function of time.
Rate = - ⍙[A]/ ⍙t
 ⍙[A]= concentration of reactant A in mol dm-3.
 ⍙t= time expressed in seconds.
 The rate of reaction is by two theories
 The rate of reaction depends on Activation energy, Frequency of
collisions, and a Probability factor (factor specifying that molecule have
proper orientation).
FACTOR AFFECTING RATE OF REACTION
:- increase in temperature result in higher speed of
molecules effecting successful collision.
:- increase in pressure, lesser the volume, particles are more
closer (mostly in case of gaseous reactant).
:-rate of reaction is directly related to increase in
concentration as more number of molecule result in more collisions.
:- more surface area results in greater space, increasing
probability of collisions (mostly in solid reactant).
:- catalyst speed up the reaction by providing alternative path
which decreases the activation energy hence reactant don’t have to
overcome the much higher activation barrier as in an uncatalysed
reaction.
:- they act as obstacles in the rate of reaction which may
decrease the rate to considerable extent or completely.
RATE LAWS AND RATE CONSTANT

 Rate law is a mathematical expression, which relates the decreases

in concentration of a reactant with time and it is determined
experimentally.
 Order of reaction :-the power to which the concentration term of
reactant is raised in the rate equation determine the order of
reaction. Order of reaction has no relation with stoichiometry of
reactant.
 aA(l ) products
 Rate =k[A]m here m represents order of the reaction with
respect to reactant (A in the present case).
 Larger the value of k is the faster will be the reaction.
 k is independent of concentration.
UNITS FOR RATE CONSTANT OF A REACTION

 The equation of rate is given as, RATE= ___mol L-1s-1

 Concentration of A is given as [A]=____mol L-1
 Hence, we get k= ___[mol L-1](1-n)s-1
 k(for a gaseous reactant)=___ atm(1-n)s-1
 For of reaction of various order the unit of k can be written as
ORDER OF UNITS Units for gaseous
REACTION reactant.
Ist s-1 s-1
IInd mol-1dm3s-1 or Atm-1s-1
mol-1 L s-1
IIIrd mol-2dm6s-1 or Atm-2s-1
mol-2L2s-1
 The overall order is the sum of the exponents of all the reactants in a
rate equation. Reaction rates are classified as zero order, first order,
second order or mixed order.
 The order of a reaction is determined experimentally by following
methods.
 Half rate method, initial rates methods, graphical method, etc.,
 Half rate method
 Half time (t1/2) is the time taken for one half part of reactant to
react.
 Faster reaction have larger rate constant and shorter half life.
 The (t1/2) for various order is deduced from following equations
Order of reactant Half time (t1/2)
0 [A] 0/2k
1 ln2/k or 0.693/k
2 1/{k[A] 0}
 Initial rates methods:-
 In this method, the concentration of reactants is kept constant, except
that of one reactants, in each experiment for which the rate is
determined.
 Example: Bromination of acetone
O O
acid
Br2
-HBr Br

Rate of reaction =k[acetone] a [Br2] b

 The data obtained is as follows,
Experiment [acetone] [Br2] Rate in
mol-1dm3 mol-1dm3 mol-1dm3s-1
1 0.1 0.1 1.64 ×10-5
2 0.2 0.1 3.29 ×10-5
3 0.1 0.2 1.645 ×10-5
 Hence, Rate = k[acetone] 1 [Br2] 0
 The rate is first order in the case of acetone and zero order in the case of
bromine, hence the overall order is a+b=0+1= 1 (first order reaction).
 Graphical method (Valid for one reactant)
 Also called pseudo rate law method
 Consider a reaction A +B Products
 Initially the concentration of A is kept 100 times greater and the rate
equation is deduced for a constant concentration of B
Rate = k[B] n
 The same procedure is followed by keeping reactant A constant &
concentration of reactant B 100 times greater than A
Rate= k[A] m
 The rate of reaction can be determined graphically by plotting the co-
ordinate as follows, the graph which give a straight line plot correspond
to the order of reaction.

X-axis Y-axis Integrated Rate law Rate law Order

[A] t [A]= [A]0 - kt Rate= k 0
ln [A] t [A]= ln[A]0 - kt Rate =k[A] 1
1/[A] t [A]= [A]0/{1 + k t [A]0} Rate = k [A] 2 2
Basic Stereochemical Considerations
Key words: chirality, chiral carbon, enantiomers,
diastereomers, absolute configuration, relative configuration,
optical activity

1
Key Concepts

Basics of projection formulae

chiral carbon
chiral molecules
optical activity
Stereoisomers (Diastereomers, Enantiomers)

2
Introduction
In this module, some of the key stereochemical concepts are introduced. These
concepts appear in many places in this course. The most important concepts such as
projection formulae, chirality are introduced in detail. The students are encouraged
to refer to specialized book on stereochemistry for additional details.
The concept of stereochemistry and its proper understanding is very much required
for several other chapters in this course as well as other courses in organic
chemistry. In particular, the stereochemical concepts are widely used in asymmetric
synthesis. Similarly, pericyclic and photochemical reactions use significant amount
of stereochemical details.

3
Representation of three dimensional structures-METHANE
H

H C H 2D drawing 3D drawing
H

1
1 1

2 = 3 4 = 3 4
3
4
2 2

view Fischer Projection

Perspective drawing
Or Flying-wedge formula 4
Representation of three dimensional structures-ETHANE

Flying-wedge formula

Sawhorse formula
3D Image

Newman Projection

Fischer Projection
5
Projection Formulae Inter-conversion

Fischer Projection Newman Projection

Fischer projection refers to eclipsed conformation

6
 Isomers
Isomers are different compounds with the same molecular formula

Isomers can differ in,

(1) Constitution: connectivity between atoms are different
----Constitutional isomers (Structural isomers)

(2) Orientation of atoms in space:

----Stereoisomers

7
 Isomers

E.g., C4H8

H3C CH3 H3C H

C C C C

H H H
Stereo
CH3

cis-2-butene trans-2-butene

Constitutional
H2C H

C CH

H CH3

1-butene

8
 Isomers

E.g., C8H8
H H

C C

H Used for making polymers

Styrene

Constitutional
Used as solid propellants
(strain energy of 166 kcal/mol)
Cubane

Polynitro cubane is an
explosive!
9
 Important Terms to know
conformer configuration
• Conformation of molecule arise due • It is a permanent spatial arrangement
to free rotations around single bond. of molecule which can only be
changed by bond breaking and
reforming (such as a double bond)
• Stereoisomers which can interconvert
at low temperature separated by a low • Stereoisomers having high energy
energy barrier of [E < 60 kJ mol-1 barrier [E >100 kJ mol-1] and stable at
]are called conformers. room temperature are called
conformers.
• For spectroscopic analysis of
conformers they should be subjected • A configurational isomer is relatively
to a lower temperature which can stable and can be well elucidated at
freeze or slow down the rapid flipping ambient temperature.
between two conformers to elucidate
data of particular conformer.
 Chirality
The word ‘chiral’ is derived from Greek word ‘cheir = handed
Human hands have OBJECT and MIRRO IMAGE relationship
and they are NON SUPERIMPOSABLE

Examples: Shoe, scissors, screw

11
 Asymmetric Center

Chiral Molecules
Chiral carbon has four different groups attached
to a tetrahedral center

12

12
• Examples for chiral molecules
 Chiral Molecules-Enantiomers
Presence of a stereocenter (chiral center) is neither necessary
nor sufficient requirement for molecular chirality
Cl

chiral F
* Br
* *
H

Isomers that are non-superimposable mirror images are

called ENANTIOMERS
H H H H Cl H H Cl

Cl Cl Cl Cl H Cl Cl H

Identical Enantiomers 14
 Chiral Molecules-with no chiral centers
The property of chirality is determined by overall molecular topology

There are many molecules that are chiral even though they
do not possess a chiral center (asymmetric carbon)

H3C
CH3

NH2
H2N

(R)-2,2’-Diamino-6,6’-
Rot. Barrier of more than 22 kcal/mol dimethylbiphenyl

These molecules are axially chiral (axial asymmetry)

arises due to restricted rotation around the C-C bond 15
 Atropisomers
Stereoisomers resulting from hindered rotation about single bonds (due
to high steric strain to rotation)

Vancomycin is a naturally occurring atropisomer

Used against bacterial infections

(also known as drug of last resort)

16
 Optically Inactive!
Presence of a stereo center is not a sufficient requirement for
molecular chirality
Though the following stereoisomer of tartaric acid possesses
two chiral centers, a pure sample of this compound is
optically inactive: MESO
Internal Compensation OR presence of plane of
symmetry!

COOH

H * OH
achiral meso
H * OH

COOH
17
 Chiral Molecules-Optically Inactive
When there is equal composition (1:1) of enantiomers in the
mixture, the resulting solution is optically inactive
External compensation OR cancellation due to opposite
optical rotations: RACEMIC MIXTURE

CH3 CH3
CH3 HCN +
OH CN
C2H5 C2H5
C2H5 O CN OH

1 (50%) 1' (50%)

Achiral chiral chiral

18
 Optical Activity
Chiral molecules interact with plane polarized light

Enantiomer that rotate the plane polarized light to the right (clockwise)
is called dextrorotatory. Represented as “d” or (+)

Other enantiomer that rotates plane polarized light to the left (counter-
clockwise) is called laevorotatory or “l” or (-)
19
 Optical Rotation
Optical rotations are measured by polarimeter
Optical rotation depends on
a) concentration of the sample
b) length of the sample cell
c) wavelength of the incident light
d) solvent
e) temperature

Specific rotation (α ) of a sample at 20 °C is given by,

[α]λ = α / lc
α – optical rotation (°), l – path length (dm), c-
concentration (g/mL)
20
 Properties of Enantiomers
1. Enantiomers are chiral
2. Pure sample of a single enantiomer is optically active
3. Enantiomers have identical physical and chemical
properties in an achiral environment
4. Different biological properties
(+) or dextro (-) or laevo
Example CH3 CH3

CH2OH H
C2H5 C2H5
H CH2OH
[α] +5.9 -5.9
BP 128.9 128.9
µ 1.4107 1.4107 21
 Properties of Enantiomers differ in Chiral medium
Biological properties of enantiomers are different, as the
receptor sites are chiral
HO COOH
E.g., 1 • L treatment of Parkinson’s
*
NH2 disease
DOPA HO
• D biologically inactive !
DihydrOxyPhenylAlanine
E.g., 2
O
Thalidomide • R against nausea
N • S cause fetal damage
* O

O N O
E.g., 3 H

(+)-glucose is metabolized by animals but NOT (-) glucose!

22
 Relative Configuration
Glyceraldehyde is one of the simplest chiral molecule– sugar (carbohydrate)

CHO CHO

H * OH HO * H
D-(+)-glyceraldehyde L-(-)-glyceraldehyde
CH2OH CH2OH

(+) (-)

Glyceraldehyde is used as a standard for assigning relative

configurations
Any enantiomerically pure compound that could be related to the
configuration of
D-(+)-glyceraldehyde is labeled as D
and
L-(-)-glyceraldehyde is labeled as L
23
Important: note the use of capital letters
 Fischer D and L projection nomenclature.
• Hermann Emil Fischer established configurational nomenclature for sugars &
amino acids by first studying it on D-Glucose.
• For descriptions according to the nomenclature the molecule is placed
vertically on a straight chain with most oxidised end placed at the top.
• The bottom most carbon far away from the oxidised end is then taken into
consideration. If –OH (or –NR2 ) group on that carbon is present on the
right(dextro) the molecule is assigned D configuration and if present on the
left (laevo) then L configuration.
• In the examples below the 4th assymetric carbon is the highest numbered
carbon from most oxidised carbon with –OH group on left side hence named
L-Glucose.
 Relationship with Glyceraldehyde
CHO

H * OH D-(+)-glyceraldehyde
CH2OH

Br2 / H2O

COOH COOH COOH

PBr3 Zn / H+
H OH H OH H OH

CH2OH CH2Br CH3

D-Lactic acid

Maintaining the basic

connectivity, D-lactic acid is D-optical family
related to D-glyceraldehyde 25
 Optical Families
CHO CHO

H * OH HO * H
D-(+)-glyceraldehyde L-(-)-glyceraldehyde
CH2OH CH2OH

CHO CHO

(CHOH)n (CHOH)n
D-sugars L-sugars
H * OH HO H

CH2OH CH2OH

CO2H CO2H L-amino acids

D-amino acids
H NH2 H2N H

R R

26
 R/S (absolute) versus D/L (relative)
There is NO direct relationship between the
configurational descriptors R/S or D/L
and
The sign of rotation
Sign of rotation of a sample should be measured using a
polarimeter.
CH3 CH3

Lactic acid H H
Sodium lactate
HO HO
COOH COONa

(S) -(+)- Lactic acid (S) -(-)- Sodium lactate

27
 Absolute Configuration
3D structure can be specified without the help of
formulae
Using stereochemical descriptors “R” and “S”
R = Rectus, S = Sinister [Latin word for clockwise and counter clockwise]

R-S notations are based on Cahn, Ingold and Prelog’s

sequence rules

28
 CIP-Sequence Rules
Two step process: (1) First assign priorities for four
substituents (ligands) (2) assign the name based on the
positions of these substituents

1. Ligands of higher atomic number get higher priority

than ligands of lower atomic numbers
Cl Cl
2 2
Cl Cl
Br C F = H F C Br = H

F
H
1 Br F 3 H 3
Br
1

1-2-3: clockwise : R counterclockwise : S

One interchange! 29
 CIP-Sequence Rules

2. In case of ties, use the next atom along the chain and
use rule no. 1 (as before)

CH2CH3
2
CH2CH3
H3C C CH2OH H
=
H3C CH2OH
H
3 1

counterclockwise : S

30
 CIP-Sequence Rules

3. All ligands in a given sphere must be explored before

proceeding to the next (principle of outward exploration)
22
21 23

O
2 OH 2
31

H3C C OH 1 C 3 32

3 1 33
4
H

Absolute configuration is S

31
 CIP-Sequence Rules

4. Each atom at a multiple bond is associated with a

phantom (duplicate/triplicate) atom of the species at the
other end of the multiple bond

O C O (C)

(O)

C C C (C)

(C)

32
 Permitted Changes in CIP Rules

Double exchanges OR two successive exchanges of two

ligands in a Fischer projection will retain the
configuration

Br Cl

Cl H
is same as Br F
R-enantiomer
F H

Interchange of one set of ligands in a Fischer projection

will lead to opposite enantiomer

33
 Stereoisomers
Orientation of atoms in space is different in stereoisomers
(Spatial isomers)

They are

Diastereomers Enantiomers

Cis-trans Conformers

Rotamers

34
 Diastereomers
Diastereomers are stereoisomers that are not enantiomers
They are chemically (and physically) different

OR
Stereoisomers that are not mirror images

E.g.,1 COOH
HOOC COOH

HOOC

Fumaric Acid Maleic Acid

MP: 299-300 ºC MP: 140-142 ºC

Forms anhydride upon heating35
 Diastereomers
Example 1:

NHCH3 NHCH3

R S
S S

OH OH

Ephedrine pseudoephedrine
(+)-ephedrine is used in
traditional medicine
(as a nasal decongestant)

Diastereomers can be chiral or achiral

36
E.g., cis-trans geometrical isomers
 Diastereomers
Diastereomers can be chiral or achiral

Large number of diastereomers are available which are

compounds containing two or more chiral centers (usually
asymmetric carbon atoms)

Ar Ar CO2CH3

E.g.,1 SR SS
* *
O CO2CH3 O

Enantio Enantio
CO2CH3

Ar O O
RS Ar CO2CH3
RR 37
 Practice Problems
(1) Identify the stereochemical relationship between the given pair of
compounds

(2) Draw the Fischer projection for the following compound

(3) Name the following compound with stereochemical description

(4) Comment whether the following compound is chiral and achiral. Explain

38
Answers
(1) Enantiomers, Diastereomers,
Diastereomers
(2)

(3) (S,E)-4-methylhex-2-ene

(4) Achiral, the molecule has a center of inversion

39
Key words: reaction mechanism, intermediates, kinetic
studies, trapping of intermediates, rate of reaction
Introduction
Reaction mechanism is a step by step description of a sequence of
elementary reactions through which the overall chemical change occurs.
Which bonds are broken, which are formed, in what sequence/order, how
many steps are involved and relative rates of each such steps are the details
one can obtain through the study of reaction mechanism.
Course of reaction i.e. mechanism of reaction can be determined by various
methods available.
 Nature of products :
Of all available ones, most useful information can be obtained by, study of
products obtained, in course of a chemical reaction.
In organic reactions, more than one product can be obtained. So, in order to
determine the mechanism of reaction, one should know the relative amount of
products formed. This can be done by various methods available like
chromatography, spectroscopy etc.
e.g. in reaction of p-chlorotoluene with amide in liquid ammonia,
m-toluidine is also obtained, along with expected p-toluidine and is in fact
major product.

Cl NH2
NH2

NH2 in liq. NH3

+

p-toluidine + m-touidine

Later can not be obtained by simple substitution of chloro by amino group.

And if both products are obtained through same intermediates then, the
former also, can not be obtained by direct substitution. And some different
mechanism is taking place, in which, symmetrical intermediate is formed,
which later proved to be benzyne intermediate.
Kinetic studies :
Determining reaction mechanism from kinetic data is one of the most widely
used techniques. This technique is based on the study of change in
concentration of either the reactant or product.
The choice of method depends on its applicability to the reaction being
studied. Some common methods include
Monitoring through periodic or continuous measurements (using
spectroscopy, polarimetry), quenching and analyzing the reaction mixture at
regular intervals by taking out aliquots etc.,
In a chemical reaction, a reacting species may be or usually different from
what is been introduced into the reaction mixture. The relation between these
two may be quite complex too.
In an aromatic nitration reaction, the effective attacking species is, NO2+, but
changing concentration of HNO3 is what one would typically measure.
Also, merely by observing the rates of chemical reaction, its mechanism can
not be deduced.
 In hydrolysis of alkyl halide in aqueous solution, rate is found to be,
rate=k[alkyl halide].
From this equation, it can not be concluded that, water is not taking part in
the rate determining step. But, its concentration is so large that it virtually
remains unchanged.
Many organic reactions are carried out in solution and small changes in
solvent can have profound effect on mechanism. This is particularly true for
ion forming reactions, when used in polar solvents.
In contrast, reactions involving radicals are less influenced by solvents, but
are influenced by the presence of radical sources or radical quenchers.
Use of isotopes :
Whether, a particular bond is broken or not, in the rate determining step of a
reaction under also provides useful information. Simple kinetic studies can
not explicitly provide this information. But, can be obtained by using
isotopically labeled compounds.
For example, whether C-H bond is being broken or not in the rate
determining step can be confirmed by replacing the C-H bond of interest with
a C-D bond and measuring the relative rates between modified and
unmodified substrates .
Two bond dissociation energies will be different as the two atoms have
different masses. This will influence the rate of reaction. E.g., The rate of
oxidation of Ph2CHOH is 6.7 times faster than Ph2CDOH.
OH O
MnO4

OH
Ph Ph Ph Ph

This clearly indicates that C-H bond is involved in the rate determining step.
It is known as Primary kinetic isotope effect
The change in reaction rate that occurs upon isotope substitution is known as
kinetic isotope effect.
An isotopic substitution will have a pronounced effect on the reaction rate
when the isotopic substitution (i.e. D for H) is part of a chemical bond that is
broken, formed or modified in the rate determining step. The magnitude of the
effect is dependent on whether the bond with the isotopic substitution is being
broken or formed (primary KIE) or if the hybridization of the atom to which
isotope is attached is changing (secondary KIE).
In summary, primary kinetic isotope effect is a change in rate due to isotopic
substitution at a site of bond breaking or bond making in the rate determining
step of a mechanism.
 Kinetic isotope effect can also be observed with other pair of isotopes such
as H & T; 12C & 13C or 14C; 16O & 18O; 35Cl & 37Cl etc.,
Kinetic isotope effects are expressed as the ratio of the reaction rates in the
presence of the reactants when containing one isotope as compared to the
other.
It is observed experimentally and its values are intermediate between unity
i.e. no isotope effect and maximum as large as ~7 (at 250C) in case of H & D.
For other elements, these values are low because relative mass difference is
small.
Secondary kinetic isotope effect, on the other hand, is the change in rate due
to isotopic substitution at site(s) than that of bond breaking or bond making in
the rate determining step of a mechanism.
Primary Kinetic Isotope Effect: Typical Values

Nuclide k l i ght k heavy o

(at 25 C )

C-H/C-D 6-8

C-H/C-T 15 - 16
12 13
C/ C 1.04
12 14
C/ C 1.07
14 15
N/ N 1.03
16 18
O/ O 1.02
32 34
S/ S 1.01

35 37
Cl/ Cl 1.01
 Isotope can also be used in studying mechanistic problems that are non-
kinetic and useful information can be obtained by isotopic labeling.
e.g. Aqueous hydrolysis of esters to yield acid and alcohol can, in principle,
proceed through alkyl or acyl oxygen fission.
If the reaction is carried out in labeled water containing 18O, path-a will give
alcohol with 18O and path-b will give acid with 18O (shown below)
O
+ R'18OH
(a)
O R OH
(a)
H218O
R'
R O O
(b)
(b) + R'OH
R 18OH

Most simple esters are found to yield 18O enriched acid, indicating path (b)
i.e., acyl oxygen fission.
Study of intermediates :
Among all these methods, most concrete evidence is obtained by, actual
isolation of intermediate involved in the reaction.
In Hofmann rearrangement, thus, if carefully isolated, all intermediates can
be obtained. These are N-bromoamide, its anion and an isocynate. This
clearly gives insight of the mechanism of reaction.
O
R C NH2 + NaOBr R N C O

O O
O
R C NH OH Br Br OH
R C NH R C NH
H Br
N-bromoamide
O O
R C N Br R C N R N C O
Isocynate
 The isolated intermediate should be distinguishable from the final product or
other side products. The species isolated should also be a true intermediate or
should be in equilibrium with a true intermediate (toward establishing the
mechanism convincingly)
Some intermediates are very labile to be isolated by regular techniques. Such
species can be detected by physical techniques (spectroscopic methods such
as ESR, NMR, IR), or by trapping with other species so as to divert it from
forming the final product.
Presence of one such species, carbene can be confirmed by its reaction with
cis-2-butene. It gives stable cyclopropane derivative.

Cl

+ CCl2 H Cl H
Me Me

Me Me
 Another example for the existence of of intermediate such as benzyne can be
proven by trapping through a Diels-Alder reaction as shown below.

COOH
COO
NH2 N
N
HNO2

O O
O O OR

O Diels-Alder O
reaction

O
O O
O
O
O
Application of Raman spectroscopic methods have helped in the detection of
NO2+ species in nitration of benzene.

To be convincing, evidence for an intermediate should include:

 detection of intermediate in the reaction mixture, perhaps by trapping
reaction
 demonstration that intermediate gives product when added to the reaction
mixture i.e. it can be prepared as reasonably stable compound
 kinetic evidence that the rate of formation and rate of disappearance are
adequate
Stereochemical criteria :
Study of stereochemistry of product can also provide some useful insight on
the course of reaction.
Optically active stereoisomer of a ketone (shown below), on base catalyzed
bromination, gives an optically inactive racemic product. This indicates the
involvement of a planar transition state or intermediate, which can be attacked
by the incoming nucleophile from both sides to give equal amount of both
stereoisomers.
O O
Br2 / HO
Ph Ph
Br

This implies that reaction must be taking place in two steps.

 Another useful reaction is nucleophilic substitution of epichlorohydrin by
naphthyloxide anion.

O
OH
O O
base
+ Cl

Investigation of product formed in the reaction, when enantiomerically pure

epichlorohydrin is used, suggests that, reaction can not be taking place by
simple SN2 pathway. As it would give the product with opposite
stereochemistry, than is obtained in the reaction.
Formation of the product other than expected can be accounted by taking
into consideration, the other way of nucleophilic substitution.
 O O O
SN 2 SN 2
Cl OAr
Cl OAr

ArO ArO

SN 2

O
ArO

ArO :

In fact the reaction goes through this mechanism where naphthyloxide anion
attacks other side of epoxide ring, resulting in ring opening and then followed
by ring closure other way round.
 Nucleophilic substitution
Reactions
Key words: nucleophilic substitution reaction, carbocation
intermediate, solvent effects, rate of reaction, inversion of configuration
 Introduction
In this module, details of different types of nucleophilic
substitution reactions are described. These reactions are an useful
class of reactions for carbon-carbon and carbon-heteroatom bond
formation reactions. The approach is also widely used for
synthetic transformations (e.g., leaving groups such as tosylates).
Depending on the nature of the nucleophiles and reaction
conditions, different mechanisms are possible. These reactions
typically occur on a saturated carbon atom, attached to a leaving
group. You will find terminologies such as intermediates,
transition states etc., in this module.
I. Nucleophilic substitution reactions bimolecular (SN2)

 The notation SN2 represents Substitution Nucleophilic Bimolecular.

 This mechanism is a concerted process in which the bond forming and bond
breaking occur simultaneously.

 Energy required to break the bond is compensated by bond

formation.
 Kinetics
 The rate of the reaction is found vary linearly with non zero slope with
respect to electrophile as well as nucleophile .

rate α [elec][nucl]

 In the presence of large excess of nucleophile, the kinetics tends to follow first
order even though the mechanism is bimolecular.

 Nucleophile affects the rate even being in large excess but concentration does
not vary significantly and rate is found to be determined alone by the
electrophile. Such a situation is known as “Pseudo first order reaction”.
 Mechanism
 During SN2 reaction nucleophile first approaches the anti-bonding
molecular orbital of the C-L bond.
 The attractive interaction between the donor orbital (filled electrons) and the
acceptor orbital (unfilled) results in a new bonding between incoming group
and the carbon atom. Simultaneously the leaving group begin to depart away
from the carbon center.

 Substitution may be possible either via front side or backside attack of

nucleophile.

 In SN2 substitution backside attack is preferred in which approach of the

nucleophile is 180⁰ away from the leaving group.
 Walden Inversion
 Complete inversion in stereochemistry is observed during aliphatic
nucleophilic substitution via SN2 pathway, confirming that backside
attack is preferred over the front side attack.
 Stereochemical outcome of the SN2 reaction is termed as Walden
inversion in honor of his discovery.
Additional terminologies: Nucleophile and Nucleofuge
 Nucleophile is a species that would combine with a positive charge (nucleus)
to which it can donate its electron.
 Usually nucleophiles are electron rich species.
 They have higher energy HOMO

 A Nucleofuge is nucleophile that departs from a molecule (leaving group)

 The terms Nucleophile and Nucleofuge are generally used in the

discussion of reactivity and kinetics.
 Effect of Solvent
 Solvent may play a vital role in the rate of SN2 reaction as it involves either
creation or dispersion of charge (particularly in the transition state).
 Charged species are more stabilized in polar solvent than non-polar
solvent.
 Difference between the solvation capacity of reactant and transition state in
various solvent lead to the solvent effect in a reaction.

Reactants Transition State Charge Effect of

Creation/Dispersion Increasing the
Polarity of Solvent
δ δ Charge dispersion Retard the reaction
Nuc R-LG Nuc R LG

δ δ Charge creation speed the reaction

Nuc R-LG Nuc R LG

Nuc R-LG δ δ Charge dispersion Retard the reaction

Nuc R LG

Nuc R-LG δ δ Charge dispersion Retard the reaction

Nuc R LG
 In the case of a negatively charged nucleophile, a remarkable change in the rate
of SN2 reaction is observed while changing the solvent from polar protic to polar
non-protic solvent.
 In polar aprotic solvents, negatively charged nucleophile are generally less
soluble but solvent are polar enough to solubilize the nucleophile making them
highly reactive.

 Solubility of nucleophile is a major problem in substitution reactions,

particularly in less polar aprotic solvents.
 Crown ether is added to solvate the counter-cation which induce the solubility
of corresponding anionic nucleophile.
Structure Function Correlation with Nucleophile

 In SN2 reaction stronger the nucleophile faster would be the reaction.

 Strength of a nucleophile can be determined by the following general guidelines-
1. A nucleophile with negative charge is more powerful than its conjugate acid.
Example: NH2─ >NH3, OH─ >H2O,
2. Nucleophilicity generally follows similar order as basicity
Example: R3C ─ > R2N ─ > RO ─ > F ─
NH2 ─ > RO ─ >R2NH ─ > ArO ─ > NH3 > Pyridine > F ─ > H2O > ClO4 ─

3. Going down in a group, nucleophilicity increase while basicity decrease.

Example: I ─ >Br ─ > Cl ─ > F ─(less solvation, Higher polarization)
S ─ >O ─
Structure Function Correlation with Nucleophile

4. More free nucleophile, more nucleophilicity.

Example 1: Rate of reaction using NaOH can be largely enhanced by
specifically solvating cation Na+. (use of crown ether).
Example 2: NaOHDMSO > NaOHwater (basicity)
In water Na+ and HO ─ both are solvated while in DMSO
Na+ is solvated preferably than HO ─ leaving HO ─ as free
nucleophile.
Structure function correlation with leaving group
 Negative charge develops on the leaving group during the rate determining
step. Thus, reaction proceed faster with a leaving group which stabilize the
negative charge better.
 Better leaving groups are mostly weak bases which stabilize the negative
charges.
Example: TsO ─ , MsO ─, TfO ─

 In the presence of better leaving group, SN1 reaction do not require strong
base, but for SN2 reaction it is required.

Example:
1. XH is always a weaker base than X ─. Thus XH is a better leaving group which
facilitates SN2 reaction.
HS─ > H2S, HO ─ > H2O, I ─ > HI, NH2 ─ >NH3
2. Acidic medium also protonate the base making them weaker.
ROH is converted to ROH2+ in acid medium which is a better leaving group.
 Structure Function Correlation With R Group
 R group plays vital role on the rate of reaction
 R group may have steric, electronic and neighboring group effect.
 Steric hindrance may slow the rate of reaction, as nucleophile adds to the
carbon centre in the rate determining step.
 In the transition state, the incoming nucleophile(Nuc) and leaving group(LG) are
90⁰ to the R group. Larger R groups can result in increased strain leading to slower
reaction rates.

R R

X Y

0 R 900
90
Bulkier R group increase steric hindrance
Structure Function Correlation With R Group
A bulkier adjacent group may deflect the trajectory of the nucleophile away
from the linear approach.
R
R R

LG
Nuc
R R
Strained transition state due to adjacent group steric effect

 electron withdrawing nature of groups having sp2 carbon(vinyl and phenyl)

makes the adjacent carbon more electrophilic and hence reactivity towards
nucleophile increases.
Example:
Higher rate for nucleophilic substitution at allyl and benzyl system.
 Neighboring Group Participation (NGP)
 In the presence of an electron donating neighboring group, the reaction
proceeds faster than expected. In addition, either inversion nor racemisation is
observed in such cases.
 In the following generalized representation, a neighboring group participation is
illustrated. The lone-pair bearing atom/group such as Z would help in the removal
of the leaving group by the mechanism shown below. (please note that the
incoming nucleophile “Y” attacks the carbon atom of the three membered ring,
not on the R group

 Two consecutive SN2 substitution, leads to retention of configuration.

Example 1
 Neighboring Group Participation
Example 2

_ _
OAc OAc

The most likely neighboring group participation leads to three, five, six
membered rings
 Four membered ring neighboring group participation is higher in case
of alkyl substitution on α or β carbon.
 The effect of halogen increase as going down the group ( I> Br> Cl ).

Some of the neighboring groups are COO ─, COOR, COAr, OCOR, OR, OH,
O─, NH2 , NHR , NHCOR, SH, SR, I, Br, S ─
 SN2 Reaction*
 allylic rearrangement under SN2 conditions are known as SN2 reaction

Simultaneous movement of three electron pair in the transition state

SN2' attack Usual attack(SN2)
X

Attack at γ carbon under SN2 reaction condition is termed as SN2

Note: The attack of the nucleophile is not on the same carbon atom as that of the leaving
group. But the final product resembles that of an SN2 product.
*

Read as SN2 prime

 SN2 Reaction*
 Increasing the size of the nucleophile as well as steric hindrance at the α-carbon
increases the extent of SN2 product
 Leaving group also an affect in deciding the extent of reaction in certain cases.
Stereochemistry depends on the nature of the incoming and leaving groups
in SN2 reaction, still syn-substitution is preferred over anti.
II. Nucleophilic substitution unimolecular (SN1)
Reaction
 Introduction
 SN1 corresponds to Substitution Nucleophilic Unimolecular

 The rate depends on the concentration of only 1 reactant, i.e.,

the substrate and not the nucleophile
 Highly substituted reactants undergo SN1 reactions. Increase in
substitution at carbon favors SN1 pathway.

In this example, heterolytic bond cleavage of C-Br bond leads to a tertiary

carbocation, which is subsequently attacked by the nucleophile (hydroxide
here). The speed of the reaction is decided by how fast the carbocation can be
generated
 Introduction
Example 1

In the above example, protonation of the OH group will convert it into a very
good leaving group (H2O), resulting in the formation of a carbocation. Note that
this is a stabilized carbocation due to extended delocalization of the positive
charge by the three phenyl groups. Subsequently, this will be attacked by the
bromide ion to form the final product

Example 2
 Kinetics
• The kinetics of SN1 follow first order kinetics.
rate α [reactant]
• The rate constant is dependent on how fast the leaving group can depart. It is
independent of the incoming nucleophile

• On what will the rate depend ?

1. The nature of the substrate.

2. The rate of leaving group departure.
3. The nature of the solvent.
 Mechanism
• The first step of the reaction involves the formation of a carbocation. This
is a slow process due to higher activation energy for bond breaking

• Carbocation can be stabilized by the substituents through two important

effects (i) hyperconjugation if the carbon is highly substituted or (i) by
resonance

• The second step proceeds fast as it involves combination of two ionic

substrate and the incoming nucleophile.
 Stereochemistry

• The nucleophile can approach the planar carbocation intermediate from either
of the faces (as shown above), resulting in a racemic mixture with equal
quantity of both enantiomers (provided the R groups on the central carbon are
not identical).
Example:

Attention: the position of the R groups are not

identical in the two enantiomeric products given

Note: The starting compound has a chiral carbon atom here. Upon generation of a planar
carbocationic intermediate, the incoming nucleophile (water in the present case) can either
attack from the top of bottom of the plane, leading to racemization.

In the next section, factors that influence the unimolecular substitution reaction are
described in detail.
 Stability of carbocation
• The rate of SN1 reaction depends on how readily a carbocation is formed and
the effect of such stabilizations in the developing carbocation in the transition
state.
• This will in turn depend on the substituents attached (and the pi bond electron
density in case of allylic and benzylic carbocation).
• The presence of more alkyl groups stabilizes the carbocation by inductive
effect (or/and through hyperconjugation).
C 2H 5

H 3C

CH3

• When the stabilization is assisted by π bonded electron it is called resonance

stabilization. Benzylic and allylic systems provide resonance stabilization.
• Resonance stabilization in allylic and benzylic carbocation.

• Relative stabilization comparison of carbocation :-

• 3⁰allylic ≈ 3⁰ benzylic > 2⁰ allylic ≈ 2⁰ benzylic > 1⁰ allylic ≈ 1⁰ benzylic.
• 3 ⁰ alkyl > 2 ⁰ alkyl > 1⁰ allylic ≈ 1⁰ benzylic .
• The lesser the size of substituent present on carbocation, lower is the
chances of it favoring SN1 pathway.
 Leaving group
 Leaving group has significant contribution to the rate of reaction, easier the
departure of a leaving group, faster will be the rate of reaction.
 Larger anions which can stabilize the negative charge are good leaving
groups. (e.g., a tosyl group)
 Effect of solvent
• Factors that stabilize the developing carbocation in the transition state will
increase the rate of an SN1 transformation.
• Polar solvents can stabilize the carbocation intermediate hence lower the
activation energy, leading to an increase in the rate of reaction.
• Polar protic solvents have high dipole moment which stabilize the T.S.
• Higher the dielectric constant of the solvent, faster is the rate.
• The rate-determining step of an SN1 reaction is the ionization of the leaving
group-carbon bond, polar solvent can best ionise the leaving group.
• Conversion of t-butylbromide to t-butylalcohol or t-butylester taking ethanol
as the reference solvent, conveys that smaller molecule has faster rate.

Solvent Rate of reaction

Pure Ethanol 1
Ethanol with 20% water 10
Equal quantity of both solvent 60
100% water 1200
• Reactions in which polar solvent molecules get added to the carbocation are called
solvolysis reaction.

Note: In the above example, acetic acid acts as the solvent which combines with stabilized
carbocation generated by the heterolytic cleavage of C-Br bond. This can also be termed as
a acetolysis reaction

• As per Huges-Ingold predictions an increase in solvent polarity accelerates

the rates of reactions where a charge is developed in the activated complex
from a neutral or a slightly charged reactant.
• The presence of proton will neutralize the nucleophile, but SN1 reaction rate
is independent of the nucleophile.
• Non- polar solvent provide no assistance to the carbocation stabilization,
hence slow down the rate.
• Some general Issues with SN1 reaction

The ability of certain type of carbocation intermediates formed in SN1 reaction

can rearrange to form another (usually lower energy intermediate) before the
attack of the nucleophile.

It should be noted that the intramolecular rerrangements can be quite fast as it

doesn’t require collision by another species (such as a nucleophile).
Additional/Practice problems with solution

(1)

(2)

(3)
 (4)

(5)
 Introduction
In this module, different types of elimination reactions are described. From
a practical standpoint, elimination reactions widely used for the
generation of double and triple bonds in compounds from a saturated
precursor molecule. The presence of a good leaving group is a
prerequisite in most elimination reactions. Traditional classification of
elimination reactions, in terms of the molecularity of the reaction is
employed. How the changes in the nature of the substrate as well as
reaction conditions affect the mechanism of elimination are
subsequently discussed. The stereochemical requirements for
elimination in a given substrate and its consequence in the product
stereochemistry is emphasized.
 ELIMINATION REACTIONS
Objective and Outline

 beta-eliminations
 E1, E2 and E1cB mechanisms
 Stereochemical considerations of these reactions
 Examples of E1, E2 and E1cB reactions
 Alpha eliminations and generation of carbene
 I. Basics
Elimination reactions involve the loss of fragments or groups from a
molecule to generate multiple bonds.
A generalized equation is shown below for 1,2-elimination wherein the
X and Y from two adjacent carbon atoms are removed,
elimination C C
C C
-XY
X Y
Three major types of elimination reactions are:
α-elimination: two atoms or groups are removed from the same atom.
It is also known as 1,1-elimination.
H
R
R C X C + HX
R Both H and X are removed
Carbene from carbon atom here
R
 β-elimination: loss of atoms or groups on adjacent atoms. It is also
H H known as 1,2- elimination.
R C C R R HC CH R

X H
γ-elimination: loss of atoms or groups from the 1st and 3rd positions as
shown below. Generally such elimination reactions result in cyclic
compounds. H H H R R
R C C C R
H H X
Apart from these three, there is one more way i.e., extrusion reaction in
which a fragment is lost either from a chain or a ring.

X Y Z X Z + Y
 II. More details on β-eliminations
β-eliminations can be further subdivided into three categories
depending upon the mechanistic pathway. The important aspect is to
establish the number of molecules taking part in the elimination step
(molecularity of the reaction)

The types of β-eliminations are

1) E2
2) E1
3) E1cB

These are read as “Elimination bimolecular E2”, “Elimination unimolecular” and

“Elimination unimolecular conjugate base”
 II. (1) E2 Eliminations
Key mechanistic features in this family are
• two groups depart simultaneously
• Involves one step (in other words, no intermediates are involved)
• bimolecular reaction i.e., both substrate and nucleophile participate in
a single step
• The base abstracts the β hydrogen and leaving group simultaneously
leaves such that it forms a multiple bond between α and β carbon
atoms.
Br
EtONa / EtOH + EtOH + Br
Propene

In the example given above, sodium ethoxide acts as the base, abstracting b-hydrogen.
Bromine is the leaving group.
 An illustration of a common elimination reaction is given below,

H H H H OEt H3C H
H3C EtO H 3C
C C + EtOH + Br

H H H H
Br H Br H

The sequence of events involved are,

(i) The attack of ethoxide on β hydrogen and its abstraction as a proton is
the first event. This will leave two electrons of the C-H bond available for
the formation of a new double bond between the carbon atoms.
(ii) As the new double bond is created, the C-Br bond begins to break away
(leaving group). This will result in the departure of the bromide ion.

The events summarized above are the general steps, the extend of bond
formation/breaking would depend on a number of factors described later.
Note: Often times, E2 elimination competes with SN2 reactions. This is due to the
inherent propensity of the incoming nucleophile also to attack the carbon atom
bearing the leaving group. Such situations will lead to substitution products.

E2 C C + NuH + X

H C
Nu
C X H C
SN2 + X
Nu C

Examples of E2 elimination :

O O DBN O O
800

91%
I

Note that examples given here are non-traditional, selected from the list of recently
available examples. Standard examples can be found in basic text books
Additional Examples for E2 elimiations

O O O O
MsCl / Et 3 N

HO OMe OMe

O O
O
OH OMs
N N N
MsCl / Et 3N DBU

O O O
N N N

Suggestions on problem solving skills:

Look at the given reaction and reagents first. Do not worry about the complexity of
the given substrates. Focus on the ‘site-of-reaction’
In the above examples, Et3N is obviously the base, and ‘OH-group’ should be
removed. Now, note that OH is a poor leaving group and conversion to O-mesyl is
required here (achieved through the use of mesyl chloride, MsCl).
 II. (2) E1 Eliminations
Important characteristics include,
it is two step reaction.
• First step is similar to that of SN1 reaction i.e., the generation of
carbocation intermediate. Subsequently, hydrogen is abstracted by
the base rather than attack on the carbocation as in SN1
• only one of the substrates is involved in the rate determining step
i.e., unimolecular reaction.

CH3 CH3
EtOH/ H2O
H3C C Cl H2C C
CH3
CH3
Step 1 :

CH3 CH3
slow + Cl
C
H3C H3C CH3
H3C Cl

departure of chlorine with stable carbocation

bonding electron pair (tertiary)

Step 2 :
H
HO CH3 H CH3
C C + H 3O
H C
C CH3 H CH3
H
attack of on the β hydrogen and subsequent
waterH or solvent molecule
movement of electron pair to the developing carbon carbon double
bond.
Note: Even though a sp3 C-H bond is not acidic in a general sense, the
presence of a carbocationic center adjacent to it renders increased
acidity such that even a weak base such as water can deprotate.
Similar to the competition between E2 and SN2 pathways, E1
mechanism competes with SN1.

Formation of carbocation is a slower process, as compared to the

reaction between a ‘reactive-carbocation’ and a base/solvent.
Hence, carbocation formation is the rate determining step.

Ideal conditions are for E1 mechanism are (a) highly substituted carbon
atom for the carbocation center, such as a tert-carbon atom, (b) use
of polar solvents (which can stabilize the resulting carbocation in
addition to stabilizing a polar transition state involved in the
heterolytic bond cleavage.
Examples for E1 elimination:
O
NMe 2

OH

H 2 SO 4

O
NMe2

It can be readily noticed that the carbocation generated in the first step would be
stabilized species due to effective delocalization promoted by the presence of two
phenyl groups on the tert-carbon.
 III. E1cB Eliminations
• This is a two step base-induced β elimination.
• In this reaction base first abstracts the β hydrogen, giving rise to a
carbanion or conjugate base of the substrate from which the
leaving group departs subsequently to form the product.
• An interesting comparison can be done with the E1 pathway. The
timing of departure of the groups is reversed as compared to that in
E1 reaction. In E1cB, the deprotonation occurs ahead of leaving
group departure
• Reaction usually follows second order kinetics but is designated as
E1cB to indicate that the departure of the leaving group is from the
initially formed conjugate base (i.e., carbanion).
Illustration of E1cB mechanism

Step 1 :
H C C X C C X + BH
B

attack of the base on the β hydrogen.

β hydrogen leaves without its carbon electron pair forming a carbanion.

The electron pair then move towards the new C-C double bond to be
generated.

Step 2 C C X C C + X

departure of the leaving group to give product.

These reactions require substrate which contain groups that can stabilize
carbanions i.e., presence of electron withdrawing group

Cl F
MeONa / MeOH C C + F
Cl2CHCF3 Cl2C CF3
Cl F
Additional Details on E1cB: Depending on the nature of the rate-
determining step, there are different ways by which reaction can
proceed,
a. Carbanion returns to the starting material faster than the product
formation. Step 1 is reversible and step 2 is slow. It is designated as
(E1cB)R.
b. Product formation is faster as compared to return of proton to
carbanion. Step 2 is irreverersible and step 1 is slow. It is designated
as (E1cB)I.
 R
R B
NO2 CH2 CH2 N R NO2 C CH2+ BH + N R
H R
R

c. Carbanion goes slowly to product formation as it is very stable.

Step 1 is rapid and irreversible. It is designated as (E1)anion.

H3CO Ph H3CO Ph
NO2
NO2
MeO
H

Ph Ph

NO2 NO2
rearrangement
 Mechanistic Continuum
Thus far we have studied three major classes of elimination reactions.
E2, E1, and E1cB can be regarded as ‘extremities’ or ‘ideal’
situations.
In reality, dependence on the nature of substrates and reaction
conditions have a huge influence on the course of the reaction.
In fact, one can use what is known as ‘variable E2 transition state
theory’ to explain the continuum of mechanistic possibilities. In
other words, clear demarcation between these mechanistic types
are difficult.

For additional reading: refer to “More O’Ferrall Diagram”

 IV.Variable transition state theory
for elimination reaction
Many β elimination reactions proceed via mechanisms, which are
intermediate between the extremities such as E1cB and E1. This is
called variable E2 transition state theory.
The timing of deprotonation and departure of the leaving group is the
key to the following mechanistic continuum
increasing C-X breaking in transition state

H B H B H B H B H
δ δ

X X X Xδ Xδ

E1 cB E1cB like synchronous E2 E1 like E1

increasing C-H breaking in transition state

The other way to depict the variable transition state theory is to
construct three dimensional potential energy diagram.
Consider example of ethyl halide. The two intermediates involved in
two extreme processes are;

CH3 CH2 X CH3 CH2 + X E1

base E1cB
CH3 CH2 X CH2 CH2 X + BH

When there are no suitable stabilizing groups, both primary carbocation

and primary carbanion are highly unstable. If we construct a diagram in
which progress of C-H bond breaking is one dimension, progress of
C-X bond breaking is second dimension and energy of reactant system
is third dimension, then following diagram is obtained.
 CH2 CH2 X +BH H2C CH2+ BH + X

C-H E1cB
cleavage E2

E1
CH3 CH2 X + B CH3 CH2+ X + B
C-X cleavage

This is two dimensional representation which shows that E1

corresponds to complete C-X breakage before C-H bond breaking
while E1cB corresponds to complete C-H breakage before C-X.
When energy axis is also included in this diagram it looks like
CH2CH2X + BH

CH2=CH2 + BH + X

CH3CH2X + B CH3CH2 + B + X
three dimensional diagram depicting transition state
locations for E1, E1cB and E2 mechanisms
In this diagram, E1 and E1cB intermediates are respectively
placed at front right and back left corners. These two are high
energy intermediates.
The lowest energy path is a concerted E2 path which is almost
diagonally across energy surface. Reason for this is that
double bond character developing between α and β carbon
compensates for the energy required for breaking the C-H
and C-X bonds.

Following paragraph is only for additional reading

If the substituent can stabilizes the developing carbocation, then that would
cause lowering of right front corner of diagram. The E2 transition state will
then move closer to point where it resembles E1 transition state.
Similarly, for substituents which can stabilize the developing carbanion, will
lower the back left corner of diagram and subsequently E2 transition state
will begin to resemble closely to that of E1cB transition state.
In E1 like transition state C-X bond cleavage is more advanced than C-H bond
cleavage and vice versa for E1cB transition state.
 Important factors that influence the
reaction mechanism
E1
i. electron donating ability of substituents
ii. good leaving group
iii. solvents of high polarity
These factors will favor E1 pathway. Base is not important in the rate
determining step but its presence is important.
E2
Base participates in the rate-determining step
i. strength of base
ii. nature of leaving group
iii. nature of the solvent
If strong base is used reaction will move towards E1cB like pathway
whereas good leaving group with strongly ionizing solvent will cause it
to move towards E1 pathway.
 V.Orientation of double bond

In a substrate where the double bond can be generated in

different regions of the molecule, the obvious question is
whether one can predict which one is likely to be the major
product. Here comes the issue of ‘regio’ ‘selectivity’

Regioselectivity:
In many substrate, more than one kind of β hydrogens can be removed
in an elimination reaction. Which of the β hydrogens is lost depends
on various factors. Three rules generally govern regiochemistry.

(1) Zaitsev’s Rule, (2) Hofmann Rule, (3) Bredt’s Rule

Zaitsev`s rule: In an elimination reaction, the major product formed will
be a more substituted alkene. This means that removal of the hydrogen
form the more substituted β carbon atom should occur.
2
CH3
1 H 1 CH3 C C
base H CH3
H CH2
major
CH3 CH C Br
CH3 2 H2 CH2
CH3 C C
CH3
minor
Transition state for path 1 leading to more substituted olefin is lower in
energy than in path 2. ← TS 2

f TS 1
r
e
e
e product 2
n
e reactant
r
g product 1
y

reaction coordinate→
 The relative positions (energies) of TS-I and TS-II can be explained as follows,

δ δ
OEt H CH3 CH3 H OEt
H2
CH3 C C CH3 CH3 C C C H
δ δ
H Br Br H

T S (I) T S (II)

more stable less stable

resembles trisubstituted alkene resembles disubstituted alkene

Additional information: The product stability (more substituted olefin generated as a

result of the elimination reaction) can be explained using the concept of orbital
interaction between the CH3 orbitals and that of the pi-bond
2. Hofmann rule: Although most compounds seem to follow Zaitsev`s
rule, some give product according to Hofmann rule i.e., less
substituted alkene. Hofmann elimination is observed for
compounds containing bulky leaving groups such as quaternary
ammonium or sulfonium salts.

CH3 CH2 CH CH3

+
N OH

N,N,N-trimethyl-2 butylammonium 1-butene (95%) + 2-butene (5%)

hydroxide
3. Bredt`s rule: No double bond can be generated on a bridge head
carbon of bicyclic compounds unless size of ring is sufficiently
large.

Br

Br

No elimination

Note: The origin of why Bredt’s rule can be rationalized by considering the need for
lateral overlap between two adjacent p-orbitals. Two p-orbitals can’t remain parallel
due to the bridged bicyclic structure.
 Other features of directionality of
elimination reactions
4. If compound already contains C=C or C=O functional groups, then
the newly generated double bond tends to maintain conjugation with
it.

Many factors are responsible for regioselectivity. One of them is steric

interaction. In E2 reaction when leaving group is bulky approach of
base towards β hydrogen is more likely to take place from less
hindered side to produce less substituted alkene. Similarly, large base
favors formation of Hofmann product.
 KOH / EtOH +
S Br 26% 74%

NaOEt
Br 69% 31%
EtOH
+
KOBu-t
t-BuOH 27% 73%

Acidity of terminal and internal β hydrogen is also important factor in

determining the product ratios. Terminal hydrogens are more acidic,
producing less substituted product, particularly in quaternary
ammonium or sulfonium group containing compound.

N
R-CH2-C-CH3
H
less acidic more acidic
In case of E1 reaction, the rate controlling step is the formation of
carbocation which is followed by product formation. Carbocation
generated hence has choice to adopt more stable arrangement, before
the removal of the proton.

In most E1 reaction, the product predominantly will be in accordance

with Zaitsev`s rule i.e., thermodynamically more stable, highly
substituted alkene. In general, Zaitsev`s rule is directly applicable to
molecules containing small leaving groups such as bromide.
E1 reaction :
In E1 reaction C-X bond breaking is more advanced (or ahead of) than
C-H bond breaking.
Hence, structure of carbocation will decide the fate of elimination
reaction.
H

base H base

E1 reaction mainly favors more substituted alkene because energies of

transition states are similar to those of isomeric alkenes. But, activation
energy for removal of hydrogen is low, hence transition state should
resemble carbocation and not alkene. Each β hydrogen is
hyperconjugation with the carbocation.
Thus, there is more weakening of
C-H bonds and more double bond character at highly substituted
carbon. This structural effect will govern direction of elimination as
shown below.
R2CH--X

R2CH+

less substituted
alkene
R2CHX
more
substituted
E1cB reaction : alkene

In E1cB reaction, the direction of elimination is governed by the acidity

of β protons, which in turn, is determined by polar and resonance
effect of substituents and degree of steric effect to approach of
base. Alkyl substituents retard approach and proton essentially from
less substituted carbon is abstracted, forming less substituted
alkene.
E2 reaction :
In E2 reaction, the direction of elimination depends on the nature of
the transition state. When E2 reaction resembles E1cB transition
state, then direction of elimination is governed by the ease of proton
removal and usually less substituted alkene predominates.

When E2 reaction resembles E1 transition state, then highly substituted

alkene dominates.

In synchronous E2 reaction, double bond is formed in the transition

state at expense of rupture of C-X and C-H bonds. It favors more
substituted alkene.

Additional note of the usage of ‘E1cB-like” or “E1-like”: When the geometry of the
transition state is similar to that of reactant, it is described as “reactant-like” and when
it is similar to that of the product, “product-like” is used. In the context of elimination
reactions, any transition state structures other than the synchronous E2, will
resemble either of the extremities like E1cB or E1. Depending on their structural
similarity, these are termed as “E1cB-like” or “E1-like”
 VI. More details on the stereochemical
aspects of elimination reactions
Stereoselectivity:
The product formed can either be E isomer or Z isomer, depending on
the stereochemical course of the reaction.

Coplanarity of departing group is an important criterion i.e., five atoms

in the transition state inclusive of base, β hydrogen, α and β carbon
atoms and the leaving group, should lie in the same plane. This is
necessary for the orbitals to lie in proper orientation to overlap
between each other to form the new double bond.

Two major stereochemical pathways are possible,

• Anti elimination and Syn elimination
• Characteristics of these modes of elimination are give below
1. Antiperiplanar transition state (anti-periplanar between the proton
being abstracted and the leaving group in the following example)
(1800 dihedral angle between H and X)
2. Staggered conformation– low energy
3. Anti-eliminations are more favored and more widely found
base
H
H
X
X
• Syn elimination :
1. Syn periplanar transition state
2. Eclipsed conformation
3. Possible only with certain rigid molecules
4. H and X are cis to each other (00 dihedral angle)

X X
H H
base
Examples for anti elimination :
In cyclic compounds like 4-tertbutyl-cyclohexyltosylate following two results
are obtained according to isomer under study.
OTs

cis-isomer tBu NaOEt /EtOH

tBu
E2 reaction
H
4-tertbutylcyclohexene
OEt

trans-isomer tBu OTs NaOEt /EtOH tBu

H
H
H H

tBu E1 reaction tBu

OEt H

SN1 reaction

tBu OEt

1-ethoxy-4-tertbutylcyclohexane
In the case of the cis isomer, the tosylate group and β hydrogen are far
apart with dihedral angle of 1800. This spatial arrangement is known
as antiperiplanar. This geometric arrangement is ideal for E2
elimination leading to exclusive formation of 4-tertbutylcyclohexene.

Such spatial arrangement of the two departing groups is not possible in

the case of the trans isomer. Hence, elimination proceeds
mainly by E1 mechanism and is usually accompanied by SN1 reaction.

More remarkable example is provided by acyclic substrates. In these

free rotation about C-C single bond is possible, yet elimination is
preferably anti.
Examples for anti-elimination

Cl
Ph Ph Ph Ph
Ph NaOEt / EtOH +
500
H Ph H
E-1,2-diphenylpropene Z-1,2-diphenylpropene

Ph N Me Ph
Me
Ph
H H Ph H
EtO

Me Br H Me
H

Br Me Me H
H
I
 Orbital Interaction
In an elimination reaction such as the one given below, electrons from
the sigma bond at the β carbon will delocalize into empty orbital
forming pi bond at α carbon atom. p orbitals of pi bonds are
coplanar. Also, steric interactions are minimum when two departing
groups are on the opposite side.
 2-Menthene

Cl

1-Menthene

β hydrogen and leaving group on cyclohexane ring can assume anti

periplanar conformation, if both are axial.

H Me CHMe2
EtO
H
2-Menthene
Me CHMe2
Me CHMe2
H Cl
Neomenthyl chloride 1-Menthene (major)

Me2CH H
Me2HC slow base
Me CHMe2
H Me H
Cl H
H Cl Me 2-Menthene
H (100%)
Syn elimination :
In certain rigid molecules, antiperiplanar arrangement of the departing
groups can not be attained. In such molecules, departing groups may
be on the same side i.e., syn periplanar and process is called syn
elimination.
In the example below deuterium is coplanar with the leaving group
while hydrogen is not. Hence, though deuterium is syn to ammonium
group, it is lost to give elimination product.

N
H OH
D
+ HOD + N(CH3) 3
H
N,N,N-trimethyl-3-deuteriobicyclo Bicyclo[2.2.1]-2-heptene
[2.2.1]-2-heptylammonium hydroxide (94%)
 + ROH + M

H X
O----M
R

Ion pair promoters are suggested as capable of syn elimination of

anionic leaving group.
This can be explained by proposing transition state in which anion
functions as a base and the cation assists in the departure of the
leaving group.
Ion pair interpretation is also supported by the fact that addition of
specific metal ion complexing agents such as crown ethers resulted in
diminished amount of syn elimination.

Another factor which affects syn to anti ratio is the strength of the base
used. Strong bases exhibit high proportion of syn elimination.
Steric effect is also important in determining syn to anti ratio.
 VII. Elimination v/s substitution
Elimination and substitution reactions are closely related and
competitive but form different products.
However, substitution becomes favorable as it involves less bond
reorganization and energetically being more favorable.
1) Basicity and nucleophilicity:
For elimination reaction basicity of nucleophile or base is important
while for substitution it is nucleophilicity that matters more.
Therefore, strongly basic conditions favor elimination reaction and
use of strong bases is advisable. If some compounds which are not
strong bases but are good nucleophiles are used, then substitution
predominates.
Use of strong and slightly polarizable base such as amide or alkoxide
favors elimination over substitution.

Basicity and nucleophilicity: Basicity is the ability of an atom or molecule to donate a lone pair of
electrons to a proton (H+). Nucleophilicity is the ability of an atom or molecule to donate a lone
pair of electrons to carbon.
 NaNH2 / EtONa
Br E2

AcO OAc
SN2 (~100%)
2) Substrate structure :
Crowded reactant favors elimination reaction over substitution due to
hindrance to approach of nucleophile. In primary alkyl halides, easy
approach of nucleophile is possible hence substitution is favored over
elimination. In secondary alkyl halides, substitution is difficult due to
steric hindrance and elimination is favored. Whereas ,in case of
tertiary halides SN2 reaction is not possible, elimination is favored
particularly at elevated temperature. If substitution occurs, then it is by
SN1 pathway.
Elimination can also be favored by stability of product formed.
 More examples: distribution of
elimination and substitution products
EtONa / EtOH O + CH2 CH2
Br
550 SN2 (90%) E2 (10%)

Br
EtONa / EtOH +
550 O
SN2 (21%) E2 (79%)

CH3
EtONa / EtOH + OEt C CH3
CH3
250
E2 (91%)
Br C CH3 CH3 SN1 (9%)
EtONa / EtOH
CH3 + EtOH
550
E2 (100%)
More examples: nature of the base
Structure of base has similar effect on the ratio of substitution or
elimination reaction. A more crowded base of similar strength favors
elimination over a less crowded base. Therefore, tert-butoxide gives
more of elimination product than substitution whereas ethoxide
shows opposite effect altogether.

(CH3) 2CHCH2Br t-BuOK /t-BuOH (CH3)2C=CH2 + (CH3)2CHCH2Ot-Bu

E2 (92%) SN 2 (8%)

(CH3) 2CHCH2Br EtOK /EtOH (CH3)2C=CH2 + (CH3)2CHCH2OEt

(62%) (38%)

CH3(CH2) 15CH2 CH2 Br t-BuOK / t-BuOH CH3(CH2) 15 C CH2

400 H
E2 (85%)
+
CH3(CH2) 15 CH2CH2 OBu-t
SN2 (15%)
More examples: nature of the solvent
3) Solvent :
In E2 reaction, five atoms are involved, thus, charge is more dispersed
due to which less polar solvents favor E2 elimination over SN2 reaction.
(Similar is the case with E1 reaction).
60% NaOEt /
EtOH 54% 46%
Br 40% H2O
E2 +
NaOEt / OEt
EtOH 71% 29%

60%EtOH 16% 84%

Cl
40% H2O OEt
E1
+
80%EtOH
33% 67%
20% H2O
More examples: role of temperature
4) Temperature :
Elimination reactions are favored at higher temperature than
substitution reaction because elimination reaction has high free energies
of activation than substitution due to higher degree of bond
reorganization (or change in the bonding pattern) i.e., more bonds are
broken and formed.
450 53% 47%
Br OH
NaOH +

1000 64% 36%

250 17% 83%

EtOH +
H2O
Cl 650 OEt
36% 64%
 More examples for elimination
reactions
(a) Hofmann degradation :

excess CH3I / Na2CO3 Ag2O / H2O

N N I
H

1. excess CH3I
2. Ag2O / H2O
3.
N
N OH
(b) Dehydration of alcohols :
 elimination reaction favored at high temperature
 catalyzed by acid (H2SO4, H3PO4, PBr3, SOCl2 etc.,)
 For secondary and tertiary alcohols, the mechanism goes through
carbocation intermediate, which explains why the rate of
dehydration of tertiary alcohols is greater than that of secondary
and primary alcohols (E1 reaction)
CH3 CH3
H3C C O H+ H O H CH3 C O H + H2O
H CH3 H
CH3

CH3 H
CH3 CH3
-H2O O H
H3C C O H H 3C C CH2 H H3C C CH2
-H3O
CH3 H
 Whereas, dehydration of primary alcohol is supposed to proceed
through E2 mechanism. In a protonated alcohol, the Lewis base
removes β hydrogen, simultaneously an olefinic bond is formed and
protonated hydroxyl group is departs as ‘water’.
H H H
fast slow
C C O H +H A C C O H

H H H H

H A

C C + HA + H2O
H

Metal oxides are excellent and widely used catalysts for dehydration
of alcohol. Different products are formed due to different catalytic
properties of these oxides or different reaction conditions.

Al2O3
90% 10%
OH 3500-4000
+
ThO2
3% 97%
3800
(c) Synthesis of alkynes :
Usually follows antistereochemical pathway.
H H

R C C R + 2 NH2 R C C R +2 NH3+2Br

Br Br
Here, a strong base such as an amidate ion triggers the elimination, first by
abstracting the proton as shown.

H H
R H
R C C R C C + NH3 + Br
Br R
Br Br
NH2

R H NH2
C C R C C R + NH3 + Br
Br R
(d) Debromination of vicinal dibromides:

Vicinal dibromides can be debrominated by treating them with reducing

agents such as iodide or zinc.
Br
NaI / acetone + IBr + Br
Br
I

Br

Br

Dehalogenation by iodide is stereospecific and goes through an anti

pathway.
In a reaction of NaI with 1,1,2-tribromocyclohexane, syn elimination will
give labeled product (bromine with a * is the labelled one). Whereas, anti
elimination will give non labeled product. It is found that debromination using
NaI is purely anti. However with zinc, the major product is anti, but some syn is
also formed elimination.
Br Br*
Br
Br* NaI
+
Br*
H
Anti elimination Syn elimination
(only product) (not formed)

Meso stilbene dibromide gives E-stilbene and d,l-stilbenedibromide

gives Z-stilbene. It is important realize that the anti-
Br periplanar geometries of H and Br are
Ph
Ph required for this elimination. In the
NaI
Ph Ph given stereoisomer, this is possible and
Br
Meso-stilbenedibromide E-stilbene hence it leads to a E-stilbene as the
product
For the anti-periplanar arrangement in
this stereoisomer, the molecule should Br
rotate along the C-C bond first such that Ph
NaI
both Ph comes on the same side and Ph
Ph Ph
Br
hence it leads to a Z-stilbene as the di-stilbenedibromide Z-stilbene
product
(e) Pyrolytic elimination :
Some substrates such as esters and amine oxides do not require any
external agent for elimination. Simply heating such substrates
provides elimination product. These reactions are known as pyrolytic
Elimination.
O
~ 5000 + CH3COOH
O
n-butylacetate 1-Butene
These reactions are suggested to proceed through a concerted,cyclic, six
membered transition state. They are often designated as Ei (i.e., Elimination
internal)
H H H Et H
H H 0
Et H
Et ~ 500 O + CH3COOH
O
H C
H O C O H H
CH3 CH3

These reactions follow stereospecific syn elimination pathway i.e.

leaving group must assume syn periplanar conformation with respect to each
other
 Examples for pyrolytic eliminations H
AcO D Ph
+ CH3COOD
Example-1 H Ph
Ph H H Ph
threo-2-deuterio-1,2-diphenyl- E-stilbene
ethylacetate

AcO H Ph D
+ CH3COOH
H Ph
Ph D H Ph
erythro-2-deuterio-1,2-diphenyl- E-1-deuteriostilbene
ethylacetate
OAc
Example-2
CH3
+ +
CH3
H
46% 26% 28%

CH3
OAc
+
CH3
H
55% 45%
The readers are expected to write the mechanism for these additional
examples, based on the earlier description in this module

Example-3

CH2OAc

CH2OAc
4,5-dimethylenecyclohexane
Example-4
OAc

Benzocyclooctatetraene

DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431-457.

(f) Cope reaction :
Pyrolytic elimination of amine oxide can be done under mild conditions,
to give olefin. This reaction is called as Cope reaction.

CH2CH2-NMe2 + HONMe2
O

Internal base attacks β proton, so highly basic nucleophile is not

required.
CH3
1. MeOH ,H2O2
+
2.
NH2
85% 15%
 Additional example on Cope elimination

O
H2O2 /MeOH
CH2NMe2 CH2NMe2

N,N-dimethylcyclohexyl- N,N-dimethylcyclohexyl-
methylamine methylamine oxide

Methylenecyclohexane
(g) Chugaev reaction:
In these reactions, O-alkyl-S-methyl xanthates are pyrolysed to
olefin,(oxysulfide and methanethiol) at about 2000C.
These reactions are of particular use due to its relatively milder
reaction conditions as compared to other pyrolitic eliminations.
Using this method, alkenes which are labile or tend to undergo
rearrangement can be prepared.
These reactions take place via six membered cyclic transition state and
generally proceed through syn elimination, although anti elimination
is also reported. R
H H
H
OH NaH /CS2 /
R MeI O ~2000
H S C
SMe

H H R H
R H O

O + HS SMe
H H H
S C
SMe
 SO2 p-tol H
H syn anti
SO2 p-tol elimination H
H elimination
SO2 p-tol
OCSSMe
OCSSMe
trans cis
F. G. Brodwell; P. S. Zandis, J.A.C.S., 1958, 80, 2450-2453.
C. H. DePuy; R. W. King, Chem.Rev., 1960, 60, 431-457.
OCSSMe
H

80% 20%
OCSSMe
H

20% 80%
(h) Corey-Winter reaction:
Vicinal diols are first converted into cyclic thiocarbonates which on
heating in trimethylphosphite gives an olefin. It is a syn elimination
reaction.

HO OH 1) CCl2S R1 R4
2) P(OCH3)3
R1 R4
R2 R3 R2 R3
(i) Julia olefination :
Regioselective elimination of phenylsulfonyl and benzoate from
substrate containing phenylsulfonyl group adjacent to leaving group. It
is mainly promoted by reducing agents such as sodium amalgam.
Leaving groups are carboxylates, acetates or benzoates.
Ph OCOPh
SO2

Na / Hg
MeOH
-200
 SO2Ph
Ph
SO2Ph 1. BuLi
2. PhCHO Na /Hg
3. Ac2O OAc

Ph

93%
(j) Bamford-Stevens reaction:
Treatment of tosylhydrazone with a strong base gives alkene, this
reaction is called Bamford-Stevens reaction.
Aprotic solvent mainly gives Z-alkenes while protic solvents give
mixture of E and Z alkene.

O
R2
S NaOMe
O R1
HN N
R2
R1
Mechanism of reaction is as follows
Step 1 : Formation of diazo compound

O Deprotonation step O

S NaOMe S
O O
HN N N N
R2 R2
1 1
R R

N
R2 Diazo intermediate
1
R
diazo compound
Step-II (olefination)
In protic solvent, diazo compound decomposes to carbocation
H
N
H-solvent N N H R2
N R2 R1
R2 R1
H
R1

R2
R1
In aprotic solvent, diazo compound decomposes to carbene
N
N N
R2
N R2 R1
2 1
R R
R 1 H

R2
R1
 VIII. α-elimination
Very small number of reactions are known in which 1,1 or α
elimination occurs.
These reactions follow mechanism similar to E1cB. A strong base
removes acidic protons followed by loss of leaving group i.e. first a
group or atom without its electron pair is lost, usually proton and
then a group with its electron pair is lost.
First step generates carbanion which may be stabilized by electron
withdrawing group.

H
-H R2C + Cl
R C Cl R C Cl

R R
These reactions are favored by
o Presence of electron withdrawing group on α carbon atom (i.e.
acidity of α hydrogen is increased). It is supported by the fact that
reaction of alkyl bromides or iodides with base gave very less α
elimination product than that of corresponding alkyl chlorides.
o Use of very strong base favors α elimination. PhNa, a very strong
base gave α elimination product in following reaction up to 94%
whereas NaNH2 or NaOMe did not give much yields.

H
CH3CH2CH2CH Cl CH3CH2CH CH CH3CH2CH CH2

base H

o Absence of β hydrogen atom, though not necessary, favors 1,1-

elimination.
e.g. Hydrolysis of haloforms
OH -Cl OH / H2O
HCCl3 CCl 3 CCl2 CO + HCOO

Loss of proton and chloride to generate carbene in α elimination is

proposed to proceed by a concerted mechanism. This step will be
followed by a migration of β hydrogen with its electron pair to give
an alkene as the product.

1,1-elimination can be distinguished from 1,2-elimination by isotopic

labeling.
Presence of carbenes can be detected by various reactions like
trapping or insertion reactions.

Me Me
Me Me
Me3CO in hexane
HCCl 3 CCl2 Cl
H H

Cl

Other preparative use is in electrophilic attack on phenol such as in

Reimer-Tiemann reaction.
However, in protic solvents, with use of common bases and with
substrates containing β hydrogen, α elimination is found to be less
prominent.
 + H2C

F
NaI F2C + PhHgI + NaF
PhHg C F

F
Further Reading: Some common bases
and protecting groups
DBU: Diazabicycloundecene
 Nucleophilic, bulky base.
 Stable, water soluble and air sensitive.
N N
 Tends to attack proton which is at periphery rather
than deeper in molecule.
 Incompatible with strong oxidizing agents, acids, acid chlorides and
acid anhydrides.
DBN: Diazabicyclononene
 Strong amidine base.
 Usually used for nucleophilic substitution and N N
elimination reactions.
NaHMDS : Sodiumhexamethyldisilylamide
 Strong base used for deprotonation and base
Na
catalyzed reactions. N
 Water soluble Me3Si SiMe3

KHMDS: Potassiumhexamethyldisilylamide
 Strong non-nucleophilic base.
K
 pKa 26 as compared to that of LDA 36. N
Me3Si SiMe3

TBAF: Tetra-n-butylammoniumfluoride
 Quaternary ammonium salt
 Mild non-nucleophilic base. Bu4N F
 Used for deprotection of silyl ether protecting groups
and phase transfer catalyst.
TIPS: Triisopropylsilyl
 Used as alcohol protecting group.
i-Pr3Si
 More stable to hydrolysis than TMS.

TES: Triethylsilyl
Et
 Used as alcohol protecting groups.
 Considerably more stable than TMS. Si
 Can be selectively removed in presence of more
Et
robust silyl ethers with fluoride and mild acid. Et

MsCl: Mesyl chloride O

 Protecting group for alcohol. H3C S Cl
 Excellent leaving group. O
 Stable to acids and can be removed with use of sodium amalgam.
 Additional/Practice Problems:
(1)
base

O
In both these examples, the
O N COOR formation of initial carbanion is
H
quite feasible, as such species will
be stabilized due to conjugation.
(2) F O O

base

O2N O2N

Reyberg, P; Matson, O. J. Am. Chem. Soc., 2001, 123, 2712-2718.

(3)
CH3 CH3
H MeONa
N C N C
MeOH
CN

Cho, R. B.; Chul Oh, Y.; Lee, S. H.; Park, Y. J. J. Org. Chem., 1996, 61, 5656-5658.
 Additional/Practice Problems:
Br
(4) + PhNH2 toluene

1-bromo-1-cyclohexylcyclohexane 1-cyclohexylcyclohexene

(5)

NaHCO3 / DMSO
Br

AcO AcO
O O
mild dehydrohalogenation in steroids, DMSO enhances reactivity of weak base

(6)
H2O ,
N + N(CH3)3
(7)
O
1. TsOH , acetone
O
2. hydrolysis
O

OH
Br
NaNH2 / NH3
Br
(8) Br
Br

H
6500 4500 CH3
CH3 H
(9)
OAc OAc

(10) COOH

O O
(11)

OH

KHMDS , DME
O2S -600-rt , 1.5 hr
PT

OTES

TBAF , DME
O2S -600-rt , 3 hr
PT
PT=1-phenyl-1H-tetrazol-5-yl .
J.Chem.Soc.,Perkin Trans, 1, 2002, 2563-2585.
ADDITION REACTIONS
•Key words: Addition to alkenes and
alkynes, markovnikov’s rule,
electrophilic and nucleophilic
additions
Introduction
Conversion of multiple bonds, such as a double or a triple bond, into
other functional groups are usually achieved using addition reactions.
The reaction of multiple bonds will convert an unsaturated compound to
more saturated and functionalized species. In this module, a number of
examples of electrophilic addition to electron rich double bonds are
presented. When a double bond is activated by attaching it with electron
withdrawing groups, conjugated addition is observed. Regioselectivity as
well as stereochemical considerations are presented in this chapter.
 ELECTROPHILIC
ADDITION REACTIONS

Markovnikov’ additions
Markovnikov’s rule
 Addition of hydrogen to an unsymmetrical olefin occurs at
those carbon atoms with maximum number of hydrogen
atoms. (i.e., the carbon with least substitution).
 Electronegative group goes to more substituted carbon
atom.
 Such an addition leads to a stabler carbocation.
 Such a reaction may lead to constitutional isomers but
actually one of the products is formed as major product.
X

X
Formed
H
HX
X=F, Cl.
X
Olefin
Not formed
 Origin …
X

HX X

X=F, Cl .
carbocation is more stablised in T.S.

Stereo specific product

H X X

carbocation is not enough stablilised in transition state

Olefin

 Consider two possible sites for hydrogen addition (i) terminal or (ii)
internal (substituted carbon).
 The addition of hydrogen at the terminal carbon leads to better
stabilization of carbocation, the chances of stabilization increases with
increase in conjugation with olefin.
 The terminal carbocation require higher activation energy which is not
a favorable condition, leading to slower reaction rate. However, the
generation of non terminal carbocation is assisted by hyperconjugative
stabilization leading to a lower activation energy.
Alkenes-some facts
 Due to trigonal planar geometry of olefin carbon
atoms the addition can occur on the same side (syn
periplanar) or on opposite sides (anti periplanar).
 Alkenes are generally nucleophilic. The C=C double
bond provides a higher energy HOMO (highest
occupied molecular orbitals).
 Electron donating groups increase the rate for
electrophilic attack as they assist in carbocation and
positive charge stabilization in the TS.
 REACTIONS of ALKENES
H
OH
OH

X
Hydrohalogenation X

1.OsO 4 HX
X
2.NaHSO 3 (X=halogen)
CH
Carbene addition I
2
2 ,Z Halogenation
Et n(
Cu
2O ) X2 (X=Cl,Br)
RO
DR. SUNOJ (IIT MUMBAI)
H X
1. Cl2 or Br 2
2. H2 O
1.Hg(OAc) 2 OH
2.R-OH olefins
1. acid
2. H2 O Halohydrin formation
1.Oxymercuration
2.Demercuration 1.BH 3 R-COOH Peroxy Pt ,H 2
2.H2 O2 ,OH H 2O 2 acids H
HO
H
OH

O
Hydration
Hydroboration Epoxidation
 1.HALOGENATION REACTION

 In this reaction the pi bond of alkene and σ bond of

halo acid is broken to form two new σ bonds.
 The reaction generally follows Markovnikov’s addition.
 In the first step, the alkene pi bond acts as a Lewis base
to add to an electrophile.
 In the second step, the halogen act as a Lewis base to
attack the Lewis acid, i.e. the carbocation.
 Reaction is exothermic as reactant posseses higher
energy bonds than the products .
Example of bromination reaction
 In this reaction alkene interacts with LUMO of
bromine (i.e. empty σ* orbital) to form a three
membered cyclic bromonium ion intermediate.
 The bromide anion attacks the cyclic bromonium ion
resulting in generation of product 1,2-dibromide
Br
Br
slow SN2 attack
Br Br Br

Br
cyclic bromonium ion
 stereochemistry
stereoselectivity
 Achiral olefin in halogenation reaction results in the formation
of racemic mixture as shown below. H
H
H 3C S H
H3C
Br Br S Br
Br
S R
C2 H 5
C2H5
H
H H
Br
Br
H C2 H 5 H H
H3 C C 2H 5 H 3C H
Br Br

H3 C C 2 H5 C2 H 5
BromoniumHion H H3 C
Bromonium ion
Trans-2-pentene Cis-2-pentene
Br
H 3C
H R H

H3 C
R H Br
Br R
Br
S C 2H 5 C2 H 5
H
Both cis and trans-2-pentenes (±)Enantiomers
produce racemic mixture (in the
(±)Enantiomers
absence of any chiral source)
 The reaction of olefins with halo acids in the presence of
Halohydrin formation reaction
aqueous solvents is termed as halohydrin reaction.
 Reaction generally follows Markovnikov’s rule.
 The reaction takes place with anti addition.
 Bromine water & N-Bromo succinimide are commonly used
reagents in bromohydrin formation.
 Chlorine water can be used for chlorohydrin formation.

Br

1.Br2
2.H2 O OH
Mechanism (halohydrin formation)

 The reaction starts with attack of π bond of alkene on σ* bond of

Br2 to form a three membered cyclic bromonium ion.
 Water can attack the bromonium ion as shown through a SN2
transition state . Markovnikov’s rule is generally obeyed. Anti
addition take place.

Br
R R' R Br R' Br

- Br
..
R'' R''' O OH
R'' R''' H H
O
Br Br
 Why don’t the halide ion attack
HH
as in conventional halogenation….?
stereochemistry
 Regioselectivity :-In case of alpha methyl styrene the addition of
hydroxyl occur at the more substituted carbon to give the major
product. Br HO

OH Br

N-Bromo succinimide
95% aq. acetone.

Major product Minor product

 Stereoselectivity :- the addition of hydroxyl group occur anti to

the halonium ion giving major product. In the bromohydrin
formation reaction of cyclohexene we get trans bromohydrin as
major product.
H H
O OH 2

OH
Br

Br Tr ans - Bromohydrin
Br
Br Br
Addition of water or solvent to alkene
(oxymercuration , demercuration ,solvomercuration )
 Most of the alkenes do not favor hydration when subjected to aqueous acid.
Here is a better approach to overcome this situation.
 Oxomercuration :-Convert alkene to organomercurial alcohol in aqueous solvent.
 Demercuration :- Transforms organomercurial alcohol to corresponding alcohol.
 Solvomercuration :-Transfer organomercurial ether to product ether as per the
solvent used.
 General reaction :-

HOR NaBH4
Hg(OAc)2 demercuration
oxymercuration
HgOAc H
OR
Alkene Mercuric acetate OR
organomercurial ether or alcohol

 Generation of reagent :-

O O O O

Hg Hg
O O aq. medium O O
+vely charged mercury species Acetate anion
acting as electrophile
MECHANISM ….
Mercuration /solvomercuration :-
 The reaction starts with nucleophilic attack by double bond on +vely
charged mercuric acetate species resulting in the formation of three
membered cyclic mercurinium ion.
OAc

O Hg
Hg
O

Alkene
 In this step SN2 attack by the solvent leads to the formation of
organomercurial species.
HgOAc HgOAc
OAc

Hg
SN2 attack

O OR
H R organomercurial alcohol or ether
OH
R
H2O
 Demercuration :- In this step there is substitution of hydrogen
in place of mercuric group to give the final alcohol or ether.
HgOAc

NaBH 4,NaOH,H 2O
H
OR
OR Alcohol or ether
(R = Alkyl, H)

 The reaction take place following Markovnikov’s rule i.e.

addition of hydrogen occurs at the least substituted end.
H 2O
H H
H OH
Hg(OAc) 2 H

H 2O
H H H H Hg(OAc)
Hg
(OAc) H
3,3-dimethyl-1-butene Markovnikov product

NaBH4
reduction

OH H
H

H
H

3,3-dimethyl-2-butanol (major)
 Substituted Theophylline Mercurials and Their Demercurating
O COCF
Reactions. H C O Ac H3 C
3

3
N N
N
N Hg(OCOCF3)2 in CF3COOH HgOCOCF3
Mercuration N
N O N
O N
CH3
CH3

H2 O

O H H
H3 C O
H3 C
N N
N Halo- demercuration
N
X HgOCOCF3
O N N N
O N

CH3 CH3

X = Halogen

 Bergstrom, D. E.; Ruth, J. L. J. Am. Chem. Soc. 1976, 98, 1587.

 Korn, A. P.; Ottensmeyer, F. P.; Jack, T. R. Inorg. Biochem. 1979, 10, 235.
Solvomercuration examples...

 Solvomercuration in the presence of trifluoroacetate mercury (II) salt

{Hg(OCOCF3)2}. The reason for using trifluoro acetate salt instead of
acetate salt is to enhance electrophilicity .
 Examples :-1. conversion of 1-ethyl ethene to corresponding ether.
Hg(OCOCF3) H

Hg(OCOCF3)2 NaBH4
Ethyl alcohol
OC2H5 OC2H5

 Ether synthesis from cyclopentene.

OCH2CH(CH 3) 2 OCH2CH(CH3) 2

Hg(OCOCF3)2 NaBH4
1,1-dimethyl ethanol

Hg(OCOCF3 ) H
DIOL FORMATION REACTIONS
 Diol formation in alkenes can be achieved from
various reactions :-
Hydroxylation with Potassium permangnate.
Osmium tetroxide catalysed dihydroxylation.
Upjohn dihydroxylation.
Woodward reaction.
Prevost reaction.
Epoxide ring opening reaction.
Hydroxylation with Potassium permangnate.
 Hydroxylation is carried out in cold media preferably in basic
conditions.
 Hot conditions may lead to oxidation forming carboxylic acid
 The hydroxylation occur with syn addition & formation of cyclic
intermediate.
OH
O O

Mn

O O OH

OH
COOH
MnO 4, base
cold aq solution COOH
OH
 Disadvantages :-
 The product yield obtained is very low.
 The product can be a mixture of diol & carboxylic acid.
 A better stereoselective epoxidation can be achieved with Osmium
tetraoxide.
 Osmium tetroxide catalyzed asymmetric dihydroxylation
(sharpless dihydroxylation)

 In 1980, Sharpless reported the first asymmetric dihydroxylation of olefins by

replacing pyridine with a chiral tertiary amine ligand derivatives dihydroquinine
acetate with improved yield.
 The addition of diol takes place without affecting the other functional groups in
the molecule.
 Reagents are commercially available as preformulated mixtures: (Asymmetric
Dehyroxylation) AD-mix α and AD-mix β containing the necessary bidentate
chiral ligand, stoichiometric oxidant, and the osmium tetroxide in the form of
dipotassium osmate dihydrate (K2OsO4(OH)4).

R R' OsO in catalytic amount

4 OH
chiral ligand in catalytic amount HO

AD-mix alpha or AD-mix beta

oxidant in stoichiometric amount
R'' R''' organic /aqueous solvent HO OH
R,R',R'',R''' =H ,alkyl or aryl group Entantiomeric cis vicinal diol
Recent Developments in the Osmium-
catalyzed Dihydroxylation of Olefins :

The two catalytic cycles in the asymmetric dihydroxylation

Selectivity of addition
 The addition of both hydroxyl groups occur on the syn face.
 The selectivity of the face is decided as per the reagent used.
AD-mixα :- (DHQ)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6
AD-mix β:- (DHQD)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6
HO OH
AD mix beta (top face or beta face)
R
R'

R'' R'''

AD mix alpha (bottom face or alpha face)

R= small group , R'= Medium group HO OH

R''= Large group , R'''= Smallest group or H

Enantiomeric cis or
vicinal diol
Epoxide ring opening reaction.
 Epoxide ring opening results in the formation of trans diol.
 Epoxide ring opening can be achieved by using an electrophilic or a
nucleophilic reagent.
 The ring opening occur by SN2 mechanism, hence the diol formed will
be exhibit a trans geometry.

Electrophilic ring opening

H
HO HO
O O
acid in aq. medium

OH2 OH
H2O
Nucleophilic ring opening

O H2 O HO
O O
nucleophile in aq. medium

OH OH OH
 Ring opening in the presence of organometallic reagents (RMgX,
RLi, RCºCM, LiAlH4, NaBH4,transition metal catalyst ):-
 Organometallic reagents can act as nucleophile in epoxide ring
cleavage reaction
 The reaction takes place by SN2 attack resulting in the
formation of trans product.
 Organometallic reagent react with epoxide in basic media as
they are strong nucleophlies.
 When these nucleophilic reagent attack, it results in breaking of
the epoxide ring with formation of alcohol after acidic workup.
 In the case of Grignard reaction the C-C bond formation occur
at the β position from the newly formed hydroxyl group.

O
R R
acid
OMgx hydrolysis OH
RMgX
(X=Halogen) MgX2
Cyclopropane ring formation
reactions
Simmon-Smith reaction.
Howard Ensign Simmons, Jr. and R. D. Smith

 A Organo chelotropic , stereospecific reaction of

alkene with di-iodo methane (used for synthesis of
non halogenated cyclopropane) in the presence of
copper-zinc couple is called Simmon-Smith reaction.
 The methylene group is added to a less sterically
hindered face of alkene making the reaction stereo
specific.
 General reaction :-
CH 2I2 Zn/Cu ICH 2z nI

R' R''' R' R'''

ICH2 znI ZnI2

R R'' R R''
MECHANISM
 The mechanism is concerted which involves carbene transfer
assisted by Zinc catalyst. The stereoselectivity depends on the face
on which the addition takes place & presence of different groups
on the substrate.
I
H
ZnI
Zn(Cu) C
CH 2I2 Zn H2
diethyl ether I
as solvent. I
H

ZnI2

 In substrates like allylic alcohols, the cyclopropane ring formation

occurs on the same side of the –OH group. (this is due to a weak
bonding in the corresponding TS).
weak bond with hydroxyl oxygen
in T.S. OH
OH OH HO
I ZnI
H

Zn(Cu) C
CH 2I2 Zn H2
diethyl ether I
as solvent. I
H

ZnI2
More examples on cyclopropanation
H OH H OH H OH
Z n(C 2H 5)2 , CH 2I 2 (5 eq)
CH 2I 2 , -10 C to R.T.
H3 C CH 3 H 3C CH3 H 3C CH3

H H H

75% yield sy n : anti (6:1)

H OH H OH
H OH
Zn(C2 H5 )2 , CH 2I 2 (5 eq)
CH2 I2 , -10 C to R.T . Ph CH3 Ph CH3
Ph CH 3
H H
H
86% yield sy n : anti (7:1)

H OH H OH H OH
Z n(C 2H 5)2 , CH 2I 2 (5 eq)
CH 2I 2 , -10 C to R.T.
Ph Ph C2 H5 Ph C2 H5
C2 H5

H H H
97% yield syn : an ti (130:1)

H OH H OH H OH
Zn(C2 H5 )2 , CH 2I 2 (5 eq)
CH2 I2 , -10 C to R.T.
Ph Ph C 2H 5 Ph C 2H 5
C 2H 5

H H H
87% yield syn : ant i (110:1)
Johnson-COREY-CHAYKOVSKY reaction
[A. William Johnson , E.J. Corey , Michael Chaykovsky ]
 The reaction involves the synthesis of epoxide from aldehyde & ketone,
aziridines from imines , cycloprapanes from enones.
 The reaction is diastereoselective favoring trans substitution in the
product regardless of the initial stereochemistry.
 The ylides are generated in situ by the deprotonation of sulfonium
halides with strong bases.
 General reaction :-
Sulfur ylides u sed O O
Sulfu r ylid e
O O Dimethyl sulfoxide R R'
R R'
Epoxide
S S Aldehyde or ketone

NH HN
Dimethyl sulfoxonium methylide
Sulfu r ylid e
Dimethyl sulfoxide R R'
R R' Aziridine
Imine
O O
S
S
Sulfu r ylid e
Dimethyl sulfo xide R
R
Dimethyl sulfonium methide
Enone Cyclopropanes R'
R'
mechanism
 In the reaction the nucleophilic sulfur ylide attacks the
carbonyl or imide substrate.
 The negative charge is transferred from anionic carbon of ylide
to electronegative group of substrate as a result sulfonium
cation is expelled & formation of cyclopropane or epoxide ring
take place.

Generation of sulfonium halide (In situ ,presence of strong bases)

R'
X base
S S
S
DMSO
R CH 3

R
R'
Base
S S
O CH 3 DMSO
X O

When R , R' are one or both elctron withdrawing group the ylide formed is stable.
 Contd…..
Reaction with aldehyde or ketone.
R' R''
O O
O S
1
S S
H 3C R''
R 2 R''

R' NH NH R''
HN S
S 1
S
H 3C R''
R 2 R''

O
O O
R' R' O
3 1 R''
R'' S S
S R''
2
R R 4
 Reaction with Michael acceptors:-
Unstabilised ylides(kinetically controlled product):-the epoxide formed is irreversible
,unstable undergoes ring closure to form 1,2 addition product i.e. epoxide.
Stabilised ylides (thermodynamic product):- ylides stabilized with electron
withdrawing group give 1,4 addition product. Although 1,2 addition product is
formed but it is reversible kinetic product. 1,4 addition product formation result
due to strong sigma bond formation at the expense of pi bond forming stable
product.
STEREOCHEMISTRY
In cyclopropanation, the reaction occurs with anti betaine formation
resulting in trans product formation.
 This is due to rotation around the central bond in a molecule to attain a
more stable conformation , a back side attack result in trans product
formation.
 In the case of the synbetaine the barrier to bond-rotation was higher
than reversal to starting materials whereas for the anti-betaine, the
barrier to returning to starting materials was higher than bond rotation
to the transoid conformation.
HYDRO BORATION REACTION
Herbert C. Brown

 The addition of water to alkene in the presence of boron reagent are

known as hydroboration- oxidation reaction.
 The addition follows syn addition with cis stereoselectivity.
 Unlike other addition reactions, here the hydroxyl group get added
to the least substituted carbon.
 In this reaction peroxide also play a equal role in deciding the site of
addition.
 In such reaction the reagent BH3 is used which consist of
electrophilic boron and electron donation is done by hydrogen
atom.
 No carbocation intermediate is involved in this reactions
suggesting that a concerted addition take place.
 If BH3 is used as reagent it can hydroborate three alkene units. The
number of alkenes undergoing hydroboration are equal to no. of
hydrogens attached directly to boron in the borane reagent.
 The product obtained in such reactions are a racemic mixture, the
stereoselectivity can be improved by using chiral borane reagents.
REACTION :-
 Concerted addition of boron to sterically least hindered carbon.
 The oxidation occur in the presence of peroxide to give the syn addition
product.

MECHANISM Of HydroBoration:-
 In the first step alkene acts as a nucleophile and attack on electrophilic
Boron.
 In the Second step ,Peroxide act as nucleophile & attack the electrophilic
boron followed by migration of C-B bond to form C-O bond. Hydrolysis
result in formation of alcohol.
 First Step:

Second Step:
stereoselectivity
 Some of the commonly used boron reagents for regioselective
hydroboration reactions.
9-Borabicyclo(3.3.1)nonane (9-BBN)
Disiamylborane. (Sia2BH)

 EXAMPLES:-
 Hydroboration of cis-4-methyl-2-pentene
H OH HO H
(H3C) 2HC CH3
(H3C) 2HC CH 3 (H 3C) 2HC CH3
1. 9-BBN , THF
2.oxidation
H H H
H
H H 2-Methyl-3-pentanol
4-Methyl-2-pentanol,
With 9-BBN 99.8% 0.2%
With Sia2BH 97% 3%
 Hydroboration of 1-methyl cyclopentene.

OH

OH
1.Hydroboration
2.Oxidation

2-methyl cyclopentenol
With 9-BBN 99.9%

BH3 98.5%

HBCl 2 99.8%
Epoxidation reactions
Epoxide formation reaction
Some General Feature of Electrophilic Epoxidation
Epoxidation using peroxy acids is described here
Epoxidation is favored by electron donating substituent.
More the electron donating ability of the substituent on
the double bond, higher is the energy of alkene HOMO
resulting in increase in nucleophilicity.
More nucleophilic the pi bond is, greater is interaction
with the σ* orbital of the electrophilic O-O bond
increasing the rate of oxirane formation.
A peroxy acid or peracid is an acid
in which an acidic -OH group has been replaced by
an -OOH group. They are less acidic compared to carboxylic acids.
All peroxy acids are very powerful oxidizing agents with electrophilic properties.

Peracids that are not commercially available are prepared

by the reaction of the acid
chloride or anhydride with high strength hydrogen peroxide or urea and hydrogen
peroxide.
The major attribute ofperoxy acids is the presence of electrophilic oxygen between
the carbonyl carbon and the -OH group, which is attacked by pi (π) bond containing
compound with high electron density.
Peroxy carboxylic acid have electron deficient low energy LUMO which is the sigma*
O-O bond.
 Mechanism of epoxidation

Step I :- Attack of nucleophilic alkene on electrophilic oxygen of peroxy acid.

Step II :- Transfer of electron density from O-O bond to electrophilic carbonyl
Oxygen.
Step III :- Attack of carbonyl oxygen on –OH Hydrogen leading to it’s abstraction.
Step IV :- Release of Carboxylic acid.
 Stereochemistry of epoxidation
 Formation of epoxide occurs on the same face of pi (π)
bond being attacked, hence geometry of alkene is
preserved in the product.
 e.g., epoxidation of cholesterol to 5α,6α- epoxy
cholestan-3β-ol using m-chloro perbenzoic acid.

Cl
H
H
O
OH

H H O
,heat H H

HO
HO Cl Cl O

Cholesterol 5α,6α- epoxy cholestan-3β-ol

 Epoxidation occurs from (alpha attack) lower side of

cholesterol molecule selectively .
 Influence of –OH and -NH group on
epoxidation.(The concept of hydrogen bonding).
 When an allylic alcohol or allylic amine is epoxidized the peroxy acid prefer to
attack from the same side of –OH or -NH .
 The TS stabilization through hydrogen bonding leads to a syn product in
excess.

NHR
NHR Hydrogen Bonding.
O
O H

N H
R O
O
O O
HO
cis-product
 When the nitrogen or hydrogen group is masked then the epoxidation
formation occur below the ring & the previous
Transition trend is followed.
State.
Epoxidation in the absence of hydrogen
bonding.
 In the example below when the amino group was masked, major
product was obtained with epoxide below the plane i.e., anti
addition.
NHCOCl NHCOCl
NHR
O
epoxidation
heat O

Cl

HO Me3 SiO Me3 SiO

SiMe3 Cl R-COOOH
Epoxidation
O

 Hence, distereotopic addition to double bond in compound with

hydrogen bond donors can be controlled.
Vanadium catalyzed epoxidation
 Syn epoxidation of allylic alcohol in presence of VO(acac) & tert-
butyl hydro peroxide .
 General reaction :-
VO(acac)2
O
t-BuOOH

OH OH

Formation of vanadyl complex :-

O
O
O
vanadyl V V
V O O
O O O O

O O
enolate ion of 'acac'
acetyl acetone. VO(acac)2 complex
reactions
 Vanadium catalyst works best for epoxidation of homoallylic alcohol
Ph Ph

VO(O-iPr)3 ,(1 mol%)

O
cumene hydro peroxide , toluene
rt, 24hours

OH OH
J. AM. CHEM. SOC. 2007, 129, 286-287 90%yield,96% ee
 Homogenous catalysis showed higher yield but relatively same enantiomeric excess as in case
of heterogeneous catalyst.[ACS 0002-7863/79/15OI]
OH HO HO
O O

Vanadium catalyst
t-BuOOH

cis-epimer trans-epimer

Ligand% valency % yield Cis epimer Trans epimer system

VO(acac)2 +4 83 97 3 Homogenous
VCI4 +4 86 96 4 Homogenous
VO(SO4) +4 65 97 3 Homogenous
V(acac)3 +3 79 97 3 Homogenous
V2O5 +5 29 95 5 Heterogenous
CsH5V(CO)4 +1 75 94 6 Homogenous
Sharpless epoxidation
Barry K. Sharpless

 The Sharpless Epoxidation is used for enantioselective epoxidation of

prochiral allylic alcohols (primary and secondary allylic alcohols)
 The asymmetric induction is achieved by adding an enantiomerically
enriched tartrate derivative.
 oxidant :- hydroperoxide(tert-butylhydroperoxide in a stoichiometric
amount).
 The catalyst is cheap, easily available, and the requirement is only 5-
10% mol of the substrate when used in molecular sieves.
 Yield of Sharpless epoxidation reaction are good with more than 90%
of enantiomeric excess and is determined by the isomer of diethyl
tartrate or di-isopropyl tartrate used.
 3Å Molecular sieves are used to remove water from reaction as water
destroy epoxide ring and catalyst. Catalyst consumption can be
reduced to 5% to 10% by use of molecular sieves.
 COOEt
i-Pr

Sharpless epoxidation
i-Pr
catalyst
O

O
O O
O
HO
COOEt i-Pr Ti Ti
Ti(O-iPr) 4
EtOOC Oi-Pr
Titanium isopropoxide O O
OH COOEt
L-(+)-Diethyl tartarate O OEt

 Each Titanium isopropoxide is O

co-ordinated to one carbonyl group C t-BU-OOH

ter-Butyl Hydroperoxide
of tartarate ligand. OEt

 When tert-butyl hydro peroxide is COOEt

i-Pr
added it displaces one isopropoxide O

ligand and carbonyl group from

i-Pr
EtOOC
O
tartrate to form the final catalyst O O

for epoxidation i.e. dimeric titanium

O
i-Pr Ti Ti
species. O
O O
Visual Representation :- COOEt
Isopropoxide ligand:- violet O

Diethyl tartrate:- red O

t-Bu
t-butyl hydroperoxide :- green
C
Allylic alcohol :- black
OEt
Dimeric Titanium Species.
Mechanism of epoxidation :-
COOEt
i-Pr COOEt

O O
i-Pr i-Pr
EtOOC EtOOC
O O
O O O O
O O
Ti Ti i-Pr Ti Ti
i-Pr HO R

O O O O O O
COOEt Allylic alcohol COOEt
O
O
O
O t-Bu
t-Bu R
C
C
COOEt
OEt
OEt
Dimeric Titanium Species. O
i-Pr
EtOOC
O
O O
HO O
i-Pr Ti Ti

O O O
COOEt
O
O
O
t-Bu
R
R C

Epoxide OEt
Alkene complexation
Selectivity offered by diethyl tartarate.

 The enantioselectivity of oxygen addition to the face of allylic

alkene is dependent on which stereoisomer of diethyl tartrate
(DET) used in the reaction.
 If (-)-DET is used, the addition of oxygen occurs above the plane as
shown.
 If (+)- DET is used, the addition of oxygen occurs below the plane.
D-(-)-DET
Addition of oxygen occur at the top face.

HO O
Ti(O-iPr) 4 ,cat. D-(-)DET
R D-(-)DET
t-BuOOH R

R D-(+)DET
OH

Allylic alcohol in Plane O

R
D-(+)-DET
Addition of oxygen occur below the plane.
Application of Sharpless epoxidation

O
OH 5% Ti(OiPr)4 ,7.4% (+)-DET OH
-20 C ,14hours
epoxidation occur selectively 95% yield , 91% ee
on allylic alcohol double bond.

Intermediate for synthesis of leukotriene C1

COOCH 3 COOCH 3
Ti(OiPr )4 ,(+)-DET , TBHP

OH CH 2Cl2 hours ,-20 C ,48hour s. O OH

80% yield, 95% ee
Recent modifications in Sharpless epoxidation (Additional
Information)
Problem Solution Results

Presence of water lead to failure of Use of molecular sieves which can •Increase in yield
epoxidation. absorb water . •Catalyst consumption reduced
•epoxide ring breaking, (10-15% of original value.)
•Destruction of catalyst •Ease of isolation of product

Solubility Use of chiral polymeric support with •Improved enantioselectivity.

•Some reactant may not be active functional group. (e.g. •Improved yield.
completely soluble. polystyrene support)
Heterogeneous catalysis •Use of porous silica support •Improved yield.
•Catalyst and reactant should be in •Ageing of catalyst •Lesser consumption of catalyst
different phases to perform proper •Change of solvent (less polar to •Continuous reaction & product
isolation of product. medium polar) Isolation is possible.
•Use of polymeric support.

Enantioselectivity Can be improved by higher •Improved enantioselectivity.

derivative of tartrate ligand (diethyl
replaced by iso propyl).

Temperature Use of catalyst like titanocene •Enhanced enantioselectivity and

•Some reaction require high tartrate which can work at high higher yield for reaction requiring
temperature temp. & provide better steric high temperature.
hinderance .
JACOBSON EPOXIDATION (EPOXIDATION OF CIS ALKENES) .
 The Sharpless assymetric epoxidation works better with trans alkenes and
allylic alcohols, but produces low yields with cis-alkenes.
 Jacobson Epoxidation can be used to overcome this problem.
 Jacobson epoxidation allows enantioselective epoxidation of
unfunctionalized alkyl- and aryl- substituted olefins.
 The Jacobsen catalyst is a C2 symmetric manganese(III) salen-like complex,
in catalytic amounts to achieve better stereoselectivity.

N N

Mn

R O O R
Cl

R R
R = alkyl ,t-butyl, o-alkyl ,o-trialkyl.
Jacobson catalyst.
 Reaction ,
R R' R'
Mn-salen catalyst, aq. NaOCl R
CH2 Cl2
H H
O
 The addition of Mn(V) species take place from the side with lower
steric interaction.
R1 R2 R1 R2

(I) O O
Mn
cis epoxide

R1 R2
R1
O (II) R1 R2
+
R2 MnV Mn O O
trans epoxide

R1 R1 R2
O
(III)
Mn O
R2
cis epoxide

(I) = concerted mechanism

(II) = radical mechanism
(III) = via manganoxetane intermediate
a: R1 = alkyl, alkenyl, aryl
b: R1=R2=alkyl
Hydration reactions (addition of water)
 General reaction :-
OH

H 2O H

 Mechanism :-
H
O OH
H
H H 2O B
attack of BH
nucleophile
deprotonation
Protonation to generate more stable carbocation.

 The reaction is regiospecific & follow Markovnikov rule of addition i.e.

formation of carbocation at highly substituted end.
 More the substitution with electron donating group more stable is the
carbocation formed.
NUCLEOPHILIC ADDITION REACTIONS of olefins
Condition for nucleophlic addition reactions

 Normally olefins have electron rich HOMO which favor its

reaction with elecrophiles.
 For nucleophilic addition to take place the alkene should be
attached with an electron withdrawing group, which can
withdraw electron density from the pi-bonds of alkenes.
 When electron withdrawing groups are attached to alkenes, the
LUMO gets more stabilized. This will help to improve the
interaction with the incoming nucleophile
 Some examples of this class of reactions are,
Conjugate addition reactions.
Hydroamination reaction.
Amination reactions
 The addition of nucleophilic amino group across double bond
are called hydroamination reactions.

2% Pd(OAc)2
NH
2% PCP ligand
RT, 12H N CN
CN

98% Yield

NH 2 10% Pd(OAc)2
CN 10% PCP 1,100 0C, 36 H NH
Nucleophilic conjugate addition
 The addition reaction of α, β–unsaturated carbonyl compounds and α, β–
unsaturated nitriles with nucleophiles at 1,4- position is called nucleophilic
conjugate addition.
 alkene having carbonyl or nitrile group in conjugation increases reactivity
toward nucleophiles by resonance stabilization.

Nu OH
H+
1,2
1,2
Nu O
1,4

O
+
H
1,4
Nu

1,2-additions* are also known as direct addition

1,4-additions are known as conjugate addition
Example and Key Steps
 a

Me H Me
H
O N O N OH
Me Me
Me N

Me

Me
O N O
Me
(Me)2NH +

Key factors that control conjugate addition are,

(i) Reaction conditions
(ii) Nature of the α,β-unsaturated carbonyl compound
(iii) Type of nucleophile
 Preference for addition at 1,2 or 1,4 position.
 1,2 addition occur with stronger nucleophiles such as Grignard
reagents, organolithium, lithium aluminum hydrides, sodium
borohydrides.
 1,4 addition occur with weaker nucleophiles like thiols ,
enolates, cyanides, organocopper reagents etc.
 More Examples for 1,4-additions
CH 3
O
H 2N CH 3 60-700c
N
methyl amine 1 hour , 92% O
O
OC 2H5
EtO
OEt

 1,4-Addition reaction of ethyl bromodifluoroacetate to Michael

acceptors .

O O

TMEDA as cataly st
Ref lux for 7 hrs

CF2COOEt
73% yield
ALKYENES
 R'

Addition
R H H

Addition H

Reaction
H
reaction Hydrogenation (except Lindlar catalyst)

of of R R' R H

alkynes.
alkynes H H H R'
R'
Hydrogenation Reduction X
X
2H2 , (Ni /Pt /Pd) R
Hydrogenation or
& Reduction Na , liq. NH3 X
R Li X
with active Halogenation
metals R'
2 X2 H
Whe n R or R' (X= Br,Cl)
is hydrogen R X
R R'
with bases H
(Grignard reagent) Alkynes HX (X= I, Br Cl)
X
When R or R' Hydrohalogenation
is hydrogen H 2O , H2SO4
HgSO4
1.BH 3
R MgBr O
2.NaOH , H2O
R'
O R
Hydration
R
R
Hydroboration
& oxidation
Hydration reactions
 Hydration in alkynes is carried out using mercuric salts as catalyst.
 The addition gives more stable carbocation as per the Markovnikov’s
rule.
 General reactions:-
O
HO H

HgSO4
H 3C H
H 2O H 3C CH3
H3C
H
 Mechanism :-
H 3C Hg H 3C Hg
Hg
Hg+2 SO4 -2
H3C H

H 3C H
H 2O H HO H
H 2O
H

H 3C H
O

H 3C CH3

HO H
hydrohalogenations
 Addition reaction of haloacids occur in anti fashion following Markovnikov’s rule
i.e. the more substituted carbon result in carbocation to which halogen get
attached.
 Initial attack result in haloalkene which furthur react to give the geminal dihalide.
H H
R H R X
HX HX
R H trans addition to
H
Halogenation to form Geminal dihalide
form Haloalkene
X H X

 Examples :-
Cl H H
H
 1. Cl
HCl HCl Cl
H
H 1st eq 2nd eq. H
Ph

 2. H

HCl HCl
H CH3
1st eq 2nd eq.

Cl
Cl
H Cl Cl
 3.
Cl
HCl C 2H 5
CH 3 HCl
1st eq 2nd eq. CH 3

Cl
Hydrogenation and reduction
of alkyne is carried out using gaseous hydrogen at
high pressure using transition metal catalyst (Pt, Pd, Ni ).
 Hydrogenation with Lindlar's catalyst, (prepared by deactivating
palladium catalyst by treating it with lead acetate and quinoline) give
alkene with no furthur reaction, however direct use of Pt or Ni will result
in hydrogenation to alkane.
 Reaction in the presence of above catalyst give cis alkene with syn stereo
selectivity.
 General reaction :- H H H H
Pd , Pt , Ni Pt , Ni
H3C C 2H5 H H
H2 , under pressure H2 , under pressure
H3C C2H5 H3C C2H 5

of alkyne in presence of sodium in Liquid NH3 result in

anti addition to give trans alkene.
R H

Na,Liq NH3
R R'
anti addition
H R'
 The mechanism proceed by generation of electronic centre at a cost of a pi
bond followed by transfer of electron by metal in solvent cage (ammonia) ,
this result in formation of anionic centre on the substrate .
 The ammonia molecule now donate proton forming the ionic soda amide
again , this process repeat twice but this time from opposite centre on the
second carbon , giving trans alkene as product.
H
Na,liq.NH3
-2NaNH2
H

.
Na , 1 electron transf er H-NH2 -NH2
-Na

NH2 Na
-Na
H H
H
NH 2

 Similar type of reaction occur in case of reduction of aromatic compounds

especially benzene where the reagent posses the capacity to break the
aromaticity called Birch reduction.
DIENES
Electrophilic addition
 Dienes with electrophilic reagents like halo acids give electrophilic
addition reaction.
 Consider the reaction,
X

HX

R R
R
Electrophilic reagent
Conjugated diene X

R X R

1,2 addition product 1,4 addition product

 Which is the major product formed predominantly?

 The formation of product will depend on ,
 Stability of carbocation :-
• The addition of proton occurs as per the Markovnikov rule,
the stable carbocation will be formed at the more substituted
carbon atom.

+I effect from both methyl substituent +I effect from one methyl substituent

greater STABILITY lower

 Rate of reaction :-
• The energy of activation for the formation of 1,2 product is
lower and hence formed faster. However, equilibrium is less
favored.
• 1,4 product require higher activation energy but favors
equilibrium.
 Reaction temperature:-
• Kinetic product is product which appear first in reaction but the stable
product is the thermodynamic product.
• 1,2 product is formed first at lower temperature but rearranges to 1,4
product at high temperature or on standing for some time even at low
temperature.
 Reagent :-
• Use of milder condition gives mixture of products , use of excess of
reagent result in 1,4 product .

• Examples:-
Cl

0 0C
Cl2 gas

Cl
Major product Minor product

Br

HBr

Br
Reaction temperature 1,2 product 1,4 product
0 0C 70% 30%

400C 15% 85%

DIELS ALDER REACTION (CYCYLOADDITIONS)
 A class of concerted 4+2 addition cycloaddition are known as
Diels –Alder reactions.
 In this reactions two π bond of a conjugated diene interact with
one π bond of dienophile (an electron deficient alkene) forming
two carbon bonds in single step.

 Reaction occur with breaking of three π bonds (2 from diene + 1

from dienophile ) without formation of any ionic intermediate to
give two new σ bonds one π bond .
EWG
EWG
heat

4diene pi electrons
+2 dienophile pi electrons new pi bond
Cyclic Transition state
pi bonds showing breaking of pi bonds new sigma bond
and formation of two sigma
& one new pi bond(s).
Essential characteristics….
 For a Diels- Alder reaction to take place the diene should have
electron rich HOMO and the dienophile with electron deficient
LUMO.
 The reaction is thermally favored and not photo chemically,
hence reactants should be heated at high temperature .
 This can be briefly illustrated,

 Energy :-
 Diene
 Diene should be in cis conformation, dienes in trans conformation should
change to cis conformation which require energy, hence lower the rate.
 Presence of electron donating group [EDG] on the diene increases the
reactivity. EDG raises the energy of diene HOMO, this will cause more
favorable energy interaction with the LUMO of the dienophile.
 Any group present on the diene will have effect on the rate and
stereochemistry of reaction.
 Dienophile :-
 Dienophiles are alkenes having comparatively lower electron density than
diene.
 It should posses electron withdrawing group [EWG] which can withdraw the
electron density making them more electrophilic.
 This will decrease the energy of alkene LUMO favoring better orbital
interaction. The presence of EDG retard the rate of reaction.

DIENES
EWG EDG EDG
EWG :-
Carbonyl , ester,
nitriles , quaternary
EDG
amines, Halides
Reactivity :- Normal Good Excellent
anhydrides, nitro ,
Least
ester, quaternary
DIENOPHILES amines, acids etc.
EWG EWG EDG EDG:-
Amines , -OR,
-NHCOR , alkyl,
phenyls etc.
EWG

Reactivity :- Excellent Good Normal Least

 Orientation or regioselectivity :-
 As per the frontier molecular theory approach pseudo para or ortho
orientation is favored in products, meta orientation is least favored.
 When diene contains an electron donating substituent and dienophile an
withdrawing substituent, the orientation is such that there is maximum
electron flow toward the electrophilic substituent as shown below
EDG EDG

EWG EWG

Pseudo para orientation

EDG EDG

EWG EWG

Imaginary f low of electron Psuedo meta orientation

 Stereoselectivity
 Diels –Alder reaction exhibits excellent stereoselectivity.
 The stereoselectivity of reactant is maintained in the products
both in case of diene and dienophile. The addition is syn addition
as shown below

Heat
COOEt

COOEt

NC
CN
Cis product:-
CH 3 CH 3 CH 3 CH 3
1. 2.

COOEt COOEt COOEt COOEt

CN CN CN CN

C2 H5 C2 H5 C2 H5 C2 H5
Cis product Cis product

Trans product:-
CH 3 CH 3
3. 4.

COOEt COOEt COOEt COOEt

CH3 CH3

CN NC CN
NC

C2 H5 C2 H5 C2 H5 C2 H5
Trans product Trans product
Orientation of dienophile and end/exo product

 Dienophile are electron deficient. They would try to approach the

diene in such a manner that the electron withdrawing group will
remain toward the newly developing π bond, giving endo as the
major product.
COOEt

DAR COOEt
COOEt

CN CN
CN

Major product Minor product

 In general, Diels Alder reaction are thermodynamically

controlled. Exo product is the kinetic product that appear as a
minor product in the reaction.
 Catalysis
 Catalyst increases electron withdrawal capacity of dienophile making it lower in
energy thereby decrease the HOMO-LUMO gap between diene and dienophile.
 This can be achieved by using Lewis acid catalysts (AlCl3, SnCl4, BF3, TiCl4 etc. ).
Lewis acid coordinates with Lewis base of the dienophile making it more
electrophilic by withdrawing the electron density.
 Examples:-
O

Ti (IV)
Aqueous solvent
20 hours
Conc. Yield
O

1,3-cyclohexadiene p-benzoquinone O 0 % mol 61 %

endo-tricyclo-
 Molecules 2007, 12, 1674-1678 [6.2.2.02,7]dodeca-4,9-3,6-dione
5 % mol 83 %
 Enantioselective Diels-Alder Catalysis by Chiral, Cationic
Oxazaborolidines .
 Oxazaborolidines when protonated with trifluoromethanesulfonic
(triflic) acid gave an enantioselective catalyst for reaction of 2-substituted
acroleins. Reaction :-
H Ar CHO CHO

Ar 20% mol of 1 , -950C,

1 hr ,Diels- Alder reaction

O
N
TfO H
B
95 % yield , 94% ee
H with 92% endo product
O
o-toluidene O

1. Ar = phenyl
2. Ar = 3,5-di-methylphenyl
Diels Alder reaction
CATALYST

O O O O

J. AM. CHEM. SOC. % ee

Catalyst Temp. Time % Yield (endo:exo)
2002, 124, 9992-9993 33 (>98:2) 84
20 % mol of 1 -200C 1 hr.
1hr. 80 (.98:2) 92
10 % mol of 1 -780C
1hr. 91 (98:2) 71
20 % mol of 2 -780C
(I. A) Addition of HBr across carbon-carbon double bond
H
HBr
(1)
H

(2) HBr

(3) Ph HBr
Br

HBr
(4)

H
HBr
(5) H

HBr
(6)
CH 3COOH
40°C
(I. B) Addition of HCl and HI across carbon-carbon double bond
HCl
(1)
CH 2Cl2

CH 3
D HCl
(2) D D
25° C

CH3
(3) (CH3 )3 SiCl
H3 CHC CCH 2CH3
H2 O

(4) HI

(I. C) Addition of Br2 across carbon-carbon double bond

(a) Br2
heat
(5)

(b) Br2
low Temp

(6) Br2

Br2
(7)
MeOH
(I. D) Oxymercuration-Reduction

Hg(OAc) 2
(1) (CH 3 )3 CCH CH2
H2 O, NaBH 4

(CH2 )CH CH2

Hg(OAc)2
(2) O
H 2O, NaBH4
O

(3) Hg(OAc) 2

H2 O, NaBH 4
CH 2

Hg(OAc) 2
(4)
CH 2 H2 O, NaBH 4

Hg(OAc)2
(5)
H 2O, NaBH4
(I. D) Epoxide formation

(a) Br 2, H2 O
(1)
(b) NaOH

H O
O Cl
O

(2)
(m-CPBA)

(3) m-CPBA

m-CPBA
(4)
20°C
(I. E) Cycloaddition reactions
O

(1) + benzene
40 °C
O

OAc
CH 3 O2C
85-90°C
(2) +

OAc

OAc O
benzene
(3) + O
100°C

OAc O
Solutions of Addition of HBr across Solutions of Addition of HCl and
carbon-carbon double bond HI across carbon-carbon double
H
(1)
H bond
Br
H
Cl H
(1)

Br
(2)
H 3C
Cl
D
(2) H
D
D

Ph Br CH3
(3) Br CH 3 CH 2CCH2 CH 3
(3)
Cl

I
(4)
Br
(4)

H H
H + H
(5)
Br Br
major minor

Br OOCCH 3
(6) +

85% 15%
Solutions of Addition of HCl and HI across carbon-carbon double bond

Cl H
(1)

H 3C
Cl
D
(2) H
D
D

CH3

(3) CH 3 CH 2CCH2 CH 3

Cl

I
(4)

Solutions of Addition of Br2 across carbon-carbon double bond

(a) Br
Br
(5)

(b) Br
Br

(6) Br

Br

OMe
(7)
Br
Solutions of Oxymercuration-Reduction

(1) (CH3 )3 CCHCH 3 + (CH3 )3 CCH 2CH2 OH

OH
97% 3%

(CH2 )CH CH 3

(2) OH
O

O
80%

(3)
OH
CH 3

OH
(4)
CH3

OH

(5)
Solutions of Epoxide formation

(1)
O

(2) O

(3) O

O
(4)
Solutions of Cycloaddition reactions

H O
(1)

H
O

OAc
CO 2CH3
(2)

OAc

H O

(3) O

H O
 Substitution reactions in Aromatic
compounds

Key words: Aromatic electrophilic substitution, Directing effect, Friedel Cratfs

Reaction, Nitration, Sulfonation, Halogenation, Addition Elimination, Benzyne
intermediate
 Introduction
• In this module, various substitution reactions
are discussed. Classification based on the
incoming group, as electrophilic and
nucleophilic, is followed. Mechanism is
described in detail and large number of
general and specific examples are provided.
 Electrophilic substitution

 Aromatic compounds, unlike aliphatic compounds, undergo substitution in

aromatic nucleus when treated with suitable electrophiles.

 Comparison of reaction between cyclohexene with bromine and that of benzene

with bromine can explain this.
Br

Br2

Br

cyclohexene trans-1,2-dibromocyclohexane

Br

Br2, FeBr 3

benzene bromobenzene
 Difference between this kind of behavior of benzene towards bromination
originates from it being aromatic.

 If we assume a direct 1,2-addition of Br2 across one of the double bonds of

benzene, the product obtained would be non-aromatic

Br

Not formed
Br2

Br

 Such a reaction is not favorable, thermodynamically.

 Its electrophilic substitution with bromine is only compatible in the presence of

some strong Lewis acid, making bromine electrophilic.
 Mechanism of addition to cyclohexene is as follows;

Br

Br
Br Br
Br Br
Br

 Whereas, mechanism of bromination in the presence of FeBr3 can be given as follows;

[here bromine is made more electrophilic by its association with the Lewis acid]

H
Br
Br
Br Br
FeBr3
FeBr 4

Intermediate in both the reactions is cation. But, it is bridged cation in first while stable
arenium ion (resonance stabilized) in the second case.
 First intermediate adds anion while second loses a proton so as to restore its
aromatic character.

 This unusual behavior of benzene can be explained by taking into account its
orbital interaction.

 Benzene is a planar molecule having six π electrons in three π-molecular orbitals.

These are made up of overlap of six atomic p orbitals on carbon atom [for additional
details refer to: molecular orbitals of common functional groups]

 These atomic orbitals are placed in such way that the molecule attains extra
stability (140KJmol-1) than conjugated double bonds in aliphatic system.
 It is again indicated by shift of equivalent hydrogen in PMR spectrum (δH 7.2 ppm)
showing presence of ring current and a fully delocalized π system.

 The special reactivity of aromatic systems towards electrophile arises mainly from
two factors:

a. presence of π electron density above and below the plane of the ring - making it
nucleophilic.

b. drive to regain the aromatic character by opting for substitution as opposed to a

simple addition reaction.

 It can be best explained by energy profile diagrams of two reactions:

Br

HBr
  Mechanism for general reaction can be given as follows:
E
E H
E

E+: electrophile

 Two step mechanism:

 first step is the rate determining involving interaction of the π system with the
electrophile to give a benzenium ion intermediate
 it undergoes a rapid de-protonation by the base in the second step to restore
aromaticity
 The benzenium ion formed exists in several resonance forms
E H E H E H
E H
 Some common electrophilic aromatic substitution reactions are:

a) Halogenation

b) Nitration

c) Sulfonation

d) Friedel-Crafts alkylation and Friedel-Crafts acylation

 These differ only in the nature and mode of generation of electrophile, but in
general follow the same two-step mechanism described above.
 Halogenation

 Reaction of halogens with aromatic compound in the presence of Lewis acid

 Electrophile is a halonium ion i.e. a cation of halogen (X+)

 Main function of the Lewis acid is to polarize halogen-halogen bond

 Reaction goes as follows:

X
X2
AlX3 / FeX3

X: Bromine, Chlorine.
 Br

Br 2 / FeBr 3

δ δ
FeBr 3 + Br Br Br Br FeBr 3

H
Br
FeBr 4
δ δ
Br Br FeBr 3
Br

FeBr 4 HBr
FeBr 3

 X can be chlorine or bromine

 Analogous reactions with iodine or fluorine are not synthetically useful because I2
is too unreactive and F2 reacts too violently.

 Iodination requires an acidic oxidizing agent, like nitric acid, which oxidizes the
iodine to an iodonium ion.
 Nitration

 Where a H atom attached to an aromatic ring is replaced by a NO2 group

 Reaction conditions are concentrated nitric and sulfuric acid at elevated

temperature
NO 2

HNO3 / H2SO4

 Nitronium ion (NO2+) is the electrophile that attacks the benzene ring

 Generation of the electrophile in nitration requires strong acid

 O
O O O O

S N
N H N
O OH O OH O OH 2
O

O
O H NO 2
N
N O

 Mechanism is similar to that of typical aromatic electrophilic substitution

 Sulfuric acid is stronger and protonates nitric acid, which loses water molecule to
give electrophile, nitronium ion.

 Introduction of nitro group in aromatic system is of particular significance because

it provides general entry into aromatic nitrogen containing compounds
 Sulfonation

 Introduction of sulfonic acid group to aromatic system by treatment with

concentrated sulfuric acid

SO 3H

SO3 / H2SO4

Sulfur trioxide, SO3, in fuming sulfuric acid is the electrophile (This mixture is
industrially known as oleum)

Or benzene reacts slowly with sulfuric acid to give benzenesulfonic acid
 Two molecules of sulfuric acid react to form electrophile and then reaction goes
through general route

O
O O O O O O

S S S S
H
HO OH O OH HO OH 2 HO O

O O
O H SO 3H
S
S OH

HO O

 In the case of SO3 and H2SO4 mixture, SO3 alone can act as electrophile instead of
protonated SO3

 Sulfonation, unlike other electrophilic substitution reactions, is reversible.

 Sulfonic acid group can be removed by heating in dilute sulfuric acid.

 For reaction to proceed in the forward direction, it is necessary that water being
generated in the reaction is continuously removed.

 Interestingly, this process is used to place deuterium in place of hydrogen in a

benzene ring.
H D

H H D D
excess
D2SO4 / D2O

H H D D

H D
 Friedel-Crafts Reaction
Alkylation

 Preparation of alkyl benzenes from alkyl halides and a Lewis acid (usually AlCl3).

 The carbocation is the electrophile

 The role of the anhydrous aluminum chloride is to generate a stable carbocation

complex. R

RCl / AlCl3

R-Cl: alkyl chlordie

 For CH3Cl and 10 RCl, Lewis acid-base complex itself serves as electrophile.

 For 20 and 30 RCl, Lewis acid-base complex reacts further to furnish 20 and 30
carbocation respectively, due to the increased stability of such carbocations.
 Mechanism of alkylations

AlCl 3 δ
Cl 3Al
Cl δ
Cl

Primary alkyl chlorides

H

δ AlCl 4
AlCl3
δ
Cl

AlCl 4 AlCl 3
HCl

tert-alkyl chlorides
AlCl3
δ δ
Cl Cl AlCl 3

H
 Cl AlCl 3
+

 Carbocation rearrangement is seen in case of alkyl halides [example above involves

rearrangement of primary to secondary carbocation]

 The alkylbenzene product is more reactive than benzene, so polyalkylation occurs.

OH BF3
600C
+ +

isopropylbenzene diisopropylbenzene
(24%) (14%)

Alkyl group activates ring by +I effect for further substitution.

 Vinyl halides and aryl halides do not undergo Friedel-Crafts alkylation [cannot
generate vinyl cations]

AlCl3
+ Cl
No reaction

 Poor yields are obtained if powerful electron withdrawing group is present on

aromatic nucleus (such as NO2, NR3+, C=O)

NO2 CHO CF3 SO 3H

N(CH 3) 3

 Other sources of carbocation are alkenes + HF or alcohols + BF3 or alcohol + H2SO4

H 2SO 4
+
OH
 Acylation

 Replacement of H in aromatic nucleus by an acyl group (R-C=O)

 Synthesis of aromatic ketones from acyl halides and a Lewis acid, usually AlCl3.

 Acylium ion is the electrophile

O

O
AlCl3
+ R

R Cl

O O
O
AlCl 3

R Cl R Cl AlCl3 AlCl 4
R

O O
O Cl
H

R R

R HCl
 In Friedel-Crafts acylation, no polysubstitution is seen, as carbonyl group is
electron withdrawing and makes aromatic ring less electrophilic and AlCl3 forms
complex with the carbonyl group, further preventing the reaction.

 The same result is obtained if an acid anhydride is used instead of an acid

chloride.
O AlCl 3
O
O
AlCl3
R O + AlCl 3(RCOO)
R O

R
O R
O R

 The acylium ion intermediate is resonance stabilized and does not rearrange
like a carbocation.

 Reaction can be used to prepare n-alkylbenzenes in two step process

i. Friedel-Crafts acylation

ii. Clemmensen’s reduction

O
AlCl3 Zn-Hg / HCl
+

Cl

 Starting materials that contain both benzene ring and an electrophile are capable
of intramolecular Friedel-Crafts reactions.
O O

AlCl3
Cl

α-Tetralone
 Reactivity in substituted aromatics

 Substituent groups on a benzene ring affect electrophilic aromatic substitution

reactions in two ways:

1.Reactivity

 activate (faster than benzene)

 deactivate (slower than benzene)

2.Orientation

 ortho- & / or para- direction

 meta- direction
 If the aryl substituent donates (releases) electrons to the ring:

 The electron density of the ring will increase, resulting in activation the ring.

 The free energy of activation will decrease, as resulting transition state enjoys
additional stabilization due to a more delocalized arenium ion.

 Therefore, the reaction rate is increased relative to the rate on an unsubstituted

aromatic ring.

 The resulting resonance forms of the arenium ion favor the substitution of the
second group at the ortho/para positions, i.e., positions 1, 4, 6 relative to the original
group.
 Activation of ring by substituent can arise due to:

 Inductive effect

 Resonance effect

 Inductive effect is seen in the case of alkyl substitution

 Resonance effect is seen in the case of substituent having lone pair of electrons
Thus, alkyl groups stabilize the sigma complex by induction, donating electron density
through the sigma bond and substituents with a lone pair of electrons stabilize the
sigma complex by resonance.

 eg. alkyl, vinyl, phenyl, NH2, NHR, NR2, NHCOR, OH, OR etc.
 -CH3 group directs electrophilic attack ortho and para to itself because an electron-
donating inductive effect stabilizes the carbocation intermediate.
CH3 CH 3 CH 3
E E

E H H

ortho attack
CH 3 CH 3

E
E
H

CH3 CH 3
CH 3

meta attack
E E

H H
CH 3 CH 3

E
E
H
CH 3 CH3
CH 3

para attack E

H E H E
CH3 CH 3

H E E
 NH2 group directs electrophilic attack ortho and para to itself because the
carbocation intermediate has additional resonance stabilization.
NH2 NH 2 NH2

ortho attack
E E

H H
E

NH2 NH 2 NH2

E E
E
H H

NH2 NH2
NH2

meta attack E
E E

H H
NH 2 NH 2

E
E
H
NH2 NH 2
NH 2

para attack E

H E H E

NH2 NH 2 NH 2

H E H E E
 Comparison of the resonance structures involved in electrophilic aromatic
substitution of toluene and aniline, it becomes clear that when the electrophile
attacks at the ortho and para positions, the resulting arenium ion is more stabilized
due to electron donation through inductive and resonance effect.

 It can be explained graphically as follows

 Similar effect can be explained using the resonance structures of phenol and
acetanilide as representative examples to identify the preferred site of attack for the
incoming electrophile

OH OH
OH OH

OH
 O
O O O

HN HN HN
HN

HN
 If the substitutents withdraws (accepts) electrons from the ring:

 The electron density of the ring decreases leading to deactivation the ring.

 Energy of the transition state thereby increases and leads to the formation of less
stable delocalized arenium ion.

 Therefore, the reaction rate decreases relative to the rate on an unsubstituted

aromatic ring.

 The resulting resonance forms of the arenium ion favor substitution of the second
group at the meta position, i.e., position 3 relative to the original group.
 Deactivation of the aryl ring can be attributed due to:

 Inductive effect

 Resonance effect

 The atom attached to the aromatic ring will have a partial positive charge.

 Electron density is withdrawn inductively through the sigma bond, so the ring is
less electron-rich than benzene.

 eg. CHO, COR, COOH, COOR, NH3+, NR3+, CF3, CN, NO2, SO3H etc.
 With the NO2 group (and all meta directors) meta attack occurs because attack at
the ortho and para positions gives a destabilized arenium ion intermediate as shown
below. O
O O

N N
N
O O
O

H H
E
E E
O O

ortho attack
N N
O O

E
E
O O
O
N N
N O O
O

E
H E H E

O O

meta attack
N
O O

H E E
O O
O

N N
N
O O
O
E
E E

H H
O
O

N
N
O

para attack
O

H E
 Comparison of the resonance structures involved in electrophilic aromatic
substitution of nitrobenzene, it becomes clear that when the attack is at the ortho
and para positions the resulting arenium ion is more destabilized than when the
attack occurs at the meta position.

 It can be explained graphically as follows

 The resonance structures of nitrobenzene and benzaldehyde are given below.

O O O O
O O
N N
N

O O O O
N N
 H O H O
H O
C C
C

H O H O

C C

 electron density at the ortho and para positions, relative to NO2 and CHO is less as
compared to that at the meta position, making these positions less electrophilic.
 Substituents like, NR3+, PR3+, CF3 will exert electronic effect on benzene ring,
polarizing Ar-Z bond because of electronegativity of Z.

R R R R F F F F

N R P R F F
Halogens provide a peculiar effect when attached to an aromatic nucleus.

 They are ortho / para directors with deactivating effect.

 This is because they are highly electronegative elements and therefore inductively
pull the electron density towards it through sigma bonds.

 But halogens have lone pairs of electrons that can stabilize the sigma complex by
resonance.

 There are two aspects to this behavior, one is orbital size containing lone pair of
electrons and other is electronegativity.
 X X
X

H E E
E

 For Cl, Br and I, there is size mismatch and poor overlap of orbitals of 2p of carbon
and 3p, 4p and 5p of Cl, Br and I, respectively.

 F 2p orbitals are of similar size to that of C 2p, but F is far much electronegative,
hence F 2p is much lower in energy than C.

 On inspection of reactivity of fluroarenes, it is seen that the para position is much

favored over other positions.
 F
F
HNO3, H 2SO 4
250C

O 2N
 When more than one substituent is present in aromatic nucleus, then, position of
the incoming group is determined by

 most strongly activating substituent for the incoming group

NHCOCH 3 NHCOCH 3

Br

Br 2 / FeBr 3

CH 3 CH 3

In this reaction NHCOCH3 is powerful activator than CH3, hence, substitution occurs
ortho to this group, than less activating CH3 group
 When the directing effects of two groups reinforce, the new substituent is attached
to the position directed by both groups.

CH3 CH 3

Br

Br2 / FeBr3

NO 2 NO2

 In bromination of p-nitrotoluene, incoming Br group attaches ortho to CH3 and

meta to NO2 group as, CH3 is o /p-directing and NO2 is meta directing
 There will be little or no substitution between groups that are meta to each other.

CH 3
CH3

HNO 3, H 2SO 4

CH3
CH 3
NO 2

 In nitration of m-xylene, NO2 group is substituted ortho to one CH3 while it is para
to the other CH3 group, rather than at position 2, to avoid crowding
 For substituents with opposite effects, the resonance effect overrides all other
effects.
CH3 CH 3

Br2 / FeBr3

Br

OH OH

 In bromination of p-cresol, Br is substituted at position ortho to OH than at ortho to

CH3, as OH is powerful activator due to resonance
 donor substituent overpowers an acceptor substituent

CH 3 CH 3

O 2N
HNO 3, H 2SO 4

NO 2 NO 2

 resonance donor substituent overpowers a hyperconjugative donor substituent

CH3 CH 3

Br2 / FeBr3

Br

NH2 NH 2
 Course of reaction is determined by taking all these facts into consideration.

 In syntheses of disubstituted benzene derivatives, order of addition of reagents are

important

 Let us consider, syntheses of p-nitrobromobenzene

Br

O2N

 It can be synthesized in two ways,

 first bromination followed by nitration

 first nitration followed by bromination

 Br Br

Br2, FeBr 3 HNO 3, H2SO4

O 2N

Br

HNO3, H 2SO 4 Br2, FeBr 3

O2N
O2N

 In the first case, Br present on benzene ring directs NO2 group to para position and
required product is obtained

 whereas, in the second case, NO2 group directs Br to meta position and unwanted
product is obtained
 Summary of directing effects of substituents in
electrophilic aromatic substitution
ortho / para directing meta directing
 strongly activating  strongly deactivating
-O-, -NR2, -NHR, -NH2, -OH -NO2, -NR3+, -PR3+, -CF3, -CCl3

 moderately activating  moderately deactivating

-NHCOCH3, -NHCOR, -OCH3, -OR -CN, -SO3H, -COOH, -CONH2
-COCl, -COOR, -COR, -CHO
 weakly activating
-OCOR, Me, Et, alkyl, phenyl, -CH=CR2

 weakly deactivating
-F, -Cl, -Br, -I
 Nucleophilic substitution
 Nucleophilic substitution in an aromatic compound though not common, can be
observed in many aromatic systems, which has even found industrial importance.
 Example is industrial synthesis of phenol from chlorobenzene by Dow’s process.
Cl OH

i. NaOH
3500C
pressure
ii. H3O +

Reaction does not go through simple SN2 or SN1 mechanism.

 SN2 is not possible because carbon atom is sp2 hybridized and bromine is in same plane
as that of carbon.

 Due to this hydroxyl can not attack from back side of C-Br bond as is required in SN2
reaction.
 SN1 is possible in some cases but is unfavorable because the aryl cation formed will
be planar but will not contain empty p orbital. Instead it will have filled p orbital as it
is part of the aromatic system.

 Also, C-X bonds of aryl halides are shorter and stronger than those of aliphatic
halides because of the hybridized state and the resonance, hence, ionization to form
a cation is a high energy process.

 Such a mechanism is observed only with leaving group such as gaseous nitrogen.

N
OH
N
OH

N2
 Instead, reaction proceeds through a different mechanism altogether- addition-
elimination mechanism.

F O O NR2 O
R 2N F

R2NH

 Nucleophile first adds to the aromatic system and then elimination of the leaving
group provides the product.

 The reaction is best observed in substrates having anion stabilizing group such as
NO2 or CHO etc., when present at the ortho and para positions with respect to the
leaving group.
 Nucleophilic substitution in 4-nitrochlorobenzene.

Cl HO Cl OH

OH

N N N
O O O O O O

 Negative charge can be pushed through the aromatic ring if an electron

withdrawing group is present at the ortho or para position.
 Such an assistance can not be seen when an electron withdrawing group is at the
meta position.
Cl HO Cl OH

OH

O O O
N N N

O O O

 The number of electron withdrawing groups present in the aromatic nucleus also
affect the course of reaction, as can be shown in following reactions.

 o-nitrochlorobenzene requires higher temperature as compared to 2,4-

dinitrochorobenzene and 2,4,6-trinitrochlorobenzene which can easily be converted
to phenol at 350C.
 Cl OH

i. aq. NaHCO 3
NO 2 NO 2
130 0C

rate: 7 X 1010
ii. H3O +

Cl OH

NO 2 NO2
i. aq. NaHCO 3 rate: 2.4 X 1015
100 0C
ii. H3O +

NO 2 NO 2

Cl OH

O2N NO2 O2N NO2

i. aq. NaHCO 3
35 0C
ii. H 3O+
rate: too fast to measure

NO2 NO2

Pay attention to the temperature employed in each of these reactions

 C-X bond braking occurs after the rate-determining step in the reaction.

 Carbanion formed after the nucleophilic attack, is most stable in the case of
fluorobenzene and is the least stable for iodobenzene.

 F being most electronegative stabilizes the negative charge in the intermediate

carbanion.

Nuc F Nuc Cl Nuc Br Nuc I

N N N N
O O O O O O O O

most stabilised least stabilized

 Nucleophilic substitution in heteroaromatic compounds takes place much faster
than in aromatic compounds.

 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under

similar conditions.
NaOCH3
CH3OH
50 0C
N Cl N OCH3

 Nitrogen is more electronegative than carbon and stabilizes the anion formed and
increases rate at which it is formed.

OCH3
OCH3 this anion is more stable
N Cl N
Cl

OCH3
than this anion
OCH 3

Cl
Cl
 Synthetic application of aromatic nucleophilic substitution

(1) Syntheses of ofloxacin, an antibiotic. O

F COOH

ofloxacin
N N

N O

 It is synthesized from following starting material, containing four fluorine atoms.

O

F COOEt

starting material f or
of loxacin synthesis

F F OEt

 Reaction involves nucleophilic substitution of fluorine atoms. Steps involved are as

follows.
 O
O

F COOEt
F COOEt

H F F OEt
F F OEt
HN
NH 2 F
F
OH
OH

O
O
F COOEt
F COOEt

F F
H F N
HN
F F
F OH
OH
 O O

F COOEt F COOEt

NaH

F N F N

F F
OH O

O O

F COOEt F COOEt

F N F N

F O O
 O
O

F COOEt
F COOEt

F N
N N
NH F
O
MeN O
MeN

O
O
F COOH
F COOEt

NaOH
H 2O
N N
N N
MeN O
MeN O

of loxacin
 Benzyne mechanism

 Bromobenzene reacts with a strong base such as sodium amide in liquid ammonia
to give aniline through nucleophilic substitution reaction.
Br NH2
NaNH 2
NH 3

 Reaction goes through different mechanism than stated earlier.

 It involves formation of a benzyne intermediate hence name benzyne mechanism.

 It is reverse of normal addition-elimination mechanism.

 Sometimes it is called elimination-addition mechanism.

 In the first step, the ortho proton is removed by the action of a strong base to
furnish a carbanion.

 This anion then loses the bromide ion to give a highly reactive benzyne
intermediate.

 This benzyne intermediate then reacts with the nucleophile to give the product. In
the above example amide ion acts as a nucleophile.

 Strong bases such as amide ions, oxyanions, carbanion are required for the
reaction to go forward.
 Due to the presence of electronegative bromine, ortho proton is relatively more
acidic, resulting in its removal by the base.

 Benzyne intermediate is formed from this carbanion by syn-periplanar elimination

of the bromide ion.

 Benzyne intermediate appears like an alkyne in its representation with triple bond
in the benzene ring. However, this triple bond is not like an usual triple bond as its is
formed by the lateral overlap between two sp2 hybridized orbitals outside the ring.
 This external π bond is weak, making benzyne intermediate unstable and highly
reactive.

 It can not be isolated but it can be trapped in order to detect its presence as an
intermediate.

 Reaction such as Diels-Alder reaction (as shown below) can be used to trap this
intermediate.

+ O
 First major evidence for the presence of benzyne intermediate was given by J. D.
Roberts in 1953.

 He showed that 14C labeled bromobenzene on treatment with amide in liquid

ammonia gives aniline in which 14C label is equally distributed in two positions.

∗
Br NH2 NH2
NaNH 2
∗ NH 3 ∗
+

 Benzyne is a symmetrical intermediate. For this reason probability of formation of

both products is equal. But, when aromatic nucleus has more than one substituent
then product formed will be depending upon existing group.
 Formation of exclusively m-(trifluoromethyl)aniline from
o-(trifluoromethyl)chlorobenzene can be explained by taking into consideration the
carbanion formed after the addition of the nucleophile to benzyne.
CF3 CF 3

Cl NaNH2
NH3

NH 2

CF 3

NH 2

CF3 CF 3

Cl NaNH 2
NH 3
less stable carbanion
CF3

NH2

more stable carbanion as negative charge is closest

to e-withdrawing group
 In intramolecular attack of nucleophiles, selectivity is not an issue. It simply gives one
cyclization product with the nearer end of the triple bond.

H
Cl
Cl NaNH2
NH3

CN CN
CN

H H
NH 2

C C
N N

CN CN

NH3
 Practice problems
(1) Identify the unknowns in the following equations

(i)

(ii)

(iii)

(2) (i) (ii)

(iii) (iv)

(v)
 Answers
(i)
(1) (ii)

(iii)

(2) (i)
(ii)

(iii) (iv)

(v)
Reactions involving carbonyl
compounds
Chapter Introduction
The reactions of carbonyl compounds are one of the
most important class of synthetically useful reaction
in organic chemistry. The carbonyl functional group
is also regarded as the most important functional
group. This functional group can participate in
multiple modes of reactions. The reactions of
carbonyls can be broadly classified as the direct
nucleophilic addition reactions wherein a
nucleophile adds to the carbonyl carbon atom. The
other equally important and versatile family of
reactions of carbonyl arise due to the acidity of the
alpha-C-H groups. Upon treatment with a base, such
compounds are capable of yielding a very useful
nucloeophile, known as enolate. The chemistry of
enolates are widely exploited for the generation of C-
C bonds in various reaction. This module is therefore
very important for the practice of organic reaction
and its mechanisms.
I. Nucleophilic addition
reactions Carbonyl group of aldehyde, ketone, carboxylic
acid, ester etc., a very common of all functional
Introduction groups in organic chemistry, shows most
important and simplest of all reactions i.e.
nucleophilic addition.

O
Addition of cyanide to NaCN, H2SO4
CN
H2O C
acetone gives acetone OH
cyanohydrin.
Reaction proceeds in two steps. In first step
nucleophilic addition of cyanide occurs
followed by a protonation of the resulting
alkoxide anion.
In fact, this is general feature of all nucleophilic
addition reaction of carbonyl compound.
Mechanism of nucleophilic addition
H-CN
O CN O NC OH
+ CN

CN

Reactivity of carbonyl Orbital considerations give a clear picture of these

group towards nucleophiles addition reactions.
C=O of carbonyl compounds is sp2 hybridized
and is planar. It has shorter bond length than
typical C-O and is twice strong than C-O. What
makes it reactive toward addition reaction is
polarization of C=O bond.
(Electronegativity of C is 2.5 while that of O is
3.5 )
Polarization makes carbon partially positive
which encourages addition of negatively
charged cyanide ion.
Orbital considerations: Why carbonyl groups are
electrophiles?
O 3.5
2.5
C O
δ+ δ

The C-O bond is polarized towards the more electronegative oxygen

Bonding in carbonyl group

LUMO
Unfilled orbital

Filled orbital HOMO

 When nucleophile adds to carbonyl group, its
HOMO reacts with LUMO of carbonyl group.
So when this LUMO is more polarized i.e.,
coefficient of LUMO at carbon is greater, then
Complete diagram of filled this interaction is better.
orbitals of carbonyl
compounds

When the HOMO of a nucleophile interacts

with the LUMO of a carbonyl group, a new
σ bond is formed and π bond is broken due
to filling of electrons to the antibonding π*
orbital of carbonyl group. Electrons from
HOMO of nucleophile now migrate towards
oxygen giving it negative charge.
new σ bond is formed at
expense of π bond.

O OH
Cyanohydrin formed from CN
NaCN, H2O
this cyclic ketone is used in
syntheses of 5HT3 agonists. N
N

The reaction is facilited by acid catalyst and

is in equilibrium with starting material.
Hence only reaction favoring product will
give good yield.
 O CN
Cyanohydrins can also be Me3SiCN
obtained from addition of 1 mol% cat OSiMe3
24h
trimethylsilylcyanide.
F3C F3C
100% (56% ee)

Bolokon,Y.N; Green,B; tBu tBu

Ikonnikov, N.S; North,M;
Parsons,T; Tararov,V.I; Tet.
Lett., 2001, 57, 771. tBu tBu
N O O N
O
Ti Ti
Catalyst : O
N O O N
tBu tBu

tBu tBu
 Reaction of organometallic compound with
(A). Reactions with
organometallic compounds carbonyl compound is a very important
reaction as it gives alcohols by C-C bond
formation.
(A.1) Lithium and Lithium and magnesium containing
magnesium in nucleophilic organometallic compounds are of importance in
addition reaction these reactions.
Lithium and magnesium are very electropositive
metals and hence electron density is highly
polarized towards carbon in these reagents.
Hence, making them good nucleophiles which
attack carbonyl compounds.
O OH
Reaction of methyllithium 1.MeLi, THF
2. H2O
with aldehyde R H
H R
 Mechanism is similar to typical nucleophilic
addition reaction.
O OH
O
Me Li H OH

H H
R H R R

Orbital diagram gives clear picture of reaction.

Orbitals involved in
addition of methyllithium

In these reactions, water is added in last step of

reaction, after methyllithium is added to
carbonyl compound. Organolithium or
organomagnesium compounds are very reactive
 towards water and react readily to give alkane.
To avoid this kind of side reaction, reaction is
carried out in presence of aprotic solvent like
THF, Et2O etc.,

Buhler,J.L, JOC, 1973, 38, nBu

O nBuLi
904. hexane OH
-780C

98%
 O OH

Maruoka,K; Nonoshita,K; MeLi

MAD
Yamamoto,H; Tet. Lett., toluene
1987, 28, 5723. -780C

Catalyst for reaction 77%

MAD-
tBu tBu
Methylaluminiumbis(2,6-
ditert.butyl-4- Me O O Me
methylphenoxide) Al

tBu Me tBu
 Organomagnesium reagents are known as
Grignard reagent and these class of
compounds also react in same way as that of
organomagnesium and organolithium
compounds.

O OH
Reaction of Grignard’s 1.PhMgBr, Et 2O
reagent with carbonyl 2. H2O H
R H R
compound

Product of reaction of Grignard’s reagent with

carbonyl compound and that of analogous
organolithium compound is same.

Victor Grignard is the name of a German scientist. Pronounced as “Grini-yard”

Addition of Grignard Reagents [carbon nucleophiles]

Grignard reagents are strong bases as well as nucleophiles

These compounds can be used for C-C bond formation reactions (construction of organic
molecules)

O OH
1. RMgBr
2. H3O+
R1 R
R1 H
H

O
H H
Br
O MgBr O OH
Mg
R
R1 R1 R R1 R
H
H H

Aldehyde sec-alcohol
Addition of Grignard Reagents
Grignard reagents and add to a range of carbonyl compounds,
OH

CO2 O C O
RMgBr Acids
O R

O OH
RMgBr
Formaldehyde p-alcohol
R
H H H
H

O OH
Aldehyde RMgBr sec-alcohol
R
R1 H R1
H

O OH
RMgBr
Ketone tert-alcohol
R
R1 R2 R1
R2
 Formaldehyde on reaction with Grignard’s
reagent gives primary alcohol whereas other
aldehydes give secondary alcohol and ketones
give tertiary alcohols. [More examples]

O MgBr
Formation of primary 1.Et2O OH
+
alcohol 2.H3O
H H

Formation of secondary O OH
1.EtMgBr, Et2O
alcohol 2.H2O, H
H

O 1.EtMgBr, Et2O
Formation of tertiary 2.aq. NH4Cl
alcohol OH
 More examples

In presence of strong acid, elimination product

is obtained.
O OH
1.MeMgI
Reaction of cyclohexanol
2.HCl
with
methylmagnesiumbromide

O
THF
Use of alkylmagnesiumate in -780C
+ EtMe2MgLi
Grignard’s type reaction 5h

Manabu,H; Tokihiko, M; HO Et HO Me
Kazuak,I; Org.Lett., 2005, 7,
573. +

89% 7%
(A.2) Reformatsky In Reformatsky reaction, aldehydes and ketones
reaction
on treatment with α-haloesters in presence of
metallic zinc give β-hydroxyester.

O C COOEt
General reaction for Zn H2O
+ C COOEt
Reformatsky reaction C
Br
OZnBr

C COOEt

OH

Reaction goes through intermediate analogous

to Grignard’s reagent.
Reaction may, particularly, in case of aldehydes
produce olefin by elimination.
 CHO Br 1.Zn
Reaction of benzaldehyde 2.H3O
with +

Ethyl 2-bromopropionate COOEt

-H2O
COOEt
COOEt
OH

Organozinc reagents are less reactive than

Grignard reagent or organolithium reagents.
Thus, they do not react with esters and
substitution product may result instead.

O
Zn C COOEt
+ C COOEt
R OR1 C
Br R O
 More examples
Reaction of benzaldehyde CHO Ph
with BrCH2COOtBu / Zn COOtBu
t-butyl 2-bromoethanoate THF, 00C
H OH
90% (62% ee)

O O
Zn, THF
+ OMe 600C

MeO Br
OMe

HO OMe O
HCl, THF
rt, 10h
O

MeO
MeO
92%
 Water and alcohol, when added to carbonyl
(B). Hydration and
hemiacetal formation compound, behave as nucleophiles and add to
them giving corresponding hydrates and
hemiacetals or hemiketal respectively.
Hydration O HO OH
H 2O

R R1 R R1

Hemiacetal formation O HO OEt

EtOH, H

R R1 R R1

Reaction is in equilibrium and position of

equilibrium depends upon nature of carbonyl
compound.
Formaldehyde reacts readily than any other
carbonyl compound and exists mostly in
hydrate form in water.
Formaldehyde is present in O HO OH
hydrated form in aqueous H2O, H

solution H H H H

Mechanism for hydration/acetal Cl

formation (example given is for acetal H

OH
formation) O
+ Cl
H
H
Water is a weak nucleophile and hence ROH

activation of carbonyl by way of

protonation is required for effective
addition of water. RO OH
RO H OH
+ HCl
H
H

Hydration of chloral is favorable

reaction and most of chloral is in O OH
hydrated form. H2O

Cl3C H Cl3C OH
H
 O O

H2O OH
O
OH

O O

Mechanism for hemiacetal formation follows

same route. It is called hemiacetal because it is
halfway to acetal.
 When carbonyl and hydroxy group are present
Intramolecular hemiacetal
formation reaction within same molecule, intramolecular reaction
occurs to give cyclic hemiacetal.

O O
OH
Reaction of
HO
4-hydroxybutyraldehyde H H
gives cyclic hemiacetal

O O O OH O
Hydroxyketones can also
P Ph P Ph
form cyclic hemiacetals
O Ph Ph
OH O
 HO HO
OH O O
HO HO
HO HO OH
OH OH
glucose (>99%)
Glucose and ribose mainly
exists in cyclic hemiacetal
form OH O
O OH
HO
HO
HO OH HO OH
ribose
C. Addition of Amines [amines as nucleophiles]

Carbonyl compounds such as aldehydes and ketones can

react with ammonia derivatives

Nature of amine Name of the product Structure

R
p-amine Imine (Schiff bases) N

NR2
sec-amine Enamine

OH

hydroxylamine Oxime N

NH2

hydrazine hydrazone N
Condensation reactions with ammonia derivatives
Condensation reactions* with ammonia derivatives lead to Schiff bases

Addition Tetrahedral Elimination

intermediate

Acid catalyzed
R
O RHN OH N

+ HOH

RNH2
Carbinolamine Imine

* One or more molecules are joined with the loss of water or another small molecules
C.1. Condensation reactions with ammonia derivatives
Generation of Enamines

HO
O R 2N
CH3 -H2O
CH3 R2N CH3
R2NH H3C H3C H3C
H
H

2°-Carbinolamine Enamine

Secondary amines can give enamines upon condensation with ketones

O
N

H+
+
N
H

Enamines are very good nucleophiles for C-C bond formation

D. The Wittig Reaction [carbanions as nucleophiles]

Georg Wittig (1954): Nobel prize winner 1979

Reactions of aldehydes or ketones with phosphorous ylides* to give alkene

R3 R3 R1

Ph3P CR1R2 + C O C C + Ph3P O

R4 R4 R2

Phosphorous stabilized carbanions

Ph3P CR1R2 Ph3P CR1R2 Due to carbanion character ylidic

carbons are highly nucleophilic
ylide ylene

* Ylides are neutral molecules with a negatively charged carbon atom and a positively charged heteroatom (P, S, N etc.,)
Mechanism of Wittig Reaction

O
Ph3P O Ph3P O
R3 R4
R1 C C R3 R1 C C R3
Ph3P CR1R2
R2 R4 R2 R4

Betaine Oxaphosphetan
e

R1 R3

C C + Ph3P O

R2 R4

Phosphine oxide is a very stable species. Formation of alkene as well as phosphine

oxide provides great thermodyanic drive for this reaction
Wittig Reaction is an olefination reaction
O
CH2
+ Ph3P CH2 + Ph3P O

Choice of R2CX is critical while planning a Wittig olefination reaction

C CR2

Br

Ph3P CR2 Ph3P CR2 Ph3P R2C Br

H H

Bu Li

Other bases used for the generation of ylides: t-BuOK, NaH

 Carbonyl compound containing α-hydrogen
II. Reaction of enolates
atom, when reacted with base, loses its acidic
proton and forms an enolate.
O O
OH
Formation of enolate ion H
R R

Enolate ion is an alkoxide ion but is more stable

to that of corresponding enol form because it is
a conjugated, three atom, four electron system.
Delocalization of enolate O O

ion
R R

Charge is mainly on oxygen atom, more

electronegative atom.
Same can be shown by use of orbitals involved.
Populated π orbital of
enolate ion

In enolate, thus, more of negative charge is on

oxygen and the HOMO is centered more on the
carbon atom.
Various reactions are shown to proceed via
enolate ion formation.
 Aldol condensation is a self condensation
II. (A). Aldol condensation
reaction between molecules containing α-
hydrogen atom in presence of base.
The product of reaction is a β-hydroxy carbonyl
compound.
Base catalyzed Aldol O O OH O
condensation of +
OH

acetaldehyde H H H
Mechanism for Aldol
condensation O O
Base first abstracts proton +
from carbonyl compound H H
and gives enolate which HO H
then adds to other molecule O O
-OH
OH O
of carbonyl compound to
give β–hydroxycarbonyl H H
compound
 Reaction is also furnished by ketones.

O O HO O
Base catalyzed Aldol OH
+
condensation of acetone

In high basic conditions, further reaction occur

i.e. elimination.

O
OH -H2O
O
OH
Elimination of water
molecule proceeds via O
E1cB mechanism
 In case of symmetrical carbonyl compound,
which way enolisation occurs is unimportant.
Similarly, in case of unsymmetrical carbonyl
compounds, containing only one α-hydrogen
atom, which way it is enolized is
unquestionable.
O HO O
Base catalyzed Aldol OH
condensation of
acetophenone

In acetophenone, only methyl protons can be

enolized.
 Similarly, in case of lactones, only methylene
protons are available for enolisation.
O O

1. HO
Base catalyzed Aldol O O O
2. -H2O
condensation of cyclic ester

Aldol reactions can also be furnished using

specific enol equivalent, such as, lithium or silyl
enol ether etc.
O OLi
Aldol reaction using LDA
lithium enolate THF
-780C

O
OLi O OH
H

82%
Aldol reaction using silyl OSiMe3
O
enol ether Me3SiCl
Et3N

O
Reaction of
2-methylbutyraldehde with OSiMe3 H O
silyl enol ether of
3-pentanone 1. TiCl4
2. TsOH

When two different carbonyl compound are

treated with base, condensation is observed,
similar to that of self condensation. This
reaction is known as cross-aldol condensation.
 O O

+H NaOH
H2O / EtOH
Cross-Aldol reaction
NO2
between acetophenone and O
4-nitrobenzaldehyde

NO2

For these kind of reactions to work, there must

be present at least one component which can not
be enolized and is electrophilic enough for
nucleophilic attack to occur and other
component must be enolizable.
 When, in a molecule present, two carbonyl
functional groups such that one can be enolized
and other is electrophilic, intramolecular Aldol
reaction takes place.
O O
Intramolecular Aldol
reaction of 1,6-diketone base

O O
O
O

-H2O

OH
~100%
 In case of unsymmetrical diketones, there are
four different sites for enolisation and the final
product depends on whether reaction is
kinetically controlled or thermodynamically
controlled.
O
Intramolecular Aldol KOH O
reaction of 1,5-diketone
O
90%

In this reaction, though there are several

possibilities of inter and intra molecular
condensation, only this product is formed in
90% yield. This is because it leads to stable
conjugated enone in six membered ring.
 O
KOH

Intramolecular Aldol O
reaction of 1,4-diketone
O

80%

In this reaction, 80% of the product, cis-

jasmone is formed, as reaction is under
thermodynamic control.
 Knoevenagel reaction is modified aldol
II. (B). Knoevenagel reaction
reaction, in which reaction of carbonyl
compound with active methylene compound,
proceeds through enolate formation, in presence
of weakly basic conditions.

O O O COOEt
base R
+
R H EtO OEt COOEt

Active methylene compound in the reaction can

be diethylmalonate, ethylacetoacetate, malonic
acid, Meldrum’s acid, cyanoacetic ester etc.
Weakly basic conditions can be maintained by
use of pyridine or piperidine in reaction.
Mechanism is as follows.
 O O
O O
Attack of base on active
methylene compound to EtO OEt
EtO OEt
give enolate H H
R2NH

O O
Electrophilic addition of O O
enolate to carbonyl EtO OEt
compound EtO OEt
H
O H OH
R O
R
O O O O

Removal of water molecule EtO OEt EtO OEt

H
by E1cB mechanism to HNR2
give final product R OH R OH
O O

EtO OEt

R
 Few more examples of Knoevenagel reaction

CHO

ethylammonium CN
nitrate, rt, 10h
+
COOEt
EtOOC CN 87%

O O
O pH 7.8
COOEt + H 2O
400C
H 4h
86%

Kourouli, T; Kefalas, P; Ragoussis, N; Ragoussis, V,

JOC, 2002, 67, 4615
II. (C). Perkin reaction
Reaction of acid anhydride and aromatic
aldehyde in presence of strong base, is Perkin
reaction.
O O
CH3COO COOH
+ PhCHO
Ph
O

Mechanism of reaction O O O O
+ AcOH
Formation of enolate of H
O O
anhydride AcO

O O O O O O
Aldol type addition of
enolate to carbonyl O Ph H O Ph
compound
 O O
Intramolecular acylation
followed by loss of O O
O O
carboxylate
O Ph Ph O

In next step mixed Ac2O

O O O O O O
anhydride formed by
addition of acetic COO
Ph Ph O
anhydride loses acetic acid
and is hydrolyzed in single
step to give unsaturated
acid O O O O
AcOH COOH
Ph
Ph O

H
AcO
 Mechanism is supported by fact that, when
anhydride containing no enolizable protons is
used, then final product of the reaction is one
corresponding to the one obtained by loss of
carboxylate.

O2N CHO + MeO CH2COOH

pyridine
Ketcham, R, J. Chem. (CH3CO)2O
30 min
Educ., 1964, 41, 565
HOOC
OMe
O 2N

trans= 82% & cis= 10%

 More examples
HOOC
CHO

NEt3, Ac2O
Gaukroger, K; Hadfield, +
J.A; Hepworth, L.A; OH
MeO OMe
Lawrence, N.J; McGown, OMe
A.T, JOC, 2001, 66, 8135 OMe

HOOC OH

OMe

MeO OMe

OMe
60%
 Self condensation reaction of enolizable ester, in
II. (D). Claisen condensation
the presence of base, is Claisen condensation.
O O O
Ethylacetate on reaction NaOEt
with sodiumethoxide gives OEt OEt
ethylacetoacetate.
O O
H
Mechanism of reaction EtO OEt OEt

O O O OEt O

OEt OEt OEt

O O

OEt
Mechanism is similar to that of Aldol condensation. In this reaction, first ester
is enolized. It then attacks another molecule of ester in the same way as that
in aldol condensation. Adduct of the reaction then loses ethoxide, as it is
good leaving group.
Product of the reaction is β-ketoester.
O O
O
tBuOK, 900C Ph
Ph solvent free, OBn
OBn 20 min
Ph
84%

Cross-Claisen condensation are those in which two different molecules of ester

or ester and other carbonyl compound are treated in presence of base.
It often forms mixture of products. Synthetically useful products are obtained,
when one of the component of reaction is non-enolizable.
 O O O
Cross-Claisen condensation O
NaOEt
of benzaldehyde and H + OEt
ethylacetate OEt

O
O
NaOEt, EtOH
OEt +
,H3O
Cross-Claisen condensation OEt
of ethylbenzoate and
O O
ethylacetate
OEt

O O O O
Cross-Claisen condensation +
NaOEt
of ethylbenzoate and Ph OEt Ph Ph Ph
acetophenone
 O O
O
NaOEt, EtOH
+
Cross-Claisen condensation ,H3O
H OEt CHO
of cyclohexanone and
ethylformate

H
N COOMe O
Cbz LDA, THF, H
+
-45 to -500C
Honda, Y; Katayama, S; OtBu
Ph
Kojima, M; Suzuki, T; O O
Izawa, K, Org. Lett., 2002, H
N
4, 447 Cbz OtBu

Ph
97%
 Thioesters also undergo Claisen condensation.

O O
MgBr2.OEt2
+ iPr 2NEt, DCM,4h
Claisen condensation of tBu
Bt SBn
thioester gives O O
β-ketothioester tBu
SBn
80%
Zhou, G; Lim, D; Coltart,
D.M, Org.Lett., 2008, 10,
3809
II. (E). Dieckmann Intramolecular Claisen condensation of diesters
cyclisation
in presence of a base is Dieckmann cyclisation.
O
O O
OR 1. base
O 2. H OR

The mechanism for the OR

Dieckmann cyclisation is O O
analogous to that of the
Claisen condensation. OR OR OR
H
Firstly one of the two O O
esters is converted into an
enolate ion. This enolate OR OR

then attacks the second O OR O O O

ester via nucleophilic acyl
substitution resulting in a OR OR

cyclic β-keto ester.

Reaction can best be carried out for 1,6 and 1,7-diesters, which give five and
six membered rings respectively.

COOEt
COOEt 1. NaH,
THF,
EtOOC EtOH
2. H3O
COOEt EtOOC
O

O
O O
NaOEt COOEt
EtO OEt
More examples

EtOOC

MeOOC 1. tBuOK, tol O

reflux
5 min
2. 18N H2SO4
THF, 4 h

N O

N O

61%
More examples

COOEt
COOEt tBuONa, rt
10 min O
Toda, F; Suzuki, T; Higa, solv. f ree
S, J. Chem. Soc., 1998, 1, COOEt

3521 68%
COSPh
BzOCHN

tBuOK, THF
Jackson, B.G; Gardner, J.P; N -780C
Heath, P.C, Tet. Lett., 1990, O
31, 6317 MeOOC
BzOCHN

N
O OH

COOMe
76%
More examples COOMe

COOMe

N CN

tBuOK
DeGraffenreid, M.R, et.al, THF, rt
0.5 h
JOC, 2007, 72, 7455
OH

COOMe

N CN
87%
Ho, J.Z; Mohareb,
R.M; Ahn, J.H; Sim, NHPf
T.B; Rapoport, H,
COOMe LiTMP
JOC, 2003, 68, 109 MeOOC THF
-780C
NHPf
MeOOC
O
 III. Michael addition
Michael addition is nucleophilic addition of enolate to α, β-unsaturated
carbonyl compound in presence of base.

H R
H R
base
+ EWG
EWG EWG
EWG

Michael reaction is conjugate addition of enolate to activated olefin and is

thermodynamically controlled.
There are two components of reaction, one is Michael donor, which is usually,
1,3-dicarbonyl compound, acetoacetic ester, active methylene compound, etc.
The other component is, Michael acceptor which is usually, α, β-unsaturated
carbonyl compound, α, β-unsaturated ester, etc.
 R R
O

O O
+ O
O base
R R

R O
R

H
R R
Mechanism : R R B
Base first, abstracts proton -BH
O O
from donor and forms O O
enolate.
R R

O O
 O
R R
Enolate then attacks
+
Michael acceptor and adds
O O
to it, giving Michael
R
addition product.
O O
B H
O O

R R R R

R O R O

O O Ph
H
Pansare, S.V, Pandya, K, N
N
NO2
H
JACS, 2006, 128, 9624 DMF, rt
+ pTsOH
NO2
Ph 86% (>99%ee)
 O
[bmim]OH
3.5 h, rt
+ EtOOC COMe

Ranu, B.C; Banerjee, S,

Org. Lett., 2005, 7, 3049
O

MeOC
COOEt
90%
 NO2
+ MeOOC COOMe

N
Okimo, T; Hoashi, Y; F3C
H
N
H
N
Furukawa, T; Xu, X; S
Takemoto, Y, JACS, 2005,
CF3
127, 119
toluene, rt, 9 h

MeOOC COOMe

NO2

89% (86% ee)

 Robinson annulation is Michael addition of
IV. Robinson annulation
methyl vinyl ketone to carbonyl compound
followed by Aldol condensation to give
annulene.
O O
NaOH
+

Mechanism : H
O
Base abstracts proton from O OH
ketone and forms enolate
O

H OH
Enolate adds to Michael O
acceptor via conjugate +
addition O
O
 O
H O

OH
Michael addition product, O
O
through intramolecular
Aldol condensation, gives
final product i.e.
α, β-unsaturated ketone OH
H
O
O OH

Reaction is useful in
syntheses of six membered O
NaOH
+
ring in polycyclic
compounds
O O
 Michael addition of enolate having second
enolizable group, to an enone, is necessity for
reaction to occur.
O
O
base
+

O
O TiOH, P4O10
DCM, 400C O
+
microwave, 8h

Mc Murry, JOC, 1975, 40, O 1. NaNH 2

+
1823 2. NaOH,
MeOH
O O
 EtOOC

COOEt
O 1. KOtBu
Marshall, JOC, 1971, 36, + 2. NaOMe/
O
178 MeOH
O

O NaOMe
+ MeOH
COOEt reflux
Wang, D; Crowe, W.E, 56%
O
Org. Lett., 2010, 12, 1232
EtOOC EtOOC H

H
OH OH
HO + HO
H H
H H
H H

syn : anti
1 : 4
When diester is used as Michael donor, Claisen
condensation, instead of Aldol condensation is
seen. This reaction gives cyclic diketone.

COOEt O EtONa
+ EtOH
reflux
EtOOC
COOEt O O

O EtONa
EtOOC EtOH
EtOOC
 Base catalyzed reaction between nitroalkane
V. Henry reaction
and carbonyl compound is Henry reaction.
NO2
O
base R3
R 1 NO2 + R1
R2 R3 R2
OH

H
Mechanism : O
O B 1
R N
Mechanism is similar to R1 N
aldol condensation. O
O
First base abstracts proton O
O O B H
from nitro compound and R 1
N
+
R 1
R3
gives enolate equivalent. It O R2 R3 R 2

adds to carbonyl compound NO2

in similar way as that in OH

Aldol reaction, to give R1

R3
β-nitro alcohol as product. R2
NO2
Reaction is analogous to aldol condensation and generally referred to as
Nitro-Aldol reaction.

NO2

CHO OH
CH3NO2, TMG
THF, rt, 12h
BnO OBn
BnO OBn
OBn
OBn
58%

Nitro group, like, carbonyl moiety is powerful electron withdrawing group. It

renders acidic properties to protons α to it and can form enolate equivalent.
Acidic nature of nitro compounds is so profound that very mild bases can
catalyze reaction.
 Like Aldol condensation, α,β-unsaturated nitro
compound can be obtained, by elimination of
water molecule. O
Et 3N, H2O
5h
H + CH3NO2

OH

NO2
Zhou, C.L; Zhou, Y.Q; H
Wang, Z.Y, Chinese Chem.
88%
Lett., 2003, 14, 355
NO2
CHO
HO OH

BnO NO2
O
TBAF/ THF BnO
+ O
rt, 10 h
O O OH
O O

75%
VI. Ester hydrolysis
Hydrolysis is a chemical process in which a
certain molecule is split into two parts by the
addition of a molecule of water. One fragment
of the parent molecule gains a hydrogen ion,
other group collects the remaining hydroxyl
group.
Ester is hydrolyzed when treated with excess of
water. This reaction is reverse of ester synthesis
from corresponding carboxylic acid and
alcohol.

O O
General reaction for ester acid /
+ R'OH
base
hydrolysis R OR' R OH
Reaction is catalyzed by acid or base. Both yield same product, except that, in
base catalyzed reaction salt of carboxylic acid is obtained from which acid can
be regenerated by acidic work up.
Acid catalyzed reaction is reversible. In order to get product in good yields, it
is necessary to use dilute acid and ample amount of water, in contrast to that of
ester synthesis, where concentrated acid is used.
Ingold in 1940 classified these mechanisms according to following factors;
 Nature of reagent
 Point of cleavage
 Reaction kinetics
Mechanism of ester Ester hydrolysis can take place by eight possible
hydrolysis mechanisms.
AAC1 mechanism : Acid catalyzed, unimolecular, acyl oxygen
fission
O
O O
slow H2O
H H
R O R'OH
R OR' R
R'
O
OH O
H
R O
R OH H R OH
H

O* O*

H2SO4
Hydrolysis of methyl O OH + CH3OH
H2O
mesitoate
AAC2 mechanism : Acid catalyzed, bimolecular, acyl oxygen
fission
OR'
O OH
H H 2O
slow R OH2
R OR' R OR' OH
OH
OH O
R' slow
O
R R'OH H
OH R OH R OH
H

AAL1 mechanism : Acid catalyzed, unimolecular, alkyl oxygen

fission
O OH O
H + R'

R OR' R OR' R OH

H
H2O
R'OH
slow O
R H H
 O OH
H

Ph O Ph Ph O Ph

O
H2
+ Ph C OH
Ph OH

AAL2 mechanism : Acid catalyzed, bimolecular, alkyl oxygen

fission
O
O
H R' H2O
R O
R OR'
H
O H
+ R'OH
O
R OH R' H H
 Base catalyzed, unimolecular, acyl oxygen
BAC1 mechanism :
fission
O O
slow OH
+ OR'
R OR' R
O O
OR'
+ R'OH
R OH R O

BAC2 mechanism : Base catalyzed, bimolecular, acyl oxygen

fission
OH
O
OH
slow OR'
R
R OR' O
O O
+ R'O + R'OH
R OH R O
 O O
+ NH3 H 3C C NH3
H3C OC2H5
OC2H5
O
+ C2H5OH
H3C NH2

BAL1 mechanism : Base catalyzed, unimolecular, alkyl oxygen

fission

O O H2O
slow + R'
R OR' R O
H
OH
R'OH
O
R' H
BAL2 mechanism : Base catalyzed, bimolecular, alkyl oxygen
fission

O O
OH
+ R'OH
R OR' R O

Though all these mechanisms are observed in many cases, AAL2 and BAC1
are not observed for any substrate.
Most common of all these mechanisms are AAC2 and BAC2
Evidence of acyl oxygen fission is obtained by following experiments.
 Hydrolysis with H218O, results in 18O appearing in acid and not alcohol
 Esters with chiral R1 group, give alcohol with retention of configuration
 Allylic R1 group, does not give allylic rearrangement
 Neopentyl R1 group, does not give rearrangement
All these observations indicate that O-R1 bond is not broken.
Different nomenclature and summary of features of ester hydrolysis

Ingold notation Type Hydrolysis

AAC1 SN1 Special case

AAC2 Tetrahedral Very common

AAL1 SN1 Very common for tertiary

alcohols
AAL2 SN2 -----

BAC1 SN1 -----

BAC2 Tetrahedral Very common

BAL1 SN1 Special case

BAL2 SN2 Rare

 Examples of ester hydrolysis

H H
N N
KOH, aq.DMSO
COOEt COOH

1. 2mol KOH
COOCH3 MeOH, COOH
25min, ~350C
2. 6N HCl

96%

O O
1. 3mol KOH
MeOH,
O O 60min, ~350C O OH
2. 6N HCl

O O
94%
 OH

OH
O

OH O
1. 4mol KOH,
MeOH, 60 min,
OH ~350C
2. 6N HCl

OH
OH

OH O
90%

Khurana, J.M; Chauhan, S; Bansal, G, Monatshefte fur Chiemie, 2004, 135,

83
 PhSe PhSe
O Me3TiOH O
1,2-DCE
AllylO NHBoc HO NHBoc
N 800C, 2 h N
H H
O O
100%

Wallner, S.R; Nestl, B; Faber, K, Tet., 2005, 61, 1517

NHBoc NHBoc
30mol% I 2, 5h OH
OtBu
MeCN, reflux
O O
89%
MeO COOtBu MeO COOH

30mol% I 2, 3h

MeO MeCN, reflux MeO

OMe OMe
82%

1. O.2N NaOH
30min, rt,
DCM/ MeOH
nC4H9 COOEt nC4H9 COOH
2. H3O
Saponification The alkaline hydrolysis of esters to give
carboxylate salts is known as saponification.
Principal content of soap is sodium or
potassium salt of higher carboxylic acid i.e. a
fatty acid.

O C15H31

Alkaline hydrolysis OH
O 0.2N NaOH
of tripalmitin gives O DCM/ MeOH O
palmitic acid ~2.5h, rt
+ OH
and glycerol O C15H31 H3O C15H31 OH
O O OH
Palmitic acid + Glycerol
C15H31
Tripalmitin
 Practice problems
Luche,J.L; Damiano,J.C; JACS, 1980, 102, 7926.
(1) nBuBr
Li, ether
)))), 15 min CHO
O HO nBu (3)
~100% THF, rt
+
MgCl
(2) O OH
MgBr
OH
H
aq. NH4Cl

Tet. Lett., 2010, 66, 3242.

(4) OH 92%
O EtMgCl
CeCl 3
THF, 00C Et

76% JACS, 1989, 111, 4392.

O
(5) HO
O PTSA
toluene
HO O
(6) Wada, S; Suzuki, H, Tet. Lett., 2003, 44, 399
calcite, 0.5h
CHO + NC CN CN

H CN
97% S. Sebi, et.al, Tet. Lett., 2002, 43, 1813
(7) CHO Calcium phosphate CN
NaNO3, MeOH, 15min
+ NC COOEt
COOEt
81%

O
(8) Al2O3 CN
+ NC 3 min
H CN
CN
88%
Francoise, T.B; Foucaud, A, Tet. Lett., 1982, 23, 4927
(9) O
NaOEt, EtOH
+

O H OEt
H

O
H
CHO
 (10) OBn
(11) KHMDS
H OBn THF, 1h
H MeOOC
N COOMe -780C
MeOOC
OTBS NaHMDS Bn
O OTBS
N THF,-780C N Bn
N

MeOOC OH
COOMe
58%
COOMe
90%

Lin, R; Castells, J; Rapoport, H, JOC, 1998, 63, 4069

 Key words: rearrangement reactions, migration to
electron deficient nitrogen, electron deficient oxygen,
electron deficient carbon. Migratory aptitude, cross-
over experiments
Rearrangment reactions are an interesting class of reactions wherein a
group or an atom migration during the course of the reaction. While
most of the rearrangements are designed in that fashion, it can also be
undesirable in some cases. Depending on the reaction conditions, the
nature of rearrangement (and the product) could also change.
In this module, various rearrangement reactions are presented. These
are classified with respect the the migration origin and migration
terminus.
Emphasis has been placed on examples involving skeletal
rearrangements that are practically used in day-to-day organic
synthesis.
Rearrangement reactions involve the migration of a group or an atom
from one center (migration origin) to another (migration terminus)
within the same molecule. W W

A B A B

In the above-mentioned generalized representation, atom-A is

migration origin from where the migrating group “W” moves to atom-B
(migration terminus)
These rearrangements can be roughly classified on the basis of the
nature of the migrating group/atom,
i.Nucleophilic or Anionotropic: migrating group migrates with its electron
pair.
ii.Electrophilic or cationotropic: migrating group migrates without its
electron pair.
iii.Free radical: migrating group migrates with only one electron.
Of these most commonly found are nucleophilic one.
These rearrangements can take place in two possible modes,
i.Intramolecular : In these migrating group do not completely detach
from the migration origin and occurs within the same molecule.
W A B A B W

ii. Intermolecular : In these migrating group is detached from the

migration origin. In this case, migration of a group/atom can take place
to different molecule.

W A B+U A C A B U+ A C W
Different pathways through which 1,2-rearrangement takes place are
given below. Examples 1-3 involve electron deficient carbon atoms
R R

C C C C
1. x x
4. + y
R a b y a b
O C C
O C
2. R
x x
5. + y
R a b
a b y
3. C C C CR

A key driving force in such rearrangement reactions comes from the

conversion from a sextet to octet electronic configuration
Some General features of 1,2-rearrangement reactions

Reactions 1 to 3, a species with valence electron sextet either carbocation

or carbenium ion is involved. Thermodynamic driving force for an 1,2-
rearrangement will be significant if rearrangement leads to a structure
with octet on all atoms or generates some other more stable carbocation
[reaction 1] i.e. if newly generated carbocation is stabilized electronically
by its substituents than its preceding carbocation. Alternatively, reduction
in angle strain can also provide the driving force.
Reaction 4 & 5 show second cause for occurrence of rearrangement. In
reactions 4 and 5, atom b is bound to a good leaving group. Heterolysis
of such a bond would provide a carbocation. Departure of the leaving
group is then assisted by neighboring group. This sometimes gives a
positively charged three membered ring I(as in reaction 5).
Rearrangement in such reactions is possible only if group x is present at
new position in product than in the reactant
Broadly these reactions consists of three steps;
a)First step is generation of electron deficient centre in the
molecule. As the migrating group migrates with electron pair, the
migration terminus must have an incomplete octet. This can be
obtained in two ways ,
i.Through carbocation: Carbocations can be formed in various ways.
The most common being dehydration of alcohol. This step is similar to
that of SN1 or E1 reaction.
R R R
H -H2O
C C OH C C OH2 C C
 Me Me
Me
SN1 C CH2Me
Me C CH2Br Me C CH2
Me
Me Me
Me Me Me

Me C CH2Me + C C

OH Me H

Rearrangement of carbocation is very important reaction in cracking of

petroleum products.

Me Me
H
Me C CH CH2 Me C CH CH3

Me Me

Me Me Me Me

C CH C C

Me Me Me Me
ii.Through nitrenes : nitrenes can be formed by decomposition of acyl
azides.

R C N N N R C N + N2

O O

b) Migration: Migrating group migrates to the electron deficient centre with

its electron pair creating new electron deficient centre.
c)In third step, newly formed electron deficient centre acquires octet either
by accepting a nucleophile or excluding proton.

It is observed in many cases that either two or all three steps take place simultaneously. As
seen in many cases SN1 type of first step is commonly followed by rearrangement to give a
more stable carbocation.
It is proved by the fact that the rate of reaction increases with the ionizing power of solvent and
it is unaffected by concentration of base.
It has been shown that the rate of migration increases with degree of electron deficiency at
migration terminus.
Majority of rearrangements are intramolecular.
Cross-over experiments are useful tools to establish the nature of
rearrangement.
Another form of evidence can be gathered by using a chiral migrating
group. If the configuration at the migrating group is retained in the
product, it is quite likely that the rearrangement is intramolecular.

Ph H O Ph
HNO2
Ph C C Me Ph C C Me

OH NH2 H

In this example inversion at the migration terminus takes place. The

reaction involves diazotization and intramolecular 1,2-phenyl
migration.
Eg. In Beckmann rearrangement, only group anti to the hydroxyl
migrates. This shows the concertedness of the reaction
R1 OH
C N R1CONHR
R

So, if racemisation is noticed, then it is probable that the first step takes
place before the second step, as in SN1 reaction.
R R R

A B X A B A B product

And, if inversion occurs, then two steps might be concerted, as in SN2.

R R
R
A B X A B A B product

In this case, the neighboring group assists the departure of the leaving
group, which in turn can increase the rate of reaction
In many reactions like Hofmann, Curtis (see later) etc., identity of the
group that migrates is quite clear. However, in certain other reactions
like Beckman rearrangement, there are more than one choice. In such
situations the question of which group migrates depends on several
factors (such as the geometry of molecule).
In the case of Wagner-Meerwein and Pinacol rearrangement, there
are many choices, as substrate contains several groups, that have
similar propensity for migration. Such reactions are used for the study
of relative migratory aptitude.
* In this example, hydroxyl group is lost from carbon bearing two phenyl

groups as it provides a more stable carbocation. The stability of the

carbocation is enhanced by group in the order aryl > alkyl > H.

Ph H Ph H Ph

Ph C C H Ph C C H Ph C C H

OH OH OH H O

Ph H

Ph C C H

OH
 In order to study migratory aptitudes, the substrate should furnish same type of
carbocation wherein the migration occurs.
Many factors control migratory aptitude. These are (a) conformational features,
(b) relative ability of the groups at the migration origin that can stabilize the
developing positive charge.
In the following example, involving the decomposition of tosylate, only phenyl
group migrates
The phenyl group in the following example assists the departure of the tosyl group
Me
Me Ph
H
Ph C C Me reflux in benzene C C
Me Me
Me OTs
In a related alkene, upon treatment an acid, a competitive migration of the methyl
and the phenyl groups are noticed

Ph C *
C Me
Me

* H Me Me
Ph C C CH2
H +
Me C C* Ph
Me

Me Me
Some general trends in the migrating aptitude of different groups

Aryl groups exhibits higher propensity for migration than that of alkyl
groups.
Migratory aptitude of hydrogen is unpredictable. Hence, mixture of
migrated products are obtained.
In the case of aryl groups, those with electron donating substituents at
the meta or para positions migrates preferentially over those
containing substituents at the ortho position.
Aryl group containing electron withdrawing groups show reduced
migratory aptitude.
A. Wagner-Meerwein rearrangement:
When alcohol containing more than two alkyl or aryl group on β
carbon are treated with acid, the product formed is generally a
rearranged product, rather than simple substitution or elimination
product. This reaction is called Wagner-Meerwein rearrangement.
Newly generated carbocation is stabilized generally by loss of a proton
to give olefin (and less often by nucleophilic substitution or loss of
some other positive group).

R H R1 R
R1 OH H

R2 R3 R2 R3
Mechanism involves rearrangement of the carbocation intermediate.

R H R H R H

R1 OH H R1 OH2 R1

R2 R3 R2 R3 R2 R3

R1 H R1 R Note that in the initial step

R a proton is consumed and
in the last step a proton is
R2
R 3 R2 R3 released.

The earliest examples of Wagner-Meerwein rearrangement was noticed in

bicyclic terpenes.

OH H

Isoborneol Camphene
 CH3 H
H3C
H
H3C C CH2 Cl C C
CH3 H 3C CH3

OH
Camphenilol Santene

In these reactions, double bond is formed according to

Zaitsev rule. Leaving group in this reaction can be
hydroxyl or other leaving groups (like chloride) which
renders carbocationic character to carbon atom.
Direction of rearrangement is usually 30 >20 >10.
There are interesting examples where a series of rearrangements occur
simultaneously. One example shown below involves a triterpene, 3- β-friedelanol.
This compound on treating with acid, 13(8)-oleanene is formed by seven
successive 1,2 shifts. [Home work: how?]

20 20

19 21 19 21

12 12 18
18 22
22 11
11 13 17
13 17
H H H
1 1 9 14
9 14 16
16 2
2
10 8 15
H 10 8 15
5 H
3 5
7 3 4 7
4
HO 6 6
H
3-friedelanol 13(18)-oleanene

Textual description of the mechanism: A carbocation is first generated at C-3,

which triggers a cascade of rearrangements. Hydride shift from C-4 to C-3; methyl
shift from C-5 to C-4; hydride shift from C-10 to C-5; methyl shift from C-9 to C-10;
hydride shift from C-8 to C-9; methyl shift from C-14 to C-8 and hydride shift from C-
13 to C-14 takes place, generating carbocation at C-13, which is stabilized by loss
of proton from C-18 to give olefin All these shifts are stereospecific.
Alkanes, in the presence of Lewis acid or other suitable initiators, can
also undergo Wagner-Meerwein rearrangement.
In the following tricyclic molecules consisting of 10 carbon atoms upon
a series of rearrangements, provides adamantane(s). The steps are
(a) successive 1,2 and 1,3 hydride shifts and alkyl group migration.

AlCl3

AlCl3

AlCl3
 AlCl3
tBuBr

These reactions take place due to the thermodynamic stability

of adamantane, diamentane and similar diamond molecules formed as
a result of the rearrangements.
Some other kinds of examples for Wagner-Meerwein rearrangement
are given below.
O O O O

OEt OEt
HO TFA, DCM
72h

76%
B.Pinacol rearrangement:
When vicinal diol (also known as pinacol) is treated with acids, it
rearranges to give aldehyde or ketone. This reaction is called as Pinacol
rearrangement.
E.g.,
CH3 CH3 CH3 O
H H3C C C CH3
H3C C C CH3

OH OH CH3
Pinacol Pinacolone

The migrating group can be alkyl, aryl, hydrogen or ethoxycarbonyl.

In the case of unsymmetrical diols, which one of the hydroxy group gets
protonated it is important. As seen earlier in this module, in general, the
hydroxyl group that can generate a more stabilized carbocation is the one
which gets protonated.
 O
OH OH
H2SO4 Ph
Ph
Ph
Ph

In this reaction, the hydroxyl group on carbon bearing two phenyl

groups will be protonated faster to form a more stable benzylic
carbocation.

When tri or tetra substituted glycol is used, different products

depending upon reaction condition is obtained. It also depends upon
migratory aptitude of different groups, as discussed earlier.
CH3 CH3 Ph CH3 Ph O
cold AcOH +
H2SO4 trace of H C
Ph C C Ph C C CH3 H SO 3 C C Ph
methyl 2 4
migration phenyl
Ph O OH OH migration CH3
When, at least one of the groups in the glycol is hydrogen (R1 = H, in
the following example), aldehyde are produced along with ketone. This
can be achieved using weak acids, low temperature etc.,.
A plausible mechanism can be represented as follows;

R2 R4 R2 R4
H -H2O
R 1
C C R 3 R1 C C R3

OH OH OH OH2

R2 R4 R2
-H
R 1
C C R 3 R1 C C R3

OH OH R4

O R2

R1 C C R3

R4
The driving force for the migration of alkyl group from the initially
formed carbocation come from the increased stability of tertiary
carbocation.

The first example (given below) involves ring expansion.

OH OH
H

OH OH
Ph O
H
Me2C C COOEt
Me2C C COOEt
Ph
 O

OH OH
H

Protonation: Ring expansion

Here the C1-C5 bond of the five membered ring cleaves

heterolytically and migrate to the electron deficient migration
terminus (C6). Note that in this process C1 of the five-
membered ring develops a carbocationic center

The resulting product is shown here with the similar

arrangement as in the reactant so that the process
is easy to understand. Student is expected to
convert this into a proper structure once the concept
is clear
deprotonation:
More useful and synthetically useful example of pinacol rearrangement
reaction that are employed is the syntheses of bridged bicyclic
compound from a diol are given below.
O OH
OH OH

H LiAlH4 H

OH2

-H2O -H

H
Similar type of reaction is also shown by compounds containing
different groups other than hydroxyl group.
This reaction is known as Semipinacol rearrangement and involves
1,2 shift of H or alkyl group from oxygenated carbon atom to neighboring
carbon atom (i.e. conversion of carbocation to carboxonium ion)
E.g., 1

BF3.Et2O -BF3

O O
BF3
O H
H H

Description: Here BF3 is a Lewis acid that coordinates to the epoxide oxygen first and opens
up the ring to generate the secondary carbocation as shown in the second structure.
 OTs
E.g., 2
LiClO4 in
HO THF, HO -H
CaCO3

O O O O

O
Note that these examples
involve ring-expansion
O O
 C.Expansion and contraction of rings using molecular rearrangement:

The following reaction represents a special case of Wagner-Meerwein rearrangement.

Generally, a mixture of rearranged and non-rearranged products is formed.

NH2 OH
HNO2 HNO2
+ CH2OH CH2NH2

HNO2
OH +
NH2 OH
These reactions in which a carbocation is generated by diazotization is
called Demjanov reaction
Mechanism is as follows.

H N
N O O -H2O O O O
H
HO O N N
N
H 2O O

-HNO2
+O O O H
N N
NH2 HN N O

-H2O
N N OH
N N OH2
H
NO2

-N2 H2O
OH
N N
More examples

O
O
NaNO2
LiAlH4 / Et2O OAc 0.25M H2SO4 /
OAc
00C H2O, 0-40C
100%
CN
NH2
O
O

O
O
12 : 1 [ Tetrahedron, 1993, 49, 1649 ]
 It is found that, ring-expansion reactions can give good yields with
smaller rings systems, wherein the ring-expansion relieves higher
angle strain. Ring-contraction reactions give good yields except for
cyclopentyl cation.
An example of such ring expansion is given below, which involves a
series of ring expansions (cascade of ring-exapnsions)

H3C OH CH3
OH

Additional information: Name of the reactant and products are respectively16-

methylpentaspiro[2.0.2.0.2.0.2.0.2.1]hexadecan-16-ol and 2-
methylhexacyclo[12.2.0.02,5.05,8.08,11.011,14]hexadecan-1-ol.
 OH
H H
H
OH
40%H2SO4

H
H

Reaction of certain amino alcohols give analogous reaction to semipinacol

rearrangement. The following is one such example known as Tiffeneau-
Demjanov rearrangement.

CH2NH2 O
HNO2

OH
These reactions are known to work better with four to eight membered ring systems
as compared to the analogous Demjanov rearrangement.
D. Dienone-phenol rearrangement : Cyclohexadienone containing C2 or C4
alkyl groups, treatment with acid undergoes 1,2-shift of one of these alkyl
groups, to a disubstituted phenol. Driving force for this reaction comes from
aromatization of the ring.
O OH

R
R R
R
Mechanism
O OH OH

H
R

H
R R R R
R
OH

R
R
A particularly useful example of dienone-phenol rearrangement can be
found in the syntheses of steroidal compound as shown below.

OH OH

H H
H2SO4
H H H H

O HO
1-methyloestradiol
E. Wolff rearrangement :
Wolff rearrangement is rearrangement reaction, in which a diazo
ketone is converted into ketene.

R' R'
R'
R -N2 R C O
N2 C
R
O O
This reaction takes place in the presence of light, heat or transition metal catalyst
such as Ag2O.
The mechanism is suggested to proceed through the involvement of a carbene
in presence of heat or light. It may also proceed through a concerted
Pathway in the presence of Ag2O with out carbene.
Migratory aptitude is found to vary depending on whether the reaction is
carried out under thermal or photochemical route. In the photochemical
pathway methyl is migrates preferentially while in thermal pathway phenyl
group migrates.
O
Ph
Ph -N2
Ph C C O
Ph
N2

O O O O

H hγ / O
EtOH : dioxane
N2 1:1
 O COOMe
N2
hγ / MeOH
O
N O N
90%

Other 1,2 migrations to carbene are also known.

CH3 CH3
H3C
hγ H 3C C CH C
H3C C CHN2 CHCH3
H3C 52%
CH3 CH3
+

47%
F. Homologation of aldehyde or ketone :
Aldehyde or ketone can be converted to their higher analogs on
treatment with diazomethane. O O
CH2N2 R'
R R' R

O O
CH2N2
R H R

Though, it appears to be an insertion reaction, it is purely rearrangement

reaction. Carbene is not formed in the reaction.
O CH2 N N
-N2
R C R' + H2C N N R C R'

O
CH2 O
H2
R C R' R C C R'

O
In case of aldehyde, hydrogen migrates preferentially which is evident
from good yields of methyl ketone
Another interesting application of Wulfs reaction can be found in the
preparation of bicyclic ring compounds from alicyclic diazo
compounds.

O O O

CHN2 +
G. Neighboring group participation:
Several rearrangements involve NGP, wherein the group responsible
for anchimeric assistance undergoes 1,2 migration.
R2
NR2 N
Ph CH CH COPh Ph CH -H
CH COPh

Br H 2O

NR2

Ph CH CH COPh

OH
In this reaction, anchimeric assistance is
offered by the morpholino group.
NR2 :- N O
 A.Hofmann rearrangement:
When an unsubstituted amide is treated with sodium hypobromite,
corresponding primary amine with one carbon less is produced. This
reaction involves Hofmann rearrangement.
O
hydrolysis
R C NH2 + NaOBr R N C O RNH2 + CO2

R in this reaction can be alkyl or aryl.

NH2
Br2 /NaOH
Examples NH2
H2O
O
O NH2
NH2

NaOBr / H2O

NO2 NO2
Mechanism of reaction is as follows,
O O
O
R C NH OH Br Br OH
R C NH R C NH
H Br
O O
H2O
R C N Br R C N R N C O

O O
H
N HN OH RNH2 + CO2
OH O OH
R H R
H

description
In the first step, base removes a proton from amide. The conjugate base of
amide thus formed reacts with bromine to give N-bromoamide. Acidity of
proton on nitrogen is increased by this bromine atom and its removal becomes
easy toward generating nitrene intermediate (in which nitrogen is electron
deficient). 1,2-shift of alkyl group in this nitrene intermediate gives
corresponding isocyanate. This isocyanate on hydrolysis gives primary amine
with one carbon less than starting material.
 When methanol is used as a solvent instead of water, then the
corresponding carbamate ester can be obtained.
O
H
N O
NH2
NBS, DBU,
MeOH, reflux O
O O

O
H
N O
NH2 NBS, Hg(OAc)2,
CH3OH, DMF
O
N N

When optically active α-phenylpropionamide undergoes Hofmann degradation, α-

phenylethylamine of same configuration and optical purity is obtained i.e.
rearrangement proceeds with retention of configuration.
Ph Ph
NaOH
H C CONH2 H C NH2
B.Curtius rearrangement:
In Curtius rearrangement, acyl azide are pyrolysed into isocynate
which can be hydrolyzed to corresponding amines.

R N C O
R N3

Curtius rearrangement is catalyzed by protic or Lewis acids.

Mechanism is similar to that of Hofmann rearrangement.

O O
-N2
R N C O
R N N N R N

However, there is no evidence of existence of free nitrene. These two

steps may be concerted.
 O

R N C O + N2
R N N N

In a similar reaction, alkyl azides provide imines.

R3CN3 R2C NR

R may be alkyl, aryl or hydrogen. In the case of tert alkyl azides, there is
evidence of existence of nitrene.
Cycloalkyl azides can yield ring expansion.

R
R
H
N + NR
N3
80% 20%
Aryl azides can also give ring expansion on heating.
NHPh
N3
PhNH2
N

Home work: (Propose a mechanism for the following reaction)

OH O O

O
N3 tBuOH NH
N3 reflux

O NHBoc

[ Tet. Lett., 19 Feb 2007, Vol.48, Issue 8, 1403 ]

C.Lossen rearrangement:
O-acyl derivatives of hydroxamic acids on heating with a base
concerts to the corresponding isocyanate. This reaction is known as
Lossen rearrangement. The isocyanate thus produced can be further
hydrolyzed to corresponding amines.
O

O R OH H2O
R N C O RNH2
R N
H
O
Mechanism
O O

O R O R
R N R N

H O O
OH

R N C O
COOH NH2
1. NH2OH.HCl
H3PO4
2. KOH

O
1. NH2OH.HCl NH2
H3PO4
OH 2. KOH

[ JACS, 1953, 75, 2014 ]

D.Schmidt rearrangement :
Reaction of carboxylic acid or aldehyde or ketone with hydrazoic acid
in the presence of mineral or Lewis acid to give corresponding primary
amine or amide is known as Schmidt rearrangement.

H H2O
RCOOH + HN3 R N C O RNH2

O
O
H R1
+ HN3 R N
1
R R H

Cyclic ketones give lactams.

O NH
HN3 / H
O
Mechanism is similar to that of Curtius rearrangement, except that
protonated azide undergoes molecular rearrangement.
O OH H N N N
HN3 -H2O
H
1 1 R C R1
R R R R
OH

N N N
-N2 H2O
R C R 1 R1 C N R

O
R1 C N R -H R1 C N R tautomerism R
R1 N
OH2 OH H

In reaction with ketone, ketone is activated by protonation for

nucleophilic addition of azide group to it.
In the case of alkyl aryl ketone, the aryl group migrates preferentially
except for bulky alkyl group.
Intramolecular Schmidt reaction can be used for the preparation of
bicyclic lactams.

O O

MeAlCl2 / DCM N

Ph
N3 96%

O
N3
MeOOC TFA / 12h MeOOC
N
O
 O
O
TFA
N
N3

[ Org. Syn., 2007, 84, 347 ]

Reaction of tert-alcohol (e.g.1) or olefin (e.g., 2) with hydrazoic acid under
acidic condition to give substituted imines is also a form of Schmidt
rearrangement.
OH R R
HN3 / H2SO4
E.g.,1 N
R R
R R

R R R R
HN3 / H2SO4
E.g.,2
R R R N R
 Mechanism of the reaction is as follows.

tert-alcohol OH R R
OH2
H -H2O HN3
R R R
R R R
R

H N N H R
N -N2 N -H R
C N R
R
R R R R
R

olefin
R R RH R RH R H
H HN3 -N2
N N N
R R R R R R

RH R
R R
-H
R N R
R N R
H
A more recent example on the
use for Schimdt rearrangement

O O O
H
H3C N
H 3C OEt OEt
CH3 CH3
O
NaN3, CH3SO3H

CHCl3, 0.5-1 h

89%

[ Tet. Lett., 1988, 29, 403 ]

E.Beckmann rearrangement :
Oximes* on treatment with Lewis acid or protic acid rearrange to give
substituted amides. This reaction is called as Beckmann rearrangement.

R R' O
PCl3
R
N R' N
OH H
Generally group anti to hydroxyl migrates. However, there are several
exception reported. R and R’ can be alkyl, aryl or hydrogen. (Hydrogen
does not migrate under normal reaction conditions, but it migrates when the
reaction is carried out with nickel acetate under neutral conditions.)

Like Schmidt rearrangement, oximes of cyclic ketones give ring-expansion.

NOH NH
O

* Oximes are condensation product between hydroxylamine and an aldehydes/ketones

Mechanism of reaction

OH OH2
N N -H2O
H R1 C N R

R R1 R R1

1
R1 C N R -H
R C N R
H 2O OH2

O
1
R C N R
R
1
R N
H
OH

The proposed mechanism is supported by detection of nitrillium ion by

NMR and UV spectroscopy.
Examples
N
N H2SO4
O
OH microwave
N
1800C N

[ Syn. Comm., 2006, 36, 321 ]

Cl H O
N
N N
N
OH Cl N Cl
DMF, rt, 8h
100%

[ J. Org. Chem., 2002, 67, 6272 ]

OH
I N I
H
12% HgCl2, N
MeCN , 8h

[J. Org. Chem., 2007, 72, 4536 ]

F. Stieglitz rearrangement:
Stieglitz rearrangement is a general term applied for rearrangement
reactions of trityl-N-haloamines and hydroxylamines to trityl imine.

PCl5
Ar3C NHOH Ar2C NAr
base
Ar 3C NHX Ar2C NAr

Mechanism is as follows,

Cl
Ph OH Cl Cl Ph O Cl
NH + P NH P
Cl Cl Cl
Ph Ph
Ph Cl Ph Cl

Ph
NPh
Ph
Stieglitz reaction can also be facilited by treatment with lead tetraacetate.

Pb(OAc)4
Ar 3CNH2 Ar 2C NAr

NH2
Pb(OAc)4 Ph2C N OCH3
Ph2 C OCH3
~98%
+

PhN C OCH3
Ph
~2%

[ J. Org. Chem., 1974, 39, 3932 ]

A.Baeyer-Villiger rearrangement :
In Baeyer-Villiger rearrangement, ketone on treatment with peracid
gives ester by oxyinsertion. Reaction is catalyzed by presence of acid
catalyst. O O
PhCO3H

R R1 R OR1

Reaction is particularly useful for synthesis of lactones.

O O
O
CF3CO3H
H H
R
R

R : H, OAc, OCOPh etc.

 Mechanism is as follows,

O
O
O HO O R2 O
O R 2 O
HO O
1
R R
R OR1 HO R2
R R1
First step is the addition of peroxy acid to the carbonyl carbon leading to a
tetrahedral intermediate. In next step, a concerted migration of the migrating
group and loss of carboxylic acid provides the product.
The mechanism is supported by fact that oxidation of Ph2C18O yields
only PhC18OOPh (i.e. there is no scrambling of 18O label in the product
Ester.)
The loss of carboxylates and migration of R is concerted, as the reaction
is known to be faster when electron withdrawing substituents are present in
the leaving group and electron donating substituents in migrating group.
 If the migrating group is chiral then its stereochemistry is retained.

Migratory aptitude in unsymmetrical ketones is as, H > 30 > cyclohexyl

> 20 > benzyl > aryl > 10 > methyl. In case of aryl group,
migrating ability is increased by electron donating groups present on
ring.
F F F O
mCPBA /
CHCl3 O Ph Ph
Ph Ph NaHCO Ph + Ph O
3

O O 71% 29%

Migration is favored when migrating group is antiperiplanar to the O-O

bond of leaving group. This is known as primary stereoelectronic
effect. Antiperiplanar alignment of lone pair of electrons on O2 with
migrating group is termed as secondary stereoelectronic effect.
 OCOR'
O
H
primary

R R secondary

In the case of unsaturated ketones epoxidation is likely to be a

competitive reaction. But, Baeyer-Villiger rearrangement is favored
because ring strain can be relieved by oxy insertion and ring expansion.

BnO
BnO

mCPBA
O

O
O
More examples

H H
O
O
H2O2, AcOH
O

H H
Chemoselective oxidation of β-lactum aldehyde has been achieved

with mCPBA in DCM where only formates are formed in better yields.

H C H H C H

CHO mCPBA, DCM OCHO

rt, 20h

O O

OMe OMe
70%
O
O
H2O2 BF3
ether
O
[ JOC,1962, 27, 24 ]
 .
One of the most important synthetic use of BV reaction is found in the syntheses of
L-Dopa (a drug used in the treatment Parkinson's disease).

O
COOH
COOH
AlCl 3, H2O2,
NH2 AcCl NaOH
HO NH2
HO
L-tyrosine

O COOH HO COOH
H3O
O NH2 NH2
HO HO
L-Dopa
B.Rearrangement of hydroperoxide :
Hydroperoxides can be cleaved in the presence of protic or Lewis acid.
Reaction goes through rearrangement.
R O
H + ROH
R C O O H
R R
R

Mechanism is as follows.

R R H
R H2O
H -H2O
R C O O H R C O O H
R C OR
R R
R O
R C OR + ROH
R R
OH2
The important steps in the mechanism can be described as follows: (a)
Protonation of peroxide and removal of a molecule of water (b)
Simultaneous shift of the migrating alkyl group to the electron deficient
oxygen to give a rearranged carbocation (b) formation of hemiketal by
the reaction of water, which then breaks down to give alcohol and
ketone. OH
O
Ph OOH
AcOH
+

Alkyl group must be showing some sort of anchimeric assistance and

the rearrangement must be going through benzonium ion.

OH
O
H2O / H
+

OOH

Benzonium ion :

S T
Stevens rearrangement :
In Stevens rearrangement, quaternary ammonium salt containing
electron withdrawing group on α carbon atom when treated with strong
base rearrange to give a tertiary amine.

Z R3 Z R3
NaNH2
N R2 N

R1 R1 R2

Rearrangement is intramolecular (as shown by cross over experiment).

Also, retention of configuration was noticed in the product.
Two mechanistic pathways are possible. One involving radical pair in a
solvent cage. Presence of solvent cage is important in order to explain
retention of configuration.
 Involving ion pair in solvent cage.

Z R3 Z R3 R3 R3
Z Z
base
N R2 N R2 N R2 N R2

R1 R1 R1 R1
Z R3
N
R1 R2

Involving an ionic pathway.

Z R3 Z R3 Z R3 Z R3
base
N R2 N R2 N R2 N
R1 R2
R1 R1 R1
Reaction can be used for ring enlargement.

Ph
Bz
N N
NaNH2 / NH3

90%

When Z group is an aryl group, the rearrangement is known as

Sommelet-Hauser rearrangement, in which reaction of tert-alkyl
ammonium salt with NaNH2 gives N,N-dialkylbenzylamine with ortho
substituted aromatic ring (shown below).

N
NaNH2 / NH3 N

Another competing reaction is Hofmann elimination, when one of the

alkyl group contains β hydrogen atom.
Some examples of Steven rearrangement are given below.
O
O N
NaOH Ph
N Ph
Ph
Ph
Et
Et2N
N KOtBu / MeCN
Et

PhLi
N
N

nBuLi in
hexane N N
PhHCN N

Ph [ JOC, 1974, 39, 130 ]

Wittig rearrangement:
Ethers, on reaction with alkyl lithium rearrange in a similar manner to
that of Stevens rearrangement to give alkoxy lithium. This reaction is
called Wittig rearrangement.[Note: Witting reaction of phosphorous
ylides are different]
H R3
1 3 R4Li
R C OR R1 C OLi + R4H

R2 R2

This alkoxy lithium can then be converted to alcohol.

R3 R3
H
R1 C OLi R1 C OH

R2 R2
R may be alkyl, aryl or vinyl group.
Migratory aptitude are allylic, benzyl>ethyl>methyl>phenyl.
Mechanism is suggested to follow a radical pair pathway.

H
R1 C OR3 R1 C O R1 C O
R4Li Li
R1 C OR3 R3
R2 R2 R2 R3
R2
R3

R1 C OLi

R2
i.Reaction is largely intramolecular
ii.Migratory aptitudes are analogous to free radical mechanism.
iii.Product obtained is with retention of configuration.

BuLi H

Ph O
Ph OLi Ph OH

NOMe NOMe

O 2eq. LDA
THF, -780C OH
MeO MeO

Bt
Ph
LDA OCH3
Ph O OCH3
O
61%
Bt : benzotriazol-1-yl
When R2 is a good leaving group and electron withdrawing functional
group like CN, then this group is eliminated and ketone is formed.

H O
R2Li
R1 C OR + R2H + LiCN
R1 R
CN

H Li R
R
R2Li
R1
C OR R1
C O 1
R C OLi R1 C OLi
R
CN CN CN CN
O

R1 R
The purpose of crossover experiment is to determine whether the given
reaction takes place intermolecularly or intramolecularly i.e. whether
reactant break apart to form intermediates, which diffuse away into
solution before they combine to give product.

In this experiment two substrate differing in substituent are mixed

together and are reacted under the same reaction condition and the
product obtained is analyzed.
Illustration for cross-over experiments:
Consider, a simple reaction in which A-B reacts to give C-D.

A B + A* B* C D + C* D*

A B + A* B* C D + C* D* + C* D + C D*

There are two possible of outcomes for the above reaction, as A, A* are
differently substituted (so are B and B*).

One in which no crossover of substituent is seen. This is possible if

reaction is intramolecular. [The reactant stay connected throughout the
course of the reaction]

The other possibility is that a mixture of products are obtained in the

crossover reaction. This is possible in the case of intermolecular
reaction.
The experiment can be illustrated by considering Fries rearrangement.
p-Tolylbenzoate (I) on rearrangement gives 2-hydroxy-5-
methylbenzophenone (II).
OH
O Ph
AlCl3
Ph
O
O
I II

In the similar reaction, o-chloro-p-tolylacetate (III) give 2-hydroxy-3-chloro-5-

methylacetophenone (IV).

Cl
Cl
OH
O AlCl3

O
O
III IV
When I and II are mixed together and product is analyzed, V and VI,
along with II and IV are obtained.
Cl

OH OH

Ph

O O
V VI

This shows that the reaction proceeds intermolecularly and fragments

are formed in solution.
 Br
Propose a mechanism
for the following HBr, THF
00C, 10 min
examples OH

NH2 OH
OH

HNO2
+

OH
EtOOC
COOEt 1 : 3 HSO3F, SO2ClF
Ph ~00C
Ph

[ JACS, 1982, 104, 2631 ]

AgNO3

I
O
OH
 Home work: Propose a mechanism for the following pinacol reaction
O O
O
CF3CO3H in H2O2
(CF3CO) 2O in DCM Ph
Na2HPO4 in DCM O Ph

Ph OH

[ JACS, 1955, 77, 2287 ] 1. Ph OH

TsOH, +
CDCl3
O Ph
Ph

2.
OH O
Ph
1. MsCl, Et 3N, DCM Ph
OH
00C, 10 min
2. Et3Al, DCM
[ Tet. Lett., 2002, 43, 6937 ]
-780C, 10 min
N N
SO2Ph
SO2Ph
90%
Practice problems/Additional Information on BV reaction

(1) (2)
Caro's reagent (KHSO5)

KHSO5, rt, 24h O

O O O
O
O

(3) (4)
O O O
O
cyclopentanone O
KHSO5, rt, 24h O
monooxygenase

98% ee

[ Chem.Comm., 1996, 2333 ]

 O O
(5) H
O
H H
H mCPBA, NaHCO3
DCM, rt, 30 min [ JOC, 2002, 67, 3651 ]
N H Cl
H N
Cbz Cl
Cbz
85%
O O
O
(6) mCPBA
[ Tet. Lett., 2009, 50,4519 ]
NaHCO3
DCM, 00C,
30min

60%

O O
(7) O
1. Fe2O3, O2
C6H5CHO O
benzene O +
2. NaHCO3

97 : 3 [ Tet. Lett., 1992, 33, 7557 ]

Practice Problems

THF, PhLi /
KHMDS
-780C
N
N [ Tet. Lett., 2004, 45, 7525 ]
OTf

BnOOC O
H
COOBn
N base

N
O
84%

Br K2CO3
EtOOC DMF EtOOC
COOEt COOEt
N 00C-rt N

EtOOC COOEt
N

[ Tet. Lett., 2002, 43, 899 ]

 Practice Problems
F 3C OH
(1) Ph

Ph N [ Org. Lett., 2001, 3, 2529 ]

F 3C O Ph O
LiHMDS
THF / ether +
Ph N -780C-rt
O OH
F3C

Ph N
O
(2)
OH
H2 MeLi H2
PhH2C O C Ph C C [ JACS, 1962, 84, 4295 ]
H
 Classifications and
reactions involving
carbon radicals

Key words: radicals, stability, addition, cyclization reactions, polymerization

 Introduction
In this module an overview of carbon radicals are
given. Some preliminary examples of their
structure, properties and reactions are provided.
Since this topic is expected to be part of physical
organic and other domains, only a brief account is
presented.
 Carbon radicals

The first organic free

This species was discovered
radical identified was
by Moses Gomberg in 1900
triphenylmethyl radical
at the University of
formed by abstraction of
Michigan USA.
chlorine by silver metal .
 A radical is a reactive intermediate with a single
unpaired electron, having very short lifetime .
 Radical reaction are non-ionic reactions judged by
the frontier molecular orbital approach (and not
the nucleophilicity or electrophilicity concept).
 It is generated by homolysis of a covalent bond.
 Radial is represented by atom with one dot.
 Electronic movements involving radicals are
represented using half headed fishhook arrows.
 Carbon radical is a neutral carbon species with
three single bonds and one unpaired electron.
 structure of radical
• A carbon radical is sp2 hybridized with an unpaired single electron occupying an
unhybridised p-orbital, having trigonal pyramidal or planar geometry possessing an angle of
120⁰.

• In most of the cases the pyramidal geometry is observed, especially when heteroatom's are π
electron donating substituent or electronegative groups like flourine or oxygen are present.
However, some of the lower group of alkyl class like methyl posses planer geometry, t-butyl
show pyramidal geometry with a slight characteristics of planer geometry.
• The energy required to invert the geometry is very low in the case of flexible pyramidal
geometry.
 Prediction of geometries.
• Geometries can be very well predicted from the product stereochemistry.
• Rigid pyramidal geometry of structure give product with retention of configuration .
• Planar or rapidly inverting radical will give racemerised product.
CH3 CH3
• Examples :-1.
Cl2 , hv
ClH2C C CH2CH3 ClH2C C CH2CH3 Geometry:- Pyramidal

H Cl

(+)-1-Chloro-2-methyl butane. (+)-1,2-dichloro-2-methyl butane.

D H D
2. N-Bromo Succinimide
CH3 CH3 CH3
H Br Br

99.7 % racemization

Geometry:- Pyramidal

However in case of cyclic compound the stereochemistry is not retained. Cis and trans isomers
both independently give cis or trans isomer .
 Stability of radical
Radicals are produced by heat or light or by the action of peroxide. Once a radical is
produced, it will attack another species and would try to abstract a hydrogen radical or bind
with another radical or with a π electron, forming σ bond in all the cases,
Radicals are formed when they are exposed to sufficiently high energy (in the form of heat or
light) to break the bond between the two atoms.
The increased substitution will improve the stability of radical formed, and lesser will be the
energy required for its formation.
CH 3

dH = 355 kJ mol-1
-H

dH = 355 kJ mol-1
-H

(CH3 )3 C (CH3 )2 CH CH 3CH 2CH2

Primary Vinyl
Tertiary Secondary
Allyl radical radical radical
radical
dH= 369 kJ mol-1
butyl radical
dH = 423 kJ mol-1 dH = 465 kJ mol-1 dH = 460.55 kJ mol-1
dH = 400 kJ mol-1 dH = 431 kJ mol-1

Hence stability decreases form allylic and benzylic radical to vinylic and phenyl radical.
• The higher stability of radical in the case of benzyl and allyl through resonance
stabilization. This type of stabilization is not present in case of phenyl or vinyl
radical.

O O

• When both electron donating and withdrawing groups are present in the same
molecule, with a suitable separation between them, it can provide additional
stabilization know as capto-dative stabilization. NMe 2
COCH3 O
N

CH3
N Ph

NMe2

F. M. Welle , H.D. Beckhaus

& G.Ruchardt Wruster's salt
J.Hermolin , M. Levin, JAC 1991 103: 4795
liebigs Ann 1997: 155
Carbocation Radical
• Carbocation are electron • Radicals posses 7 electrons with
deficient species with 6 a better stability due to lesser
electrons accounting for a lower energy compared with
stability and higher energy state. carbocation hence lower
member of radical are existent.
• The stability is supported by • Stability resulting from alkyl pi
alkyl group, pi bonding bonding or lone pair is
electron or lone pair . relatively negligible, however
• In a chemical reaction when there is assisted stability in case
carbocation MO or AOs of benzylic radical.
interact with filled MO or AOs • When a radical interact the two
the electrons are placed in electrons are placed one in
lower energy bonding orbital . lower energy and one in higher
energy antibonding orbital.
 The fmo approach for radical reactivity
• As we know that radical reactions are non ionic reactions in which energy of
the orbitals involved are most important for reactivity.
• Radical posses a single unpaired electron typically in a p-orbital known as
SOMO (Singly Occupied Molecular Orbital), which is quite higher in energy.
Any factor that decreases this energy will result in increased radical stability and
decreased reactivity. This factor is more precisely presented by the electron
donating or withdrawing group attached with radical carbon,

Interaction of radicals with electrophilic and nucleophilic substrate,

Radical having lower energy SOMO can accept an electron and can best
interact with the HOMO of the incoming substrate having nucleophilic
character.

Radical having higher energy SOMO is ready to give away the electron. It will
best interact with the LUMO of the incoming substrate having electrophilic
character.
• Energy diagram of interaction of radical.

most f avored interaction

E LUMO of
N electrophilic
substrate. High energy SOMO
E of electron rich radical
R Y= electron donating
G Y R group present on radical
Y

energy of normal Radical.

normal SOMO
orbital ( R )

most f avored interaction

X= electron withdrawing Low energy SOMO
group present on radical of electron poor radical
HOMO of
X R
nucleophilic
substrate
• Reactions of free radicals
• Consider a radical R undergoing a reaction.
H 3C
H3 C

H 3C H2
H3 C H H

H 3C
H 3C

• The addition to alkene result in radical initiation step where the molecule of reactant
alkene form a radical which then attack another similar molecule resulting in a polymer.
H 3C H H
H 3C
Cl
Cl
CH 3
H 3C
H 3C CH3

• Radical combination leading to termination

CH 3 H CH 3
H

H 3C CH 3 H 3C CH 3

H3 C H H3 C H
 Classification of radical reactions
• Radical are generally very reactive species with a short lifetime. If the reaction rate can be
controlled, selectivity of radical reactions can be improved. Radicals can undergo,
1. Substitution
2. Addition
3. Rearrangement
4. Auto-oxidation
5. Single electron transfer (SET).
Substitution Reactions: This radical reaction involves substitution of smaller molecules,
(e.g., chlorination of methane). The reaction function as a chain substitution reaction

•This radical reaction involve substitution of smaller molecules , the well known evident
reaction is chlorination of methane. The reaction function as a chain substitution
Step II :- Propagation
H
reaction. H
H H H HCl
Cl

H H
Reactant
Cl Cl CH3
Cl Cl
Product
Step I :- Initiation

Step III :- Termination

CH3 CH3 H3 C CH3

CH3 Cl Cl CH3
Addition reactions.
• Addition reactions are carried out in the presence of tinbutyl hydrides and it’s
higher analogs. Addition reaction of alkenes in the presence of radicals are
extensively used in carbon- carbon bond formation reactions in organic
chemistry.
• This reaction can furthur be classified as,
1. Direct addition
2. Intramolecular cyclizations.
 Direct additions:-
These reactions take place following the anti-Markovniokov’s rule of addition.
The peculiar characteristic of the reaction is the product radical do not abstract the
halogen from the alkyl halide, but abstract a proton from tinbutyl hydride. This
tinbutyl hydride radical will then abstract a halogen from alkyl halide.

This can be explained through this cyclic mechanism,

 Bu3SnH
RI
AIBN

Bu3Sn Abstraction of halide

to form alkyl radical
Formation of
organotin radical
CH3

Bu3SnI
R
CN

Abstraction of R
hydrogen fron tin butyl hydride.
CH 3
Addition to alkene
Bu3SnH

CH 3
CN
R
CN

• Example :-
CN

CN
AIBN
OC 2H 5
(C 4 H9 )3 SnH
• Alkylations can even be performed using alkyl mercuries, this can be done by
subjecting alkyl mercury halides to reduction in the presence of Sodium
Borohydride leading to unstable alkyl mercury hydride which then
disintegrate at room temperature to give alkyl radical.
H3C C 2H5 H3C C 2H5 C2 H5

HgCl2 NaBH4 H3C

C Mg Cl C Hg Cl Hg H

H 3C
H3C H3C
Unstable (cannot be isolated)

C 2H5 C 2H5

H3 C
H 3C Hg HCl
C
CN
CN H3C
H3C Initiation
Propagation

C2H5
C2H5 CH3
H3C
H Hg C
H3C
C CH3
CN
H3C
CN C 2H5 Product
H3C
Propagation
• Addition reaction involving enones
• Attack occur on the terminal alkene at that carbon away from carbonyl carbon
(Reason:- the high energy Singly Occupied Molecular Orbital of radical can
best interact with FMOs or more specifically the LUMO of electrophilic
alkene just slightly higher in energy).
O
• Example :- O
H

Bu3SnH , AIBN
CH 3
Benzene , 800C

CHO HO
H
62 % Yield
O
O
H
Bu3SnH , AIBN H
Benzene , 800
C OH

CHO H

81 % Yield

In radical addition the stereochemistry of reactant is conserved in product , here in case of

cyclohexanone derivatives (e.g. 1) the stereochemistry is conserved.
Enholm, E. J.; Whitley, P. E.; Xie, Y. J. Org. Chem. 1996, 61, 5384.
• Intramolecular cyclizations
• Intramolecular radical cyclizations are very important steps in a large family
of cyclization reactions.
• Radical cyclizations occur in a chain of three or more carbons attached at one
end to a radical and another end to an alkene.
• These reactions is not driven by excess quantity of reagent, whatever be the
substituent present on the radical or alkene part, the reaction is driven by
radical trap which is typically a double bond present in the same molecule.
• The cyclization occurs such that the resultant intermediate has the radical site
outside the ring and not in the ring (for stereoelectronic reasons). As per the
stereoelectronic factors, to release or minimize strain, the radical should
approach a double bond at nearly 109⁰ angle (an essential factor for
formation of sp3 carbon).
• According to the above explanation, it would be feasible to approach
the inner carbon attached to chain and not the terminal carbon which
is far away from radical (if we try to do so, it will result in a highly
strained structure, sterically unfavorable).
 ROOC ROOC
• Examples :-1.
Br

Bu3 SnH , AIBN

Toluene , 80 0

t-Bu
t-Bu
75 %

• Heteroatom in radical cyclization

• 1.
n-Bu3SnH , AIBN
Benzene , reflux
N R N
Br
Ph
Ph
R
R = Me , 87%
Visvanathan, R. et. al. JACS 2003, 125 ,163 R = Ph , 86%

• 2. Bu3Sn
Bu3Sn H

PhS
hv , 450 C
N
N O
N

O
O
 I

Samarium iodide mediated

radical cyclizations.
O
• Samarium di-iodide is an excellent
SmI 2
catalyst for synthesis of cyclic
systems. The reaction follow O

similar type of ring closure as in the

case of tinbutyl hydride. Ph CH 3

• The reaction is carried out using O

SmI 2

THF as the solvent in presence of

Hexamethylphosphoramide OSm( III )

(HMPA).
• Samarium complex is added to the Ph CH3
substrate to be cyclized. HMPA is O Ketyl radical

added separately to the ketone to

OH
form ketyl radical. The cyclic
CH 3
radical was then added to reaction
mixture to obtain the final product Ph

in good yield.
O
• Examples :-

• Intramolecular cyclization of mixed enone–enoate for preparation of

spirocyclic ethers.
O

OH
O OEt
O
SmI2 (2 eq.)

THF/ MeOH (4:1) OEt

-780 C

O O

1-oxaspiro[4.5]decan-7-ol
Seperable Diastereomeric ratio
(16: 67)

J. Meng et al. / Tetrahedron Letters 52 (2011) 928–931 929

 rearrangement REACTIONS
• The first type of 1,2- radical rearrangement reported by Heinrich Otto Wieland
was the conversion of bis(triphenylmethyl)peroxide to the tetraphenylethane.

Heat 2 O
O O

bis(triphenylmethyl)peroxide

OPh

2 O 2 O
OPh

tetraphenylethane
• Unlike carbocations, radicals undergo migrations less readily.
• In the above mentioned example and similar type of 1,2- rearrangements, the
transition state involves bonding to three atoms simultaneously.
• In a radical reaction, the odd electron present in the transition state is stabilized
by a pi electron system (In the above example, the benzene ring provide
stabilization).
• An another class of reaction exhibited by radical when they are quite stabilized
are coupling reactions, in some cases the radical have longer lifetimes, leading
to radical coupling reactions.
• The most familiar reaction is conversion of Benzophenone to Benzopinacol ,
the reaction is quite easy to set i.e. mixing the reactant with isopropanol which
act as the hydrogen donor as well as the solvent & is set conveniently in UV or
visible light to obtain the crystalline benzopinacol .
O O
HO OH
hv
isopropanol Ph Ph
H3C CH3
Ph Ph
Benzopinacol
Benzophenone
 auto-oxidation reactions
• The reaction of radicals involving molecular oxygen in the presence of UV
radiation to form peroxides and hydroperoxides are called oxidations
reactions.
• E.g., cumene process for synthesis of phenol and acetone from benzene and
propylene,
• OH
OH
O2 O
H2SO4

cumene
 Radicals in polymerization
• Polystyrene, poly(methyl methacrylate), poly(vinyl acetate) and
branched polyethylene are commonly synthesized by radical
polymerization.
• Radical Polymerization involve three major steps
• Initiation:- starting a radical process i.e., formation of monomer
radical.
• Propagation:- the newly-formed activated monomer attacks and
attaches to the double bond of another monomer repeatedly to
form a long polymer chain.
• Termination:-stopping the process of addition of monomer at the
required step to isolate the chain.
 initiation
• It involves thermal decomposition of weak bonds (like in peroxides or azo compounds),
which furthur attack the monomers to create a radical site on the monomer. This step
occurs in a solvent cage i.e., solvent do not take part in the reaction
• The process can be initiated by peroxide(t-butyl and cumyl hydroperoxides, t-butyl
perbenzoate etc.,) or AIBN (or its analogues like 2,20-azobis(2,4-
dimethylpentanenitrile), 4,40-azobis(4-cyanovaleric acid), and 1,10-
azobis(cylohexanecarbonitrile)). N

CH3
N 60 0C
N N H3C C N C CH3
N N
CH3
2,2-Azobis(2-methylpropionitrile)
N

O O O
0C
40-90

O O O O

O
Benzoyl peroxide
CO2
• The initiation step in the polymerization of polystyrene
O

Ph
O
O

O C 6H 5 C 6H 5

The free radical attack the monomer creating a new radical site on the monomer
through which it attacks another monomer in the propagation step leading to a
chain formation.
propagation PhOC O PhOC O
C H 6 5

C 6H 5
C 6H 5 C6 H5 C 6H 5

PhOC O C6 H 5

n
C 6 H5

C 6H 5
The propagation step continues till a required molecular weight of polymer is
obtained.
 • During the addition of free radical (R) to monomer there can be two types of
interactions ‘head-to-head’ or ‘head-to-tail’
R
The addition occur as per two
considerations :-
Stabilizing effect offered by the substituent
R
Head to tail on the monomer
Steric effect at the addition site which favor
R
addition at the least substituted carbon.
According to following preferences the
head to tail addition is favored in most
Head to head
cases.

Termination :-
It is the final step for completing polymerization. It can be achieved by following
methods.
1. Combination :- this method result in doubling of polymer chain
Ph Ph
Ph
H2 H2 H2
R C CH CH 2 R
CH CH C CH C R
R
Ph Ph n
n Ph n
Ph n Ph
2. Combination with initiator radical :- Poly- vinyl chloride polymerization can be terminated
by reacting it with initiator phenyl radical.

Cl n Cl Cl n Cl

3. Use of inhibitors or retarders:-

Inhibitors stop every radical, and polymerization is completely ceased until they are
consumed.
Retarders, on the other hand, are less efficient and halt a portion of radicals. In this case,
polymerization continues at a slower rate.
Inhibitor or retarders are compounds which combine with polymer chain by giving it electron
and form a radical site on itself which can be stabilized by resonance. They are better
called chain transfer agents. O

E.g. Benzoquinone is common inhibitor for polystyrene.

O PhOCO C 6H 5
PhOCO C6 H 5

O
n
C6 H5
n
C6 H5
O C 6H 5
C 6H 5
4. Disproportion :- In disproportion a hydrogen present on the carbon next to the
radical site is abstracted by another radical centre to form alkene at one end and
saturated carbon at the other end.
Termination by disproportion in poly- methyl acrylate.
H

H
n n n

O O O O
O O O O O O O
O

O O
O O
 examples
• Synthesis of poly(vinyl acetate) from vinyl acetate .

free radical polymerisation

O

n
O

O
poly- vinyl acetate
vinyl acetate

O
 Practice Problems
• Identify the product of the following reactions
• (1)

• (2)

• (3)
 Answers
• (1)

• (2)

• (3)
Key words: oxidations using chromium and manganese reagents, cleavage of double
bonds with ozone and osmium tetroxide, oxidations with aluminum isopropoxide,
peracids,
Introduction Broader definition of oxidation and reduction respectively refer to the
loss and gain of electrons, or an increase in oxidation number (oxidation)
Definition and a decrease in oxidation number (reduction).
In organic chemistry, the gain of oxygen or loss of hydrogen is often
referred to as oxidation.
In practice, a series of functional groups have been qualitatively
identified in the order of increasing oxidation state. Then, oxidation is
referred to as the conversion of one functional group higher in the
sequence to another lower in the list.
Conversion within a group are neither oxidation nor reduction.
It is summarized in following table.

This module has been organized based on the reagent that are used
for oxidation reactions
 oxidation
Table summarizing
O
functional groups
RH CO2
arranged according
OH
to oxidation state.
ROH O O
RCl
RNH2 CCl4
etc.
R R R NH2

Cl

C Cl C Cl

Cl Cl

C C etc.

Cl Cl

C C

OH OH

etc.
reduction
I. Oxidation of For oxidation of alcohols to corresponding carbonyl compounds, generally
alcohols using Cr(VI) reagents such as K2Cr2O7, Jones reagent, PCC etc., are employed.
Cr(VI) reagents  Oxidation of alcohols to carbonyl compound occurs via Cr(VI) acid
monoester.
Mechanism is as follows.

OH O
CrO 3

R1 R2 R1 R2

O
HO
H
O O Cr O
O
O Cr O
+ + H 2CrO 3
R1 C H
O R1 C H R1 R2

R2
R2
 Example for chromium oxide based oxidation
Oxidation of fused aromatic
system is generally carried
4mmol CrO3
out using CrO3 reagent 60 min, rt

Juaristi M. et al, Can.J.Chem., O

1984, 62, 2941
O
80%
 PCC (pyridinium chlorochromate) is other efficient reagent used widely
for oxidation of primary and secondary alcohols.
E J Corey and W Suggs in 1975 suggested PCC as oxidizing agent. PCC is
Reagent can be used in slightly acidic but can be buffered with NaOAc
close to stoichiometric
amounts with substrate O
HN
Cl Cr O

O O

OH H
HO H

O
1,6-Hexanediol Hexanedial (68%)
Corey E J & Suggs W,
OH
Tet.Lett., 1975, 16, 2647 O

Benzhydrol Benzophenone (100%)

OH O

4-tertbutylcyclohexanol 4-tertbutylcyclohexanone (97%)

 H
Corey and Suggs used
OH
following method for O
preparation of PCC. R
R

100g (1mol) CrO3 is

added to conc. HCl, R
R
rapidly with stirring over
5 min time. Homogenous Presqalene alcohol Presqalene aldehyde (78%)

solution obtained is
R : (CH3)3CCH(CH3)CH2CH2C(CH3)=CHCH2CH2-
cooled to 00C. To this,
1mol of pyridine is
added. Yellow-orange OH O

solid obtained is filtered

H
and dried in vacuum.
This solid is PCC and is
not hygroscopic. It can
be stored at room Citronellol Citronellal (82%)
temperature.
 PCC is used particularly for the oxidation of primary alcohol to aldehyde.
It does not have any effect on C=C or any other easily oxidizable
functional groups.
In this reaction, double PCC, DCM
O
bond is not affected.
OH H

Geraniol Geranial

PCC is used in aprotic solvents, usually, dichloromethane.

As no water is present in the reaction mixture, no aldehyde hydrate is
formed which is oxidized to carboxylic acid in presence of Cr(VI)

Agarwal S; Tiwari H PCC, dry CHCl 3,

anhy. AcOH, rt, 1h O

P; Sharma J P, OH
H
Tetrahedron, 1990, 46,
1-Hexanol 1-Hexanal (89%)
4417
 Another similar oxidant is PDC (pyridiniumdichromate)

H
O 1.5eq PDC
OH DCM, 25 0 C O
O
90%

O O

NH O Cr O Cr O HN

O O

pyridiniumdichromate

Since PDC is less acidic than PCC it is often used to oxidize alcohols
that may be sensitive to acids.
In methylene chloride solution, PDC oxidizes primary and secondary
alcohols in roughly the same fashion as PCC, but much more slowly.
However, in DMF solution saturated primary alcohols are oxidized to
carboxylic acids.

In both solvents allylic alcohols are oxidized efficiently to conjugated

enals and enones respectively.
Stanfield C F, et al, J. examples
Org. Chem., 1981, 46,
4797
3.5eq PDC 1.5eq PDC
COOH DMF, 25 0 C DCM, 250 C CHO
OH

83% 92%

1.5eq PDC,
OH DCM, 250C, 24h
O O CHO

90%
Corey E J & Schmidt
G, Tet.Lett., 1979, O OH
COOH
O
20(5), 399 3.5eq PDC,
DMF, 25 0C, 7-9h

H H

85%
Collins reagent can be  Collins reagent is the mixture of chromium
prepared and isolated or trioxide with pyridine in dichloromethane.
generated in situ.
It is used to selectively oxidize primary alcohols to aldehyde, and will
Isolation of reagent often tolerate many other functional groups in the molecule.
leads to improved yields.
CrO 3-2Py R H
R DCM
OH
O

It can be used as an alternative to Jones reagent and PCC in oxidation of

secondary alcohols. Moreover, Collins reagent is especially useful for
oxidations of acid sensitive compounds.
This complex is both difficult and dangerous to prepare, as it is
very hygroscopic and can inflame during its preparation.
It is required to be used in a sixfold excess in order to complete the
reaction.
 examples
one of the steps in the O
O
synthesis of O
O
prostaglandin F2α CrO 3-2Py
DCM, 0 0C
employs Collin’s reagent
as oxidant
H
OH
Corey E J, JACS, 1969, AcO
AcO
O
91, 5675
one of the steps in
synthesis of longifolene OH
O
employs Collin’s reagent H CrO 3-2Py, DCM,
H
rt, 15min
as oxidant

McMurry J E, JACS,
OH
1972, 94, 7132 H O

100%
one of the steps in
synthesis of triquinacene
employs Collin’s reagent
as oxidant CrO 3-2Py, DCM

Woodward RB, JACS, H

OH O
1964, 86, 3162
74%
Jones described for the  Jones reagent is used for the oxidation of primary and
first time a convenient secondary alcohols to carboxylic acids and ketones, respectively, that do
and safe procedure for a not contain acid sensitive group.
chromium (VI) based
oxidants, that paved way
for some further
developments such as
Collins Reaction
and pyridinium
dichromate.
It is chromium oxide, sulfuric acid and acetone. A mixture of potassium
or sodium dichromate and dilute sulfuric acid can also be used.

CrO 3, aq.H 2SO 4 O

acetone
R OH
R OH

OH CrO3, aq.H2SO4 O
acetone

R R' R R'
 H2SO4 O
Mechanism : O
H2O
HO Cr OH
Chromium trioxide or Cr
O O
sodium dichromate with O
dilute H2SO4 in situ Chromic acid
forms chromic acid . O O H2SO4
H2O
Chromic acid and HO Cr O Cr OH Na2Cr2O7
alcohol then through O O
chromate ester gives
Dichromic acid
carbonyl compound in ..
presence of base (water H2O
O OH O H
in this case). VI VI R'
HO Cr OH + HO Cr O
The intramolecular R R'
O H O R
reaction occurs by way ..
of β-elimination through

..
..
O O
cyclic transition state. + ..Cr IV H3O

R R' HO O
O
VI
Aldehydes can form O
OH HO Cr OH
H2O
hydrates in presence of O
R OH
water and further R H H
oxidized to carboxylic
acid in presence of O H .. ..

..
O O

..
OH H2O
Cr(VI) reagents. HO
VI
Cr O + IV Cr ..
-H3O R OH HO O
O R
The Jones reagent is The oxidation of primary allylic and benzylic alcohols gives aldehydes.
prepared by adding Some alcohols such as benzylic and allylic alcohols give aldehydes that
chromium trioxide to do not form hydrates in significant amounts; these can therefore be
dilute sulfuric acid in selectively oxidized with unmodified Jones Reagent to yield aldehydes.
acetone and is added to
the alcohol at 0-25oC.
K 2Cr2O 7, H2SO4 CHO
OH H 2O, acetone, 0-25 0C

The excess Cr(VI), if any

is remained, is destroyed
in the reaction workup CrO 3, H 2SO 4, H2O,
O
acetone, 0-25 0C
by adding isopropyl
alcohol. OH H

For the synthesis of aldehydes, the Collins Reaction or use of more

modern although more expensive chromium (VI) reagents such
as PCC and PDC can be an appropriate choice.
Tertiary alcohols cannot be oxidized by this reagent.
It is a powerful oxidizing reagent and exhibits only poor
chemoselectivity.
 OH CrO 3, aq.H 2SO 4 O
oxidation of secondary H2O, acetone, 0-25 0C

alcohol gives ketone

whereas primary alcohol
is oxidized to aldehyde
OH CHO COOH
first and then to CrO 3, aq.H 2SO 4
H 2O, acetone, 0-25 0C (O)
carboxylic acid.

H H
Jones reagent, acetone,
Panda J; Ghosh S & 0 0C - rt, 1h
O O
Ghosh S, ARKIVOC,
2001(viii), 146 H H H
OH O
 MnO2 is used widely as oxidant in organic synthesis.

II. Oxidation using It oxidizes allylic alcohols to corresponding aldehydes or ketones.

Mn reagents O
MnO2
R OH
(a) Mn(IV) reagent R H

The configuration of double bond is preserved in the reaction.

Also, acetylenic alcohols and benzylic alcohols are oxidized under similar
conditions.
Applications of MnO2 are numerous. These include many kinds of
reactions such as amine oxidation, aromatization, oxidative coupling,
and thiol oxidation.
Activity of MnO2
depends upon method of S
MnO 2, DCE
S

preparation and choice R2 R2

R1 N R1 N
of solvent

1,2-Diols are cleaved by MnO2 to dialdehydes or diketones.

OH
MnO2, DCM, O
rt, 24h
Ph
Ph
2
Ph H
OH
 examples
MnO2, rt, 5d
CH 2OH
Pet. ether

vit.A

Taylor R J K; et al,
Acc. Chem. Res., 2005, CHO
38, 851.

retinal (80%)

oxidation of benzylic and 10eq. MnO 2,

DCM, rt, 24h
allylic alcohol with OH
CHO
MnO2 in mild condition
84%

Aoyama T; et al, O
OH
10eq. MnO2,
DCM, rt, 24h O CHO

Synlett, 1998, 35.

O O
95%

dehydration is also
10eq. MnO 2,
accomplished in good DCM, rt, 24h
+
yields N N
NH

1,2,3,4-tetrahydroisoquinoline 3,4-dihydro- isoquinoline (8%)

-isoquinoline (83%)
 More examples

Oxidation of allylic OH
COOMe
alcohol to
corresponding ester in MnO2, hexane
methanolic solvent. MeOH, NaCN

E J Corey; N W
Gilman; B E Ganem,
JACS, 1968, 90, 5616

N N O
MnO2,
1,4-dioxane

Husinec S; et al, COOMe COOMe

Tet.Lett., 2011, 52, COOMe COOMe
2733 45%
(b) Mn (VII) reagents Manganese can function as oxidant when it is in +7 oxidation state.
KMnO4 is one such oxidant. It is a very strong oxidizing agent.
Alkyl side chains on aromatic rings are oxidized to carboxylic acid group.
This method is more generally applied to methyl group, however, longer
side chains can also be cleaved.
Tertiary alkyl groups are not oxidized and are usually accompanied by
ring cleavage.
KMnO4 is also used to oxidize primary alcohol and aldehyde to
corresponding carboxylic acid.
 Protected hydroxy aldehydes are oxidized to corresponding carboxylic
acids with KMnO4 buffered with mixture of tBuOH and aq. NaH2PO4
Abiko A; Roberts J C;
Takemasa T & KMnO 4, 5min
CHO COOH
tBuOH -5%NaH2PO4
Masamune S, Tet.Lett.,
O O O OSiMe2tBu O O O OSiMe2tBu
1986, 27, 4537
Ph Ph
97%

Jefford C W; Li Y;
Wang Y, Org. Syn., KMnO4, CuSO 4
DCM, 6-8h, 25 0C
1998, 9, 462
HO O

HO

In this reaction KMnO4 first oxidizes primary alcohol to corresponding

carboxylic acid which subsequently cyclizes to give a lactone.
 More examples
O
KMnO4, MnO2
solv. f ree, 6h

oxidation using KMnO4

supported on MnO2
under heterogenous and 85%
solvent free conditions
O
S
KMnO 4, MnO2 S O
Shaabani A; et al, Tet., DCM, 29h
2004, 6, 11415.

72%

OH KMnO4, MnO2, )))) O

solv. f ree, 2h 30min

H H

64%
This reaction is also used Dilute solutions of KMnO4 convert alkenes into diols.
as a qualitative test for
KMnO4
the presence of double or
triple bonds in a
HO OH
molecule, since the
reaction decolourises the Dihydroxylation of alkenes using alkaline KMnO4 is a stereoselective syn
permanganate solution. It addition of two hydroxyl groups across a double bond.
is sometimes referred to
The reaction is believed to proceed through a cyclic permanganate ester
as Baeyer's reagent.
intermediate.

O OK O OH
OK
hydrolysis
Mn Mn

O O O O
OH

Though the presence of such an intermediate can not be confirmed by

actual isolation. But, some of them are detectable spectroscopically also
use of Mn18O4- in the reaction lead to formation of 1,2-diols in which
both the oxygen atoms were labeled. So, it can be concluded that both of
them are coming from Mn18O4- , and hence the presence of an
intermediate cyclic permanganate ester can be confirmed.
 Under acidic conditions, the alkene double bond is cleaved to give a
carboxylic acid.

D J Sam; H E
Simmons, JACS, 1972, KMnO 4, H +
17
17
94, 4024 COOH

KMnO4, DC-18[C]-6

Synthesis, 1984, 43,

COOH
443
 NaMnO4, sodium permanganate is similar oxidant to KMnO4. It oxidizes
primary alcohol to acid and secondary alcohol to ketones but does not
have any effect on multiple bonds.
OH O

Menger F M and Lee NaMnO4 .H2O,

DCM,410C, 24h
C, Tet.Lett., 1981, 22,
1655.
HO HO
H H

5α-Androstan-17β-ol 5α-Androstan-17-one (84%)

III. Oxidation using OsO4 is primarily used in cis dihydroxylation of olefins.
Os reagent
OH
Os(VIII) reagent OsO4
hydrolysis

OH

O O
OH
1. OsO4, THF, 250C, 48h
2. H2S

p-electrons of olefins act Mechanism of reaction goes through the formation90%

of 5-membered
OH cyclic
as a nucleophile and ester intermediate.
forms favorable 5-
membered ring as cyclic
osmate ester by attacking
OsO4. This is considered O O O OH HO O
O
as the origin of cis hydrolysis
Os Os + Os
stereoselectivity.
This osmate ester upon O O O O HO O
OH
hydrolysis liberates cis
diol and reduced osmium
species.
OsO4 is toxic and is used in catalytic amounts in reaction. It can be
reoxidized using co-oxidant such as NMO, K3Fe(CN)6, etc.

NMO = N-methyl morpholine

O OH
O OsO4, NMO
O
O OH
OH

OH

OCOCH3 OCOCH3

OH
OsO4-NMO
tBuOH/ THF/ H2O
HO (10:3:1) HO OH

O O

78%
The use of NMO in catalytic OsO4 reactions was first reported for the
introduction of corticoid side chain (an α-ketol) in a steroid (as shown
above).
 OsO4 is also used for oxidative cleavage of olefin. It forms carbonyl
compound.
H

O
O
O O

O O
OsO4, NMO
O
Oxidative cleavage of O
O
olefins using OsO4 -
NaIO4 in presence of 2,6- O O
lutidine OCO2CH 2Ph
O O

OCO 2CH2Ph
Yu W; Mei Y; Kang
Y; Hua Z and Jin Z,
Org.Lett., 2004, 6, 3217.
0.02eq OsO4, 4eq NaIO4,
2eq 2,6-lutidine, 3h,
O dioxane-water (3:1) O

O O
CHO

OTBS OTBS
81%
 Oxidation of primary and secondary alcohol with ketone in the presence of
metal alkoxide to corresponding aldehyde or ketone is known as Oppenauer
IV. Oppenauer oxidation.
oxidation
OH O O OH
Al(iPrO) 3
+ +

R1 R2 R1 R2

The reaction is completely reversible and can be driven to completion

according to Le Chatlier’s principle by addition of excess of ketone.

In the first step of the

iPrO OiPr
mechanism, alcohol, Al
OH O
aluminium and acetone -iPrOH O O
+ Al(iPrO)3 +
coordinates to form a
complex. This complex R1 R2
R1 H
then, via a six-membered R2

chair like transition state

transfers hydride from α- iPrO OiPr i PrO OiPr

carbon of the alcohol to the Al Al O

O O alcoholysis
O
carbonyl carbon of acetone O
to give the desired ketone R1 R2
R1 H H
as product. R2 R1 R2

six membered T.S.

 In 1937, Oppenauer Oppenauer oxidation has many advantages.
discovered this reaction.
 mild reaction conditions.
 most functional groups are tolerated (If substrate contains basic
 Reaction is reverse of nitrogen then use of alkali metal alkoxide is necessary instead of Al-
Meerwein-Ponndorf- isopropoxide).
Verley reduction.
 in order to achieve reasonable reaction rate, stiotiometric amount of
Al-alkoxide to be used (Al-isopropoxide, Al-tertbutoxide, Al-phenoxide
can be used).
 wide range of substrates are oxidized.
 secondary alcohols are oxidized faster than primary alcohols. Due to
this secondary alcohols can be oxidized chemoselectively over primary
ones.
 over oxidation to carboxylic acid does not happen.
 oxidation of 1,4 and 1,5-diols yields lactones.
 acetone is most often used as an oxidant but aromatic and aliphatic
aldehyde are suitable as oxidants due to low reduction potential.
  addition of protic acid dramatically increases the rate of
oxidation.
 oxidation can be conducted using heterogenous catalysis. It has
advantage over homogenous catalysis as product can be separated
easily from a reaction mixture.
O O
Synthetic applications 1. Al(OiPr)3, toluene TsOH, Et2O
OH ref lux, 5h OH 18h, rt

N O

Syntheses of Estrone
HO 2. 1% HCl, 0 0C O
from tetracyclic diol 78%
O

HO
Estrone
Syntheses of linearly 1. 1.7eq Al(OiPr)3
fused triquinane dry tol, reflux, (4+2)
acetone, 9h
(±)-hirsutene. 2. 10% HCl, 250C

OH O
47%

H H H

COMe

( )-Hirsutene

O O
syntheses of hormone
Al(OiPr) 3
progesterone acetone
H H

H H H H

HO O
Pregnenolone Progesterone
Syntheses of steroid
derivative OBz OBz
18.1eq p-quinone
Oppenauer oxidation 1.6eq Al(OtBu)3
tol., 1h,
H H
using strong oxidant
p-quinone H H H H

acetone, cyclohexanone HO O

or N-methylpyridinone
gives over oxidation OH O

Cl 3CCHO
trichloroacetaldehyde Al2O 3, CCl 4
on alumina is used as
oxidant.
HO HO
secondary alcohol gets
readily oxidized over
primary.

p-quinone
oxidation of Al(OiPr) 3
tol., 45 min
cholesterol using H H

p-quinone H H
H H
HO O
 Oxidation of Carveol:

OH O
1mol% cat.
1.2eq tBuCHO
Ooi T; Otsuka H; tol., 21 0C, 1h
Miura J; Ichikawa H;
Maruoka K; Org.
Lett., 2002, 4, 2669. 94%

Catalyst:
3mol% cat.
1.2eq acetone
SO2C8F 17 tol., 21 0C, 2h
OH O
N
AlMe
80%
O

Mello R;
Martinez-Ferrer J;
Asensio G; Slena
M, JOC, 2007, 72,
9376.
 OH O
3eq 3-nitrobenzaldehyde
10mol% AlMe3, tol., rt, 0.5h

>99%

OH O
3eq 3-nitrobenzaldehyde
Graves C R; Zeng B 10mol% AlMe3, tol., rt, 0.5h

S; SonBinh T N,
JACS, 2006, 128, S S
12596. >99%

OH O
1.2eq 2,4-dinitrobenzaldehyde
10mol% AlMe3, tol., rt, 1h

88%

OH O
F3C
H H
EtOAlEt2,
Mello R; Martinez- DCM, rt, 18h
Ferrer J; Asensio G;
Slena M, JOC, 2007,
H H
72, 9376.
26%
 H
Al(OiPr)3, tol., ref lux, 6h
Raggio M L; Watt D H
S, JOC, 1976, Vol.41, N O

No.10, 1873. H H

HO
β-Sitosterol

H H

O
24-Ethylcholest-4-en-3one (71%)
 V. Ozonolysis Ozonolysis involves the cleavage of olefins with ozone. It forms either
carbonyl compound or carboxylic acid depending on work up procedure.

R1 R3 1. O 3 O O
2. Zn/ H 2O
+

R2 R4 R1 R2 R3 R4

Ozonolysis is an oxidative cleavage (like permanganate). But, it is

comparatively mild reaction and no overoxidation is seen.

R1 R2 O O
O 3, DCM Me2S
R1 R2
R1CHO + R2CHO
O
H H H H

example O

1. O 3, MeOH, -78 0C
oxidation of eugenol to 2. Me2S

corresponding aldehyde
O O

OH OH
 Reductive work up forms aldehydes and ketones while in oxidative work
up aldehydes are further oxidized to corresponding alcohol.

H R' O O
O 3, DCM
H R'

O
R R" R R"

reductive work up oxidative work up

work up of ozonide NaBH 4 PPh 3/ Me2S H 2O 2

O O

R OH
R H R OH
+ + +
OH O O

R' R" R' R" R' R"

Overall result is that double bond is replaced by an ozonide ring.

Ozone is high energy Ozonolysis is a two step reaction.
form of oxygen,
produced when UV First step is 1,3-dipolar addition of ozone across the double bond, to give
light or electrical molozonide. It rapidly undergoes rearrangement to give ozonide.
discharge passes R2 O
through oxygen gas. O O
O
O O
O O retro R1
1,3-cycloaddition 1,3-cycloaddition
+
R1 R3
Lewis structure has R1 R3
R4

central oxygen R2 R4 O
positively charged and R2 R4
molozonide
R3
each outer oxygen has
½ negative charge.
O O O O
O 1,3-cycloaddition acidic work up
R1 R3 +
O O
O R4 R1 R2 R3 R4
R2

ozonide

Second step is work up. Oxidative work up can be done by aqueous acid
O
while reductive work up by zinc and water or dimethyl sulfide or Pd-H2.
O O
More details on Molozonide or primary ozonide has peroxy linkage which makes it
ozonolysis reaction unstable and it undergoes rapid rearrangement to give ozonide.
On the other hand, ozonide is stable but is rarely isolated. It is reduced
with mild reducing agents to give aldehydes or ketones.

S O O
O
O +
S
O

O
O3

O O

H H
+
O O

H
CHO
H H
1. O 3
2. Me2S CHO

CHO
H H
CHO
H
 Ozonolysis does not afford information about stereochemistry of alkene.
Thus, 1 and 2 give same carbonyl compound.
R1 R3 O O R1 R4
Key facts about O3 O3
+
ozonolysis
R2 R4 R1 R2 R3 R4 R2 R3

1 2

Ozonolysis is mainly used to determine the position of a double bond in

an alkene.

1. O 3
2. Me2S
CHO
CHO

O
1. O 3
2. Me2S

1. O 3
2. Me2S
CHO

CHO
 O 3/ O2, 0 0C O
5%H2O/ acetone
AcO H AcO H

81%

Schiaffo C E & H O 3/ O 2, 0 0C H
5%H 2O/ acetone
Dussault P H, JOC,
O
2008, 73, 4688.
O O
100%
 VI. Epoxidation
Epoxidation is a reaction in which C=C of an olefin is converted to an
epoxide (or oxirane), a cyclic ether.

O
peracid

Commonly used reagents are peracid or peroxyacid, peroxide, etc.,

Addition of oxygen to C=C is syn stereoselective
O
epoxidation of styrene
perbenzoic acid
using perbenzoic acid CHCl 3, 00C

Styrene Styrene oxide

The reaction is an example of a concerted process (all bonding changes

occur in one step)
 R3
R1 R3 R
O R R1 O O
R3 R4
O
O
O
H O H R1 R2
R2 R4 R2 RCOOH
R4
Since the reaction is concerted the stereochemistry of the alkene is
preserved in the product.
For example if the alkyl groups of the alkene are cis then they are also cis
in the epoxide.
H

O
H
mCPBA, DCM,Na2CO 3,
J.Chem. Edu., 2001, 78. H 00C, 20 min
H

H3CO

H3CO

Dubois G; Murphy A O 2eq CH 3CO3H, 0.25 mol% cat.,

O

MeCN, 5 min, 00C

and Stack T D P,
Org.Lett., 2003, 5, 2469. OEt
OEt
O
Ethyl sorbate 87%

Catalyst: [{(Phen)2(H2O)FeIII}2(µ-O)](ClO4)4
 Epoxidation of an olefin is distereoselective reaction. The reagent attacks
alkene from less hindered face.
O
H H
only important Si Ph
conformer has H H
eclipsing double bond SiMe2Ph
SiMe2Ph

mCPBA attacks the

less hindered f ace

O O

mCPBA
+

OH
OH OH

95 : 5

Villa de P A L; Sels B F;
O
De Vos D E and Jacobs P O 2mmol H2O2, 2mg cat.,
MeCN, 380C, 24h
A, JOC, 1999, 64, 7267. O
O

O
94%

Catalyst: PW4O24[(C4H9)4N]3-Amberlite IRA900

Sharpless The Sharpless Epoxidation is an enantioselective and distereoselective
epoxidation epoxidation of allylic alcohols.
The stoichiometric oxidant is a hydroperoxide, usually tert-
butylhydroperoxide in the presence of catalyst Ti(O-isopropoxide)4.
K. Barry Sharpless won
It allows the enantioselective epoxidation of prochiral allylic alcohols. The
the 2001 Nobel prize in
asymmetric induction is achieved by adding an enantiomerically enriched
Chemistry for his work
tartrate derivative.
on asymmetric
oxidations.
R3 tBuOOH, Ti(OiPr)4, R3
(+)-DET, DCM, O
R2 OH 3A0 MS, -20 0C R2 OH

R1 R1

The stereochemistry of the resulting epoxide is determined by the

diastereomer of the chiral tartrate diester. Usually diethyl
tartrate or diisopropyl tartrate are employed in the reaction.

Assymetric Assymetric
epoxidation epoxidation
O O
(-)-DET (+)-DET
OH OH OH
Advantages: tBuOOH
5mol% Ti(OiPr) 4 O
Ph OH
7.5mol% (+)-DIPT Ph OH
Epoxides can be converted -20 0C, 3h
into diols, aminoalcohols 89% (>98%ee)
or ethers. The formation of
chiral epoxides is a very tBuOOH O
OH
important step in the 5mol% Ti(OiPr) 4 OH
7.4mol% (+)-DIPT
synthesis of natural -20 0C, 0.75h
products.
95% (91%ee)
Can be carried out with
many primary and
O
secondary allylic alcohols. tBuOOH
Ph OH
Ph OH
120mol% Ti(OiPr) 4
High enantiomeric 150mol% (-)-DET
-20 0C, 5h
excesses > 90%.
Ph Ph
The products of the
90% (94%ee)
Sharpless Epoxidation are
predictable using the It can be used for preparation of intermediates in natural product synthesis,
Sharpless Epoxidation such as in the synthesis of Lekotriene C-1.
model.
COOCH 3 tBuOOH, Ti(OiPr)4, COOCH 3
The reagents are (+)-DIPT, DCM,
-200C, 48h
commercially available
and relatively cheap.
O
OH OH

80% (95%ee)
Robinson A and
HO
HO tBuOOH, Ti(OiPr)4,
Aggarwal V K, (-)-DET, DCM, -200C, 5h
Angew. Chem. Int. O

Ed. 2010, 49, 6673. 75% (97%ee)

HO OBn

Ghosh A K and Liu C,

Org. Lett. 2001, 3, 635. tBuOOH, Ti(OiPr) 4,
(-)-DET, 4A0MS,
DCM, -230C, 20.5h

HO OBn

90%
Additional/Practice Problems
OH 1.5mol CrO 3 H
6h, rt
(1)
Cl Cl O
78% Zou J D; Xu Z N, Tet.Lett., 2002, 43, 6095

(2) PCC, SiO2, DCM

rt, 90min

OH O

d,l-Menthol d,l-Menthone
Luzzio F A, et al, J Chem. Edu., 1999, 76, 974.
(3) O O
HO PCC, acetone, Al2O3 O O
O
DCM, ref lux, 4h

AcO AcO

3-Acetoxy-17-ethylene- 3-Acetoxy-17-ethylene-dioxyestra-
dioxyestra-1,3,5(10)-trien-11-ol 1,3,5(10)-trien-11-one (79%)
McNab H, et al, Org. Biomol. Chem., 2010, 8, 4383
OH O
(4) PCC, DCM
rt, 1h

N N

O O
1,2-dihydro-1-hydroxypyrrolizin-3-one Pyrrolizine-1,3-dione (68%)

(5) OH 2 mol% PCC, 1.05eq H 5IO 6 O

MeCN, 00C-rt, 2h

Ph Ph

89%

(6) OH 2 mol% PCC, 1.05eq H 5IO 6

MeCN, 0 0C-rt, 2h
O
Hunsen M, Tet.Lett., 2005, 46, 1651
Ph Ph

96%
Jones reagent,
acetone, 0 0C
(7)
OBn OBn O
CHO
OH
PDC, DCM, rt
Neral : Geranal = 7:1 (84%)
OH H

NHBoc NHBoc
80%
(8) Jones reagent,
acetone, 0 0C

CHO
OH
Neral : Geranal = 7:1 (84%)

OH Na2Cr2O 7, conc. H 2SO 4

(9) DMSO, 70 0C, 30 min CHO

Rao Y S; Filler R, J.Org. Chem., 1974, 39,

82%
3304

(10) OH
Na2Cr2O 7, dil. H 2SO 4
silica gel, rt, 1h O

α-Fenchol 98 %
Singh R P; Subbarao H N; Dev S, Tetrahedron, 1979, 35, 1789
(11)
OH O
MnO 2, alumina
DCM

O O

benzoin benzil

Crouch R D; Holden M S; Burger J S, J.Chem. Edu., 2001, 78, 951

 OH O
O
OH

(12) Al(OtBu)3
xylene

H H O H H

O
H H

(13) AcO
1. O3, MeOH, p-TsOH
2. NaHCO3, Me2S AcO
OMe
AcO
CHO
+ OMe
OMe
CHO
MeO
1 : 3

(14) O3, NaHCO3,

DCM, iPrOH, O O O O
O O OR
-780C
OHC +
HOO
HOO
OHC
OR
(15)
Ac2O, Et3N O O O O
DCM
73% +
OHC ROOC

ROOC OHC

3.6 : 1

Taber D F & Nakajima K, JOC, 2001, 66, 2515.