- . ·:·:> .

RaacI ions, ··- . ,. .~,~--·r ,~ _,o~-,J

. ·. •: ' ~ '·\ ..(';;,".·... •: ; ... .

.. ,. .

Rearranaemants ..
and
Reagents
Contents

1. Mechanism of Organic Reactions 1

Types of Chemical Bonds 2
Factors Influencing Reactivity 10
The Breaking and Making of Bonds 21
Energetics of Reactions 27
Classification of Organic Reactions 32

2. Reactions and Rearrangements 76

Acyloin Condensation n
Aldol Condensation 78
Allylic Rearrangement 83
Arndt-Elstert Reaction 86
Baeyer-Villiger Rearrangement 89
Beckmann Rearrangement 91
Benzilic Acid Rearrangement 94
Birch Reduction 96
Cannizzaro Reaction 97
Claisen Condensation 101
Claisen Rearrangement 105
Claisen-Schmidt Reaction 107
Clemmensen Reduction 109
Curtius Reaction 112
Dieckmann Reaction 114
Dials-Alder Reaction 117
Dienone-Phenol Rearrangement 121
Favorskii Rearrangement 122
Friedel-Crafts Reaction 125
Fries Rearrangement 131
Gabriel Synthesis 133
Hell-Volhard-Zelinsky Reaction 135
Hofmann Rearrangement or Hofmann Bromamide Reaction 136

( v)
 Houben- Hoesch Reaction 139
Knoevenagel Reaction 141
Mannich Reaction 143
Meerwein-Ponndorf-Verley Reduction
146
Michael Reaction 148
Oppenauer Oxidation
152
Perkin Reaction 154
Pinacol-Pinacolone Rearrangement 158
Reformatsky Reaction 161
Reimer-Tiemann Reaction 164
Sandmeyer Reaction 167
Schmidt Reaction 170
Sommelet Reaction 172
Stobbe Condensation 174
Stork Enamine Reaction 177
Ullmann Reaction 180
Vilsmeier-Haack Reaction 183
Wagner-Meerwein Rearrangement 184
Wittig Reaction 186
Wolff-Kishner Reduction 189
Wolff Rearrangement 191

3. Important Reagents 193

Anhydrous Aluminium Chloride 194
Aluminium lsopropoxide, (Me 2CH0)3AI 197
Boron Trifluoride, BF3 199
N-Bromosuccinimide (NBS) 203
+ -
Diazomethane, CH 2=N =N or CH 2N2 206
Dicyclohexylcarbodiimide 210
2
Fenton's Reagent (H 20 2 + Fe +) 213
Hydrogen Peroxide, H20 2 214
Lead Tetraacetate, (CH 3C00) 4Pb or Pb(0Ac) 4 220
Lithium Aluminium Hydride 224
Osmium Tetroxide, Os0 4 228
Perbenzoic Acid (Peroxybenzoic acid), C 6 H5C0 H
3
230
Periodic Acid , H5106 or HI0 4 . 2H 20 234
Raney Nickel 238

(vi)
Selenium Dioxide, Se0 2 241
Sodium Amide (Sodamide) , NaNH 2 244
Sodium Borchydride, NaBH 4 247
Wilkinson's Catalyst 250
Ziegle1·-Natta Catalysts 252
Appendix A
Some More Reactions and Rearrangements 255
Exercises (Chapter 1) 263
Exercises (Chapter 2) 265
Exercises (Chapter 3) 267
Simple Problems nnd Their Solutions 269

(,vii )
 Chapter 1

Mechanism of Organic Reactions

Introduction
Organic reactiof')s involve the breaking and making of covalent bonds. Chemists are not only interested in
what happens in a chemical reaction but also in how it happens. With the accumulated knowledge chemists
can design newer molecules.
I
The breaking- and making of covalent bonds usually occur in several discrete steps before
transformation into products. The detailed sequential description of all the steps of the transformations into
product(s) is called the mechanism of a reaction.
The mechanism of a reaction is satisfactorily established if intermediates involved in all the steps can be
isplated but which is unfortunately seldom possible. There are a number of guiding principles which help us to
predict the different steps of the reaction . By judiciously considering these guiding principles and the
stereochemical aspects, the different steps of the reaction can not only be explained but also the products
under different conditions can be predicted.
Complete information regarding all the steps is seldom obtained. However, a good deal of data can be
gathered from the following : (a) study of the kinetie:s of the reaction , (b) isolation 6f the intermediates if
isblable, (c) study of the reaction in the presence of other similar substrates, (d) study of the isotopically
labelled atoms in the reactants, (e) trapping of free radicals, (f) crossover experiments, (g) stereochemical
aspects, etc.
Study of reaction is an important part of theoretical organic chemistry. The knowledge enables us to
predict the products from nearly similar substrates and what is more important is to discern a pattern in
apparently diverse reactions. The conditions of the reactions may be altered to afford better yield of one or the
other product(s) and sometimes a completely different product. The revolutionary advances, in organic
chemistry, like the wild fire in the wood, have been possible through the knowledge of the pattern of organic
reactions. They have thus provided chemists invaluable guidance in synthesizing a large variety of essential
organic compounds such as drugs, vitamins, hormones, natural products, cosmetic aids, synthetic fibres,
insecticides, fuels, explosives , etc.
As we are interested in carbon compounds, we shalr first study as to how the carbon atoms form bonds
with each other and with other atoms.
 REACTIONS. REARRANGEMENTS AND REAGENTS
2

TYPES OF CHEMICAL BONDS

Organic compounds differ from inorganic compounds in the types of bond formation in the two classes of
compounds. A brief study of the electronic theory of bond formation will be helpful.
Modem physics states that atoms consist of central positively charged nuclei surrounded by a number
of electrons. These electrons arrange themselves in different shells. The shells have different energies and
different maximum capacities for electrons-two in the first shell (K shell), eight in the second shell (L shell),
eight or eighteen in the third shell (M shell), etc.
It is known that 3lements with completely filled shell are inert (stable), e.g., He (2 electrons in K shell),
Ne (8 electrons in L shell), Ar (18 electrons in M shell). He, Ne, Ar, etc., are, therefore, called inert (noble)
gases.
M

W Kosse! and G N Lewis in 1916 suggested that all elements try to achieve the inert gas configurations
by changing the number of electrons in their outermost shells. This tendency results in the union of elements
or bonds.

Electrovalent or ionic bond

Two elements can achieve stable configuration (i.e., inert gas configuration) by transfer of electrons from one
element to the other. This results in the formation of oppositely charged atoms (ions) which are bound together
by electrostatic attraction. This type of bond is called electrovalent or ionic bond.
Thus. ·

lsoelectronic lsoelectronic
with Ne with Ar

The elements in the beginning of a row in the periodic table can easily acquire their nearest 1n rt gas
configuration ~y losing electrons and those at the end of a row by gaining electrons. The former elements are
called electropositive and the latter elements are called electronegative. Thus, ionic bonds are forrned
between electropositive and electronegative elements.

Covalent bond
Since it is increasingly difficult to extract a number of electrons from an element due to increasing
development Gf positive charge on it, in general the charge on a simple cation is !limited to +3 even when
inert gas configuration is not attained. The reverse is similarly true.
Hence, the elements in the middle of a row can neither gain nor lose electrons to achieve inert ga
configurations. Also, the transfer of electrons between two electronegative or between two electropos111
elements cannot confer inert gas configurations to both the elements.
 TYPES OF CHEMICAL BONDS 3

In such cases, both the elements can acquire the desired inert gas configurations by mutually sharing
pairs of electrons-each element contributing an ~lectron to the shared pair. The shared electron pair then
belongs to both the elements. The shared electron pair binds the two nuclei, and the bond so formed is called
a covalent bond.
H
H·+·H-H:H ; H"+·~·•·H-H:p:H ..:H·+·C·-H:c:H ; :lH'•·N·-H:N:H
. .H • H
The covalency of an element is the number of covalent bonds it can form. Thus, the covalencies of
hydrogen, oxygen, nitrogen and carbon are 1, 2, 3 and 4 respectively. To satisfy the [Link] requirement,
elements often have to form multiple bonds (double or triple) by sharing more than one pair of electrons. Thus,

H... H'- ..
· c:o· c o
H· ••• • or H/ =

When pair(s) of electrons remains unbonded, as in oxygen and nitrogen in the above compounds, the pair(s)
is called lone pair or non-bonding electrons.
The covalent compounds, unlike ionic compounds, are uncharged. However, when the bond is between
two dissimilar elements, the shared pair shifts slightly towards the more electronegative of the two elements.
The covalent bond, in such case, is slightly polar which is indicated by +8 and -8 signs.

S+ H
H~ S- Is+ S-
H,.....N: H-C-CI
H I
H

The N-H, 0-H and C-CI bonds are called polar covalent bonds.

Coordinate covalent bond, dipolar bond or semipolar bond

When one element has two electrons short in its outermost shell and the other has a complete outer shell with
one or more spare pairs of electrons (lone pair) then the lone pair may be shared by both the elements. Such
a bond is called coordinate, dative or polar bond. Thus,

H
H:N: +
E <f>7 ~e
s:F ~ H-N: B-F
-
H F
.. I
H F
I

This type of bond is also called a semipolar bond, since a species with completely vacant shell (e.g., a proton)
may complete its shell by gaining a share on the pair of electrons of the donor element, which is \[Link] positively
charged.
H H H
/ I I
+:o: H-N-H - H +: N-1:1
\
H
(£)I
H
'+'
\3:1
I
H

This is essentially a covalent bond, only the resulting species is charged. It is different from ionic bond as also
from covalent bond since electrons are neithei: completely transferred nor mutually shared.

ORBITAL THEORY
The operation of electrostatic force is understandable in ionic bonds but the concept fails to account for the
 4 REACTIONS, REARRANGEMENTS AND REAGENTS

force of attraction between elements bonded by covalent bonds. Thus, the description given in the preceding
section does not account tor the strength of the covalent bonds and also the shapes of the molecules formed
by covalent bonds. To understand this, it is necessary to study the molecular orbital (MO) description of the
covalent bonds.

Atomic orbital
According to modern concept the electrons in an atom are arranged in shells of different energy levels around
the nucleus. The shells of different energy levels are indicated by the nymbers 1, 2, 3, ... , or by the letters K,
L, M, ... , starting from the nucleus. The energy of the shells increases in the order: 1 -7 2 -7 3 -7 ... . Each
shell can accommodate a definite number of electrons which is twice the square of the shell number, e.g., the
2 2 2
first shell has 2 x 1 = 2, se'cond shell has 2 x 2 = 8, third shell has 2 x 3 = 18 electrons, etc.
Within each shell there are energy subshells or sublevels. These energy sublevels are designated s, p,
d and f according to the sharp, principal, diffused and fundamental !Ines respectively they produce in an X-ray
spectra. The spectral lines indicate ones, three p, five d and seven f levels of energy.
Electrons of different energy levels are present in discrete volumes of differen't shape$, sizes and
orientations in the sublevels. around the nucleus. The discrete volume in space around the nucleus where the
probability of finding the electron of a particular energy level is greatest is called an atomic orbital. The concept
of orbital emerged from Heisenburg uncertainty principle and wave nature of electrons-an electron does not
move in an orbit round the nucleus, it is in a diffused state. Thus, orbitals can be visualised as diffused charge
clouds of different shapes, size and orientations within the subshells around the nucleus.
Different shells contain different types and different numbers of orbitals. The shell number gives the
number of types of orbitals and the square of the shell number gives the number -of orbitals.

Shell no.: 1(K) 2{L) 3(M) 4(N)

Types of orbitals s s, p s, p, d s, p, d, f
2 2 2 2
No. of orbitals 1 =1 2 = 1 +3 3 =1 + 3 + 5 4 =1+3 + 5 + 7

Orbitals of diffe ent shells are differentiated by prefixing the shell number: the s orbital of first shell is
denoted as 1s orbital, tt:le s and p orbitals of the second shell as 2s and 2p orbitals and so on. The energy of
the orbitals increases in the order: 1s -7 2s -7 2p ....
According to Pauli exclusion principle, any one orbital can accommodate up to a maximum of two
electrons with paired spin t 1~ 1·.
The general rule is this that orbitals are filled to capacity with electrons starting from the lowest-energy
orbital. A higher-energy 'orbital is not used until the next lower to it has been filled to capacity. The energy
dlfference between the orbitals of two shells is greater than the· energy difference between the two t¥pes of
I

* A spinning electron creates a small magnetic field, i.e., it behaves as a tiny magnet. Two oppositely spinning electrons
are like two small magnets with their opposite poles in the same direction. This causes attraction between them.

++++
s
Repulsion
s s
Attraction
N

It should, however, be remembered that the spin of an electron is some kind of property and is not actually spin.
 TYPES OF CHEMICAL BONDS 5

orbitals in the same shell. Thus, the energy difference between 1s and 2s orbitals is more than that between
2s and 2p orbitals. The relative energy levels, the maximum capacities of electrons with paired spin of a few
shells are given in Table below.

Shell energy Orbital capacities [Link] electrons

ll .ll .ll .ll .ll 1J. 1J. 1J. 1J.

3 3s 3p 3d 18

2
.ll 1J. .ll 1J.
8
2s 2p

1J. 2
1s
Table

In orbitals of equivalent energies (degenerate), the most stable arrangement is the one where all the
unpaired electrons have parallel spin (Hund rule}•
Thus, the electronic configurations of some elements are.:

1s 2s ~p

[ill [ill I 1 I 1 I
Carbon

Nitrogen [ill lliJ I 1 I1 I 1 I

Oxygen lli] lli] I1l I 1 I 1 I
Shape of atomic orbitals
As we are mainly concerned with the first-row elements of the periodic table, we will restrict our discussion to
only sand p orbitals without going into the details of how their shapes and orientations bave been dete~mined
by quantum mechanics. The s orbitals (1 s, 2s, 3s, etc.) are spherically symmetrical abotJt the nucleus.
Obviously, the 2s orbltal is bigger than the 1s orbital. It surrounds the nucleus from a distance. Between the
1s and 2s orbitals there is a zone called nodal zone where the probability of finding the electrons is zero.

1s

2s

• Rotating electrons (charged particles) create a small magnetic field . When electrons are placed in an external magnetic
field, .the lowest-energy state will be the one when the magnetic fields of the rotating electrons are aligned with the
applied field and higher-energy state when aligned against

+ ~
tttt
Applied field H
 e REACTIONS, REARRAN3EMENTS ANO REAGENTS

The p orbltals (2p, 3p, 4p, etc.) are dumb-bell-shaped. There are three p orbitals each of the same shape
and energy, which are directed at 90° to each other with the point of Intersection at the nucleus of the atom.
y,
y y
'

x x x

2p
2p z
y

Hence, they are designated 2Px• 2py and 2pz to Indicate their directions along the cartesian coordinates. The
probability of finding the electrons of 2Px orbital along the yz plane passing through the nucleus is zero. This
plane Is called the nodal plane. For electrons of 2py and 2pz, the nodal planes are xz and xy respectively. It is
for this reason that the three 2p orbitals do not mix up ordinarily. The 2p orbital extends slightly beyond the
radius of 2s orbital. The shape of d orbital (five) is double dumb-bell and the shape off orbital (seven) is
rosette.

Overlap of orbitals
When parts of atomic orbitals (AOs) of two atoms occupy the same space on being brought closer. it is called
overlap of orbitals. The overlap of two AOs results in the formation of two new orbitals called molecular orbitals
(MOs). These MOs are common electron clouds encompassing the nuclei of both the atoms and contain two
electrons. Mathematically it has been showr:l that the addition of two AOs generates a bonding MO and
subtraction of one AO from the other generates an antibonding orbital. This method of overlap of AOs is called
a linear combination of atomic orbitals (LCAO). (The argument for the genera1ion of the two MOs by LCAO
method is this: each AO can accommodate up to a maximum of two electrons so the combination of two AOs
should be able to accommodate four electrons for which two MOs should exist.) In the bonding MO bot
electrons reside mostly between the two nuclei in the ground state and hence aid to the binding of the two
nuclei. The bonding MO has lower energy than the two AOs. In the antibonding MO the electrons are at a
greater distance from either of the nuclei than in the individual AOs. Hence, the antibonding orbital does not
aid to the binding of the two nuclei and is of higher energy than the AOs.

A.O M.O A.O

(-['
v-0 \ (-['\ _ ~ ~
~"-JAntibonding
1 ~L .
E
Antibonding

H H o*M.0 . ~
(-['\
(-['\ ~ Bonding Bonding
v+u-~
H H o M.0 .

It is for this reason that two filled orbitals cannot successfully overlap, since a pair each will be in bonding a
antibonding orbitals. The net result will be the binding force of the bonding MO will be cancelled by 1 e
antibonding MO. Hence, He2 is not known.

MO
1

Bonding
 TYPES OF CHEMICAL BONDS 7

The antibonding orbitals will be ignored as they are not occupie~ .by th~ electrons in the ground state.
Sigma o-.;bi,tal: Sigma bond When two hydrogen atoms approach cl~~e en?ugh, their 1s orbitals, each
containing one electron, overlap with the formatior of a common molecular orbital.

An AO
@ + @ - + @ o r H-H
a-Orbital a-Bond

- As the MO has a shape nearly similar to s orbital, it is called a cr orbital from the Greek letter cr corresponding
to the letter s. The electron cloud is more dense along the internuclear axis and hence binds the two positively
charg~d nuclei firmly. Hence, a cr bond is a very strong bond.
Sigma-bond orbitals can also be formed by the linear overlaps of s and p orbitals, p and p orbitals,
between hybridized orbitals and between s and hybridized orbitals. The1 latter two types will be taken up later.

Pi orbital: Pi bond The MO formed by the sideways overlap of two p orbitals perpendicular to the internuclear
axis is called a n orbital and the bond called n bond from the Greek letter n corresponding to the letter p. The
shape of 7t orbital is different from that of cr orbital. There are two regions of electron cloud, above and below
the line joining thew011uclei. Since the n electrons are not in the internuclear axis, the binding effect is partial.
Therefore, the 1t bond is not as strong as the cr bond: they are loosely held.
'
Nodal plane
~/or '-c~c/
C) / CJ '

Hybrid orbital Formation of covalent bonds by the overlap of orbitals is accompanied by the release of
energy. Greater the overlap, greater is the energy release and greater is the stability. In the formation of
molecules greatest stability is endeavoured. For this, elements try to mobilise all their valence electrons by
mixing the atomic orbitals of the outermost shell and producing new type of orbitals called hybrid orbitals. This
is in fact a redistribution of energy.
)he hybrid orbitals have different shapes from the orbitals from which they have been hybridized. Thus,
the hybrid orbital formed on mixing s and p orbitals has the shape of a p orbital but with one lobe smaller than
the other.

p Hybrid orbital

From its shape it is evident that it is more directional and can overlap better with other orbitals than either s or
p orbitals, producing stable bonds.

FORMATION OF COMPOUNDS OF CARBONS

Formation of ~ti4'(carbon-carbon single bond) Let us consider the formation of a methane molecule.
Experimental'facts about methane are:
(i) .It has four equivalent C - H bonds.
(ii) The H - C - H bond angle is 109°28'.
(iii) It is a tetragonal molecule, i.e., the four hydrogens are at the four apex of a regular tetrahedron with
)On at the centre.
~ bond energy of a C - H bond \s high (102 kcal/mol).
2 2 2
\ectron\c conf\gurat\on of an \so\ated carbon in the ground state is 1s 2s 2p in which two unpaire
lre ava\\ab\e for bond format\on, Le., carbon should be divalent. Although divalent carbc
ssuch as :CC\2 or :CH 2 are known, they are highly unstable and in majority of compounds, carbo
lrava\ency.
t\on To have four equ\va\ent C - H bonds, carbon should have four equivalept orbitals with on
e\ectron \n each. To ach\eve th\s, \t unpairs one of the two electrons of 2s orbital and promotes itt
'\ 2p orb\ta\.
2p 2p

2s~ Unpairing ..
@---------.
Ground state
. and promotion

Tne utw,a\T\ng and promot\on ot e\ectron trG._m ~s to 2p orbital need energy which is more thar
1~ensated b'/ the \arge amount ot energy re\ea,sed in the formation of two extra bonds.
Now, the 'OUT otb\\a\s have one e\ec\ron each and so can form four C - H bonds. However, these foui
- \-\bonds w\\\ not be equ\va\en\ since the three 2p orbita\s have higher energy than the 2s orbital. Also the
, and 2p orb\\a\s have different over\apping capacities. Therefore, in order to have four equivalent orbitals,
1e \our orb\ta\s {one 2s and three 2p) are mixed up, Le .. hybridized to produce four new equivalem orbitals
3
a\\ed h'1br\d orb\ta\s. These four hybrid orbitals are called sp orbitals as \hree p and ones orbitals have bee
rn\xed.

·r
2p

~
~
I' I ' I ' I •P'hybridlz•tion
one 2s + three 2p
I1 I1 1 I1 I
1 o avoid maximum repu\sion between the e\ectrons, the four hybrid orbitals take up a tetrahedral direction.
3
\he ang\e between the axes o1 any two sp orbitals is 109°28' when mathematically calculated. Orbital picture
o1 the process is given below.

Ex~itation sp3 hybridization

Four sp3orbitals

f=Of \he \orma\ion ot methane, tour hydrogen atoms, each with one electron in 1s orbital, overlap with ea
\he \om sp mbita\s axia\\y . Each bonding MO is..-a ~orbital. i.e .. four C - H
3
CT bonds are formed

-~H H H
 TYf>ES OF CHEMICAL BONDS 9

· "11 ox~lains the geometry of the molecule and the c - H bond strength.
~tl)fttttlon of l!thylene (tarbon""'carboh double bond) In ethylene, each carbon is bonded to two hydrogen
atom§ aticl one carbon ~to.m with cr bohds. For this, each carbon hybridites the 2s orbital with two 2p orbitals
2 2
t~ f)roduce three sp orbitals to form three strong cr bonds. To attain the1state of lowest energy, the three sp
2
orbitals are directed at 120° to each other in a plane. The geometry of sp carbon is, therefore, triangular
platiat, The remaining Ur.1hybridized 2p orbital is perpendicular to the plane.

2p
2p
2p ~·2p2 2p
25
0].
l 1J 1 I 1 Isp2hybrldizatlon
. I 1 I
sp
1
2

I 1 l
f1l
L!J; • 2s •
P
~
120°
sp 2~~~
one 2s + two 2p
sp2

2
In the formation of ethylene molecule, one of the sp orbitals on each carbon overlap axially to form a
2
s_trong C - C cr bond. The remaining two sp orbitals on each carbon overlap with the 1 s orbitals of four
hydrogen atoms to form four C - H CJ bonds.

The rema'ining unhybridized 2p orbitals on each carbon are vertical to the plane containing the carbon
and hydrogen atoms. These 2p orbitals are parallel and overlap laterally to form r.: bond. The bonding n MO is
-situated above and oelow the plane containing the atoms of the molecule.

+ ~2p _c:.
sp2 ~.--s-.p2

® sp2carbon @

Th'e binding effect of then bond is reflected in the bond distances, e.g., the C = C distance is 1.33 A and
C - C distance is 1.54 A. The lateral overlap in n bond is less effective in binding the carbon atoms than the
axial overlap in ·CJbond. Thus, the bond energy of C - C is 83 kcal/mol and that of C = C is 143 kcal/mol and
not double· of 83 kcal/mo!.

The reactivity of unsaturated molecules is due to the more exposed and loosely held n electrons.
Formation of acetylene (carbon-carbon triple bond) In acetylene each carbon is bonded to the other carbon
1
amd one hydrogen atom. For this each carbon hybridizes 2s orbital with one 2p orbital to produce two sp
hybrid orbitals. (Atoms usually mobilize as many hybrid orbitals as it has to form strong cr bonds) . The two·
s-p~ orbitals .take up a diagonal position to avoid repulsion, i.e., the angle between the two sp
1
orbitals is 180°.
1
These two sp orbitals on each carbon form two cr bonds-one between the two carbons and one with
hydrogen.

The residual two unhybridized 2p orbitals on each carbon are at right angles to each other. Hence, the
2p orbitals on one carbon which are parallel to the 2p orbitals of the other carbon, overlap laterally to form two
• 7t bonds. Thus, there are three bonds between the two carbons-one cr and two n bonds. Then-electron cloud

I
[Link] around. the C - C CJ bond and exposed to reacting species.
10 REACTIONS. REARRANGEMENTS AND REAGENTS

sp 1hybridization
ones+ one p
NC

w
~- sp1 hybridization alkyl
electron·reh
by +t effect.
effect.

®• ~'.~~'
w~ w~
•··
@- ~~
~
o, H-C:C-H
Applicatio1
Inductive et
(a) Acid stJ
Bond formation ionization-
The molecule is [Link]. The C =C bond distance 1s 1.20 A and the bond energy 1s 194 kcal/mol. numerical v
is the acid.
In ac
bond; cons•

FACTORS INFLUENCING REACTIVITY

Reagents which are charged species can attack a particular bond only when there is imbalance of electron
density, i.e., polarity. The saturated hydrocarbons are unreactive (hence the name paraffins) since there is no
polarity in C - C bond and practically no polarity in C - H bond, thus giving hardly any opportunity to the
Greater ior
reagents (electrophiles and nucleophiles) for the attack. Hence, to study the reactivity of a molecule it is
(PK.a = 4.7E
necessary to study the structural factors which cause electronic imbalance in a particular bond. There are a
number of such factors as given below. promotes i1
Whe
INDUCTIVE EFFECT is because
The electron cloud in a cr bo~d between two unlike atoms is not uniform. It is more dense towards the more closer to th
3
electronegative of the two atoms, i.e. , the electron pair forming the cr bond is slightly displaced towards X. This sp orbital!
permanent state of polarization is called the inductive effect. This is refli

The atom X thus acquires a slight negative charge (~n and the carbon atom a slight positive charge (o·1. i.e..
(b) Arom<
the bond is polarised. If the electronegative atom is joined to a chain of carbon atoms, the positive charge on
the carbon atom is relayed to the other carbon atoms. (PKa = 4 .21
Electron-~
o+ o+ o+ Ii+
c --c --c --c --x
4 3 2 1
(c) Dioic a
stronger tt
Since C 1 is slightly positively charged it exerts a pull on the electrons forming covalent bond between C, an H-COC
C 2 but less strongly than X on C 1• The effect thus rapidly dies out. Hence, the effect is not significant beyond
the ~econd C·atom. Tnis electron displacement relayed through cr bonds, albeit through a s~ort distance. is The electr
known as inductive effect. The effect is permanent but feeble (since it involves shift of strongly held a-bond carboxyl g
ele"ctrons) and other stronger factors may overshadow th is effect. (d) Alipha
Inductive effect may be due to atoms or groups. Relative inductive effects have been measured with electron p
 FACTORS INFLUENCING REACTIVITY. 11

· rence to hydrogen. The order of electron-withdrawing effect is:

N02 > F > COOH > Cl > Br > I > OH > OR > C6H5 > H > Me3C- > Me2CH- > MeCH2- > CH3

Electron-withdrawing (-1 effect) Electron-releasing (+I effect)

e alkyl groups are less electron-withdrawing than hydrogen and are therefore considered as
~ectron-releasing. Electron-withdrawing character is indicated by -I effect and electron-releasing character
!by +I effect. The effect is additive-the greater the number of electron-withdrawing groups the stronger is the
e1fect.

Applications
Inductive effect is useful in correlating structure with reactivity.
(a) Acid strength of aliphatic carboxylic acids The strength of an acid depends on the extent of its
Ionization-the greater the ionization the stronger is the acid. The strength of an acid is denoted by the
numerical value of pK8 (pK8 == -log 10 K8 , where Ka is the acidity constant). Smaller the numerical value stronger
·is the acid.
In acetic acid, the electron-releasing inductive effect of methyl group hinders the breaking of 0 - H
bond; consequently reduces the ionization . This effect is absent in formic acid.
0 0 0 0
11 lie® II lie <B
C H 3 - c - o - H ~ CH3-C-O + H ; H-C-0-H ~ H-c..:....o + H

Greater ionization in formic acid over acetic acid makes formic acid (pK8 = ~. 77) stronger than acetic acid ·
([Link] = 4.76). Monochloroacetic acid (PKa = 2.86) is stronger than formic acid since -I effect of chlorine
promotes ionization. As this eifect is additive, trichloroacetic acid (PKa = 0.66) is a still stronger acid.
When·an unsaturated carbon is conjugated with the carboxyl group, the acid strength is increased. This
is because with the increasing s contribution to the hybrid orbitals, the electrons are progressively drawn
2
closer to the nucleus of the carbon resulting in the increase in -I effect. Since the s contributions in sp, sp and
sp3 orbitals are respectively 50%, 33.3% and 25%, the order of -I effect of hybrid orbitals is sp > sp2 > sp3 •
This is reflected in the pKa values of the following acids.

CH3 -CH2 -COOH CH2=CH-COOH HC~C-COOH

Propanoic acid (4.88) Propenoic acid (4.25) Propynoic acid (1.84)

2
(b) Aromatic carboxylic acids The a c:arbon of benzoic acid is sp -hybridized. Hence benzoic acid
(PKa =4.20) is a stronger acid than its saturated analogue. cyclohexane carboxylic acid (pK8 =4.87).
Electron-withdrawing groups substituted at o- and ,o-positions enhance the acid strength.
(c) Dioic acids Since carboxyl group is itself an electron-withdrawing group, the dioic acids are in general
stronger than their monocarboxyl analogues, e.g .•

H - COOH (3. 77) HOOC - COOH (1.23) HOOC - CH 2 - COOH (2.83)

The electron-witl;ldrawing effect of one carboxyl group over the other falls off sharply on separating the two
carboxyl groups by at least two saturated carbons.
(d) Aliphatic bases The strength of nitrogenous bases depends on the ease of availability of the u~shared
electron pair oni the nitrogen-atom to the proton. Due to the increasing +I effect in amines, the order o~base
--------
12 REACTIONS, REARRANGEMENTS AND REAGENTS

strength should be NH 3 < MeNH 2 < M~NH < Me3 N. However, the pKa values are 9.25 (NH 3 ) , 10.64 (t.~eNH 2),
10.77 (Me 2NH) and 9.80 (Me3N). The pKa value tor the base B: is a mesasure of the acid strength of its
conjugate acid Be:H. Stronger the acid BeH, weaker is the base B:. In other words, smaller the numerical
value of pK8 for the acid, BeH, the weaker is the base B: . From the pKa values it is seen that 2° amine (10.77)
is a stronger base than 3° amine (9.80) . This is because the base strength of an amine in water depends not
only on the ease of availability of lone pair but ~lso on the extent of sofvation of the protonated amine by
hydrogen bonding. The protonated 3° amine has' one and protonated 2° amine has two hydrogens on the
nitrogen for hydrogen bonding.

R R
I(±) I(±)
R -N -H----·OH2 R -N-H----·OH2
I I
R H------·OH2

Hence, 2° amine is a stronger base than 3° amine. Solvation is an important factor for the determination
of the base strength. This is supported by the fact that the order of base strength of amines is 3° > 2° > 1° in
chlorobenzene in which hydrogen bonding is absent.
(e} Aromatic bases Aniline is a weaker base (pK8 =4.62) than its saturated ~nal ogue , cyclohexylamine
2
(PKa =10.68). This is because the nitrogen atom in aniline is bonded to an sp carbon which pulls the
unshared electron pair on nitrogen. This results in the delocalization of the loan pair with the n electrons of the
ring. Thus, the lone pair is not easily available for protonation .

Hence, aniline is a weaker base than ammonia or cyclohexylamine. Electron-withdrawing substituents at er

.
and p-positions have marked base-weakening effect. Substituents that have unshared electrons, e.g..
.
-~H or -~R exert electron-donating mesomeric effect from o- and p-positions increasi11g the base strength.

Electromeric effect
On the close approach of a reagent, the electronic system of an unsaturated molecule is deformed. When the
reagent is removed without allowing the reaction to take place, the electronic system reverts to the original
ground. state of the molecule. This kind of polarizability of multiple bonds is known as electromeric effect.
Electromeric effect causes complete transfer of the loose n electrons from one carbon to the other.
Consequently, one end is positively charged and the other negatively charged which aid the reagent to attack.
The shift of the electrons is shown by a curved arrow (""') indicating the direc.t ion of the electron shift.

The effect is temporary since the electrons revert to the original state on removing the reagent.
 FACTORS INFLUENCING REACTIVITY 13

Reagent added "'-@c+ 8C-/

I - ...._
Reagent removed

When the multiple bond is between two d1ss1m1lar elements the shift of electrons takes place towards the more
electronegative of the two. Inductive effect may also determine the direction of the shift of electrons, e.g.,

CH 3 --cH b'cH 2

Electromeric effect differs from the inductive effect as given below.

Inductive effect Electromeric effect

1. It is a permanent polarization. 1. It is a temporary polarization.
2. Operates through er bonds. 2. Operates through 1t bonds.
3. Weak effect since the cr-bond electrons are 3. Strong effect since the loose n electrons shift
strongly held. completely.
4. Charge developed on the carbon joined to the 4. Complete transfer of electrons causes full charge
substituent (electron repelling or attracting) is on thP carbons, which is shown by ffi and e
small and is shown as o- or o+. signs.

RESONANCE
Many organic compounds are known which are not adequately represented by single valen~e bond
structrues. All the properties of such a compound are not explained by a single structure. Thus, the valence

bond structure of benzene (1) indicates three each carbon-carbon single and double bonds
. 0cv·
Measurement of bond distance in benzene, however, shows that all the carbon-carbon bond distances are
the same and it is 1.4 A, i.e., between a single (1 .54 A), and a double bond (1 .34 A). Further, benzene on
hydrogenation gives out heat which is less than the heat calculated from its structure (1 ).
For such compounds it is necessary that other structures be devised to explain all their properties. This
is the basis of the concept of resonance. Thus, when two or more good Lewis structures can be devised for a
compound, resonance is invoked.
The different structures of a compound devised by different methods of pairing electrons in a fixed
atomic skeleton are called resonance or canonical structures. The actual structure of the compound is then a
combination of these structures and hence the compound is called a resonance hybrid. A hybrid is more
stable than any one of the contributing structures . The contributing resonance structures are shown by
double-headed arrows ( H) indicating that the real structure involves both ways of pairing electrons.
Each resonance structure represents only partially to the real state of the compound and all of them in
combination represent the compound completely. Final struc~ural description of the molecule is then what is
obtained on superimposing all the resonance structrues on one another. The actual molecule therefore does
not vibrate or oscillate from one structure to another but has one and only one structure which is an average
of all the structures. The different resonance structures do not exist, they are drawn by different schemes of
pairing electrons to consider the extent of delocalization and hence to assess the stability of 'the hybrid.
4 3 2 1
Thus, in 1, 3-butadiene, CH 2 = CH - CH = CH2, the C 1 - C 2 and C 3 - C 4 bonds are found to be longer
than a carbo~rbon double bond and C 2 - C 3 bond is slightly shorter than a carbon-carbon single bond. To
 REACTIONS, REARRANGEMENTS AND REAGENTS
14

explain this, several other structures may be devised by shifting a pair of 1t electrons:

e ® @ e
CH 2 :CH-CH =CH2 - c H 2 -CH -CH =CH2 - CH2 =CH -CH-CH2
(2) (3) (4)
e
-cH2-CH =CH-CH2 -
® @
CH2-CH =CH-CH2
e
( 5) ( 6)

Since
The structures (3) and (4) show partial single-bond character of C1 - C2 and C3 - C4 bonds and structures (5)
experiment<
and (6) show partial double-bond character of C2 - C3 bond. This explains the observed anomalies in the bond anticipated ·
distances in the hybrid. There
Thus, in the hybrid structure (i.e., real structure) of the compound, lateral overlaps of all the four p atomic n electrons
orbitals have taken place, i.e., the electrons are delocalized. Reso
nuclei are b
CH2- CH - CH - CH2 All th1
Hybrid will contribt

As a result, two bonding and two antibonding MOs are formed. The hybrid representation shows that each pair Rules of re
of electrons binds four carbon nuclei instead of two. This gives a net stability to the hybrid over any one of the 1. Al
contributing resonance structures. of
Experimental confirmation about the stability of the hybrid is afforded from the qualitative measurements 2. n
of [Link] of combustion or hydrogenation. 3. Al
Calculated for the structure Determined by experiment for Cl
CH2= CH- CH= CH2 the actual compound
4. R1
I TR,E
oJaE
2
Ot6E
m
re
5. R
C02, H20
Heat of combustion re
C(
It is seen that the actual compound gives out lesser energy than that calculated for the structure
6. S
CH 2 =CH - CH =CH2 • Hence, the actual compound is at a lower-energy state, i.e., more stable.
t~
The difference in the experimental and calculated energies is the amount of energy by which the
compound is stable. This difference in the energies is known as the resonance or delocalization energy (RE). >
It is about 4 kcal/mol for 1, 3-butadiene and 36 kcal/mol for benzene which is also a resonance hybrid. 7. A

0 -0
The resonance or stabilization energy of benzene has been calculated from the heat of hydrogenation as
8. C

given below.

0 • 0• Hz - 28.6 k<al
 FACTORS INFLUENCING REACTIVITY 15

0 -0 + 2H 2 + 57.2kcal

0 -0 + 3H2 + [Link]

Since benzene has three double bonds, the heat evolved should have been 3 x 28.6·= 85.8 kcal/mot but
experimentally it is found to be 49.8 kcal/mol, i.e., benzene evolves 85.8 - 49.8 = 36 kcal/mot less energy than
anticipated for the hypothetical cyclohexatriene.
Therefore, the resonance energy of benzene is 36 kcal/mol which is due to the delocalization of the
n electrons in a cyclic molecular orbital.
Resonance stability increases with increa~ed number of resonance structures, for larger number of
nuclei are brought closer by the binding effect of the loose electrons.
All the resonance structures, however, do not contribute significantly to resonance. [Link] a structure
will contribute significantly to resonance or not has to be considered from the following rules of resonance.

Rules of resonance
1. All the resonance forms must conform to Lewis structure, e.g., carbon cannot be pentavalent in any
of the resonance forms.
2. The positions of the nuclei in all resonance structures must be the same.
3. All the resonance structures must have the same number of paired electrons, e.g.,
• •
CH 2 - CH= CH - CH2 is not considered a resonance structure of butadiene (2).
4. Resonance structures with greater number of covalent bonas are more stable than those with lesser
numbers. Thus, the nonpolar structure of butadiene (2) is more stable than any of the other
resonance structures.
5. Resonance structrues with similar charges on adjacent atoms are insignificant due to electrostatic
EB e e EB
repulsion and consequent instability, e.g., the resonance form CH 2 -CH - CH - CH2 does not
contribute to the stability of the hybrid.
6. Structures with positive charge on multiply bonded electronegative element are .unimportant since
the electronegative element will not adapt to such distribution of electrons. H~nce the canonical form,
e e
> C - 0, of carbonyl group is insignificant.
7. Resonance stabilization is greatest when there are at least two equivalent structures, e.g.,

@ @
0-0 ; CH2 -CH =CH2 - CH2 =CH-CH~

8. Charge-separation structures are less important than those in which the charge is delocalized. This
is due to electrostatic attraction between unlike charges

e e @
-70 /g 0
~ CH3-c(~ -cH3-C~
/0
+ H
CH3-C \OH - CH3-C~H
Less resonance stability More resonance stability
16 REACTIONS, REARRANGEMENTS AND REAGENTS

Hence, acetic acid favours ionization.

9. Dissimilat canonical structures vary widely in their energy contents, those of higher energy contribute
too little to the hybrid. In such case the lowest-energy structure resembles the hybrid in energy, i.e.,
the RS is less, e.g.,
oe
CHrC/(i)
----- ~OH

t 0
CH -rf'
----- L--~OH
___Rs_ _ Hybrid

Hence, acetic acid and ethylene are well represented by their QQnv~ntional ~tn,.1ctL1res .
In contrast, similar canonical structures have nearly equal energies anq contribute 111ore to the
hybrid, so that the RS is more, e.g.,

------Hybrid

Thus, acetate ion is more stable than acetic acid which therefore lonli~~ to b~have as &eip. Similarly,
phenol is acidic since phenoxlde ion is more stable than phenol (see +M effect).
1O. ~II the atoms in a molecule taking part in resonance should be coplanar, This is ni:i~essary for
effective overlap of the p orbitals and the delocalizatlon of the electrons. Hence, cji~tQrtiori ef pl~manty
will impede resonance with all that is consequent upon.

MESOMERIC EFFECT
The permanent polarization of a group conjugated with a n bond or a set of ~lternate n bonos is tr~nsmitted
through the n electrons ot the system resulting in a different distribution of electrons in the unsi'ltl,ff@ted chain.
This kind of electron redistribution in unsaturated compounds conjugated with electron ~ r@l~asing or
electron-withdrawing groups or atoms is called mesomeric effect.
We know that carbonyl group is a resonance hybrid.

When the carbonyl group is conjugated with a carbon chain of alternate single and double bonds, the
positively charged carbonyl carbon exerts electron transfer towards itself via the n electrons. Thus, the
polarization of the carbonyl group is transmitted via the n electrons of the carbon chain.

o o
CH2 =CH -CH =CH -c =O
r.:\ <±>
- - CH2 -CH =CH -CH =c-o
e
I I
Similarly, the lone pair on the nitrogen atom repels the n electrons of the conjugated chain of the amino
 FACTORS INFLUENCING REACTIVITY 17

compound.

Ttie 1t electrons of molecules are delocallzed due to the mesomeric effect resulting in a number of
resonance structures which give stability to the ions. Therefore, this kind of electron transfer is also called
resonance effect Qr conjugative effect besides mesomeric effect.
This is a permanent effect in the ground state of the molecule which is indicated by the dipole moment.
The electron-attracting mesomeric effect is Indicated by -M effect and the electron-repelling mesomeric effect
i~ indicated by +M effect.

+M effect possessing groups are: -OH, .-OR. -NH2 ,-[Link]. -N·R2 • -SR,
a• •• ••
-·x•• :, etc.
-M effect possessing groups are: -CHO , :::co , -CN , -No2 , -S03 H , etc.

The low reactivity of halogens bonded to unsaturated carbon is due to the +M effect of the halogen. The
C - Br bond in vinyl bromide has a partial double-bond character due to the +M effect of bromine with
consequent low reactivity of bromine.

"' ()_. e G>

..
OH2 =CH-Br:............ Ct+z -CH =e r

The acidity of phenol is due to the +M effect of OH group. The mesomerlc transfer of the loan pair on the
oxygen atom of phenol to the 7t electrons of the benzene ring results In several resonance structures with a
positiv~ charge on the oxygen atom. This aids the hydrogen atom of OH group to leave as proton.

T~~ ipnization is sp~cially aided due to the formation of the relatively more stable phenoxlde Ion.
The charge delecalization in phenoxide Ion affords greater stability over phenol In which charge
S@~aration occµrs in the canonical forms.

Herice, phenol prefers to ionize, I.e., it is acidic.

Th~ essential differences, between inductive effect and mesamerlc effect are:
 18 REACTIONS, REARRANGEMENTS AND REAGENTS

Inductive effect (I effect) Mesomeric effect (M effect)

--
~

2. I effect involves electrons of a bonds. 2. M effect involves electrons of n bonds and lone
pairs.

3. I effect is transmitted over a short distance. The 3. M effect is transmitted with undiminished
effect dies out rapidly since the a-bond electrons intensity right up to the end of the unsaturated
are tightly held. chain since the effect involves loose n electrons.

HYPERCONJUGATION
The inductive effect of alkyl groups is found to be in the order Me3 C - > Me2CH - > MeCH 2 - > CH3 - whe
attached to a saturated carbon. When, however, they are attached to an unsaturated carbon (e.g., C = Cor
aromatic ring) the order is reversed. In this case, electron-releasing effect operates by a different method than
in inductive effect.
The electron-releasing effect is explained by assuming that the cr orbital of the a C - H bond overlaps
with the adjacent n orbital. The displacement of the electron pair of the a C - H bond causes a partial positive
charge on the hydrogen atom without the actual proton release.

This ability of the cr-bond electrons of an a C - H bond to undergo conjugation with the adjacent rr electrons is
called hyperconjugation. It is in fact a low-order resonance effect and is also known as 'no bond resonance'.
Thus, all the three C - H bonds of a methyl group in propylene can polarize the adjacent n bond as shown:

H+ H
+ I -
. - . . H -C =CH -CH2 ._..... H C =CH -CH2 etc.
I I
H H

Hence, the site of electrophilic attack is the terminal CH 2 group. As the effect is additive, it is at a maximum
with CH 3 group. Hence, the order of this effect is CH 3 > RCH2 > A2CH.
Hyperconjugation satisfactorily explains the preferential formation of the alkene (8) over (9) on
dehydration of the alcohol (7) .
CH3
I
CH3 -C-CH -CH3
I I
H OH CH3
I
CH3 -C-CH =CH2 (9)
(7) I
H

Nine ex-hydrogens, by hyperconjugative effect, stabil ize the olefin (8) over (9} where there is only one
ex-hydrogen atom for hyperconjugation.
The ortho- and para-directing effect of methyl group is similarly attributed to electron release bY
hyperconjugation.
 ~~------------ ........................
FACTORS INFLUENCING REACTIVITY 19

The effect is feeble and may be overshadowed by other powerful factors. Thus, in the dehydration of
3-hydroxy-4-methylpentanal (10)

H CH3-C=CH-CH2-C=O (11)
I I I
M e-C-CH-CH2-C =O CH3 H
I I I
Me OH H

(10) CH3 -CH-CH =CH-C =O (12)

I I
CH3 H

the aldehyde (11) should result according to hyperconJugat1on but the major product is the aldehyde (12). This
is due to conjugation of the double bond with the carbonyl group in (12) which gives resonance stability, a
stronger stabilizing factor.

STERIC EFFECT
The structural feature which influences the chemical reactions due to bulky substituents in the molecule is
called steric effect. When the bulky groups hinder the reaction, it is called steric hindrance which may be due
to (a) the sheer bulk of the substituents causing the approach of the reagent more difficult or may be due to
(b) electronic factor, i.e., promoting or inhibiting electron availability at a particular site. Thus-
(i) Bulky alkyl groups in ketones restrict the space around the carbonyl group to undergo addition
reactions. Such hindrance is not observed in aldehydes since one of the groups is hydrogen which occupies
small space. Hence aldehydes are more reactive than ketones (inductive effect also plays its part}.
Cyclohexanone is, however, as much reactive as methyl ketone to addition reactions, since the two groups
effecting the ring closure are held back, providing more space for the attack.
(ii) Carboxylic acids with highly substituted a-carbon are esterified with difficulty due to steric hindrance.
(iii) The two substituents at the ortho positions in 2,6-dimethylbenzoic acid block the approach of alcohol
towards the carbonyl group so that no esterification occurs under normal conditions.

When the carboxyl group is shifted away from the two ortho substituents as in 2, 6-dimethylphenylacetic acid,
esterification occurs readily.

(Iv) Tertiary butyl benzene produces exclusively the para isomer since the bulky substituent (- CMe3)
sterically blocks attack at the ortho positions.
 20 REACTIONS, REARRANGEMENTS AND REAGENTS

~
8;(5c;e
I~
,,,
(v) N, N-Dimethylaniline undergoes ready azo-coupling but its 2,6-dimethyl derivative (13) does not.
Crowding of the four methyl groups in (13) sterically disturb the planarity of the molecule and prevent the lone
pair on the N atom to interact with the n electrons of the ring. Hence, the ring is not activated towards
azo-coupling.
This is an example of steric inhibition of electron availability at the site of reaction.

HYDROGEN BONDING
The covalent bond between a highly electronegative element such as N, 0 , F, etc. , and hydrogen is polar in
which the hydrogen forms the positive end of the dipole.

6- 6+
a- H where Q = N. 0, F. etc.

The specificity of hydrogen attached to an electronegative element is due to the development of proton
character in hydrogen where there is no core electrons {deshielded nucleus). It can therefore strongly attract
a nucleophile (anion or a molecule having an unshared pair of electrons).
An intermolecular attraction between the positively charged hydrogen and the electronegative element
of another molecule results in the association of molecules. Thus, water or alcohol is associated as shown
below:

H-O---------·H-O·········H -.-0---------· R -'0---------·H -0--- ------H -0---------·

\H \H \H \H \R \

1his type of bond (shown by dotted lines) is known as hydrogen bond or proton bond to distinguish it from e
covalent bond. The bond may be ionic or partially covalent.
In a
Since the disruptiV-e forces of thermal agitation act against the attractive force (association) between e
. are
molecules, three m0lecules are associated in water, on an average. The strength of a hydrogen bond is abo
5 kcal/bond which though small is not insignificant. Hydrogen bonding may be intermolecular
intramolecular.
(a) lntennolecular hydrogen bonding causes:
In~
(i) rise in the b.p. or m.P,. which is due to the extra energy required to break the hydrogen bond. . H.:
(ii) increase in the solubility which is due to the salvation of the solute molecules in polar solvents b • Oft
hydrogen bonding. Thus, alcohols, amines, acids, etc., are water soluble. . the
(b) lntramolecular hydrogen bonding causes:
(i) decrease in the solubility in polar solvents due to restricted hydrogen bonding with polar solvents.
thus, the enolate form of ethylacetoacetate is less· soluble in water and more soluble in cyclohexane
 THE BREAKING AND MAKING OF BONDS 21

([Link] like) since intramolecular hydrogen bonding prevents solvation in water.

CH3-C / o, H
II !
He, ~o
c
I
OEt

(ii) decrease in the b.p. or m.p.-intramolecular hydrogen bonding nrevents ·association and so less
energy is required for [Link] m.p. Thus, crhydroxybenzoic acid ha~ lower m.p. than its isomers.

~o't;t m-isomer m.p 201°C

~l0 p-isomerm .p214 °C
cr
I
OH
m.p. 159 °C

(iii) increase in acid- strength by stabilization of the acidic ion by intramolecular hydrogen bonding, thus,
crhydroxybenzoic acid ·is a stronger acid than its isomers.

Hydrogen bonding causes shift in the IA spectra. The position of 0 - H stretching spectra is shifted to
longer wavelengths since lower energy is required to stretch the 0 - H bond which is to some extent already
stretched by hydrogen bonding.

Thus, the 0- H stretching' absorption for alcohol in the vapour phase is 3700 cm-; and for dilute alcohol
1
(i.e., hydrogen-bonded) it is 3300 cm-

THE BREAKING AND MAKING OF BONDS

an
In or~nic reaction the molecules undergoing change are called reactants and the new molecules fonned
. are called products.

Reacants Products

In this reaction a C - H bond and a Cl - Cl bond in the reactants have broken, and a new C - Cl bond and a
H..:.. Cl bond have rormed in the product. Therefore, an qrganic reaction Is a process of breaking and making
of bonds. A reaction is successful if the bonds formeq in the products are stronger than the bonds broken in
· the reactants. There are two posible ways by whict\ a covalent bond can break. When the bond breaks
symmetrically it is called hemolytic cleavage or homolysis and when dissymmetrically it is called [Link]
cleavage or heterolysis.
(;a) Homolytic ~leavage The covalent bond between two elements can
break in such a way that each element
 22 REACTIONS, REARRANGEMENTS AND REAGENTS

retains an electron of the bonding pair, e.g.. p:a __,. P •+·a

The resulting fragments are called free radicals. Both have an unpaired electron (odd electron). Reactions
involving free radicals are called free radical reactions and the mechanism is called free radical mechanism.
(b) Heterolytic cleavage The bonds between two elements can break in another way in which one element
<t> e
retains the bonding pair and the other loses, e.g., p :a -.. P +:a. As one element has lost and the other
has gained an electron, positively and negatively charged ions (1.e., ion pair) are formed. This process of
breaking of bonds is called heterolysis. Since ions are formed, reactions involving heterolytic cleavage are
called ionic reactions. Most organic reactions are ionic. Heterolysis occurs more readily in polar solvents.
These radicals or ions may recombine or attack other species to form covalent bonds.

REACTION INTERMEDIATES
In the process of bond breaking, radicals or ions are formed. These are called reaction intermediates. They
are of extremely short life but they play a very important role in the reaction. Since we are dealing with the
organic compounds, our attention will be focused on the 'carbon fragments' (radicals or ions) of the substrate.

(i) Carbon radical

Carbon radicals are those in which the carbon carries one unpaired electron. They are usually formed on
homolytic cleavage of bonds at high temperature in the gas phase, in non-polar solvents, by ultraviolet light or
by the addition of other radicals. When the bond energy is low, the carbon radicals may be formed
spontaneously or at low temperature, e.g.,
solution

140°C
Et4 Pb 4Ef + Pb
Carbon radicals are neutral but are extremely reactive due to unpaired electron. Hnece a fast chain
reaction occurs on homolytic fission.
Some common reactions are:
(a) Propagation of chain reaction-Abstract an atom from a molecule to produce another free radical for
the propagation of the reaction. ·
.. . . .
Cl + CH4 ~ CH 3 + HCI ; CH3 + Cl : Cl ~ CH3 CI + Cl

(b) Polymerization-Add to multiple bond resulting in polymerization. Vinyl polymerization occurs inthis
method.

(c) Termination of reaction-They may react with each other to stop the reaction.
. .
CH 3 + CH 3 ~ CH 3 - CH 3
3 2
Geometric shape The carbon carrying the odd electron is supposed to be sp - or sp -hybridized.
01
Stability of the carbon radical The stability of the carbon radical increases with the increase in the number
alkyl groups attached to the carbon carrying the odd electron by hyperconjugation.
 THE BREAKING AND MAKING OF BONDS 23

H CH3 H CH3
I •
H
I
CH3
I
I I• H C=C etc.
H-C-C - H-C=C -
I I I I I I
H CH3 H CH3 H CH3

Hence, the stability order of carbon radicals is 3° > 2° > 1° > CH3 . Carbon radicals in suitable unsaturated
systems are more stable than alkyl radicals due to delocalization of the unpaired electron.
.
CH2-CH =CH2 - CH2 =CH -CH2
.
Allytfree radical

O=
Ph • Ph ~h
0{·
Ph
0 6I
Ph
.....-· c
Ph
I
etc.

Triphenytmethyf radical

Hence, allyl and triphenylmethyl radicals are more stable than tertiary carbon radlcals.

(ii) Carbocation•
An Ion in which the carbon carries a positive charge is called carbocation. They·are formed by heterolysis, e.g.,
(a) By the addition of acids to-
(i) Unsaturated compounds.

e
('l
-c==o
I
+ H
(±)
- (±)
-C-OH
I
r"
-C=:Q + AICl3-... -C-O-AICl3
I
(±)
I

-c==c- + H
(±)
~
(±) 7
-C-C- {See footnote)
I I I I

(ii) Compounds containing oxygen atoms.

•• (±) (±) (±) •• (±) ~

R-£H + H ~ R-<;.H2 ~ R + H20; R-0-R + H ~R-0-R + R-OH
(±)
8~F 3 (±) e
..
R-OH + BF3 ~ R-o-H ~ R + BF3-QH
(±)

• A carbocatlon is called primary (1°), secondary (2°) or tertiary {3°) when the carbon bearing the positive charge is
attached to one, two or three alkyl (i.e., carbon) groups respectively. If the charge on the carbon is negative, It is called
1°, 2° or 3° carbanion in similar way.
H R R
I(±)
R-t(±) R-t(±) R-C
I I
H '
H R
{1°) (2 ") (3 ")
 24 REACTIONS, REARRANGEMENTS AND REAGENTS

(iii) Organic halides.

@ @ @
R-X + H :;;=!t: R-XH ;;:::!!& R + XH

(b) By the decomposition of diazonium salts.

[R-~:NJ~ _. ~ N2 + + ~
(c) By ionization.

Reactions of carbocatlons-
(i) Recombine with electron-rich species (electron pair of an ion or molecule).

@ 8 R R' ~ @ R' @ R
R-CH2 + :O-H -
••
R-CH20H ; R-b@+
I
:o\/:
H
- R-c-o( ~ R-t-OR '
R
I H I
R R

(ii) Eliminate a proton to form olefin.

I I I I ~
-c-c- - -C=<;- + H
@~~
(iii) Rearrange to form more stable carbocat1on
@
CH3-y~CH2
H
(10) (2 0)

(iv) Add to alkene to form bigger-earbocation .

R ~RI R R
I f.i:\ r I I I@
R-Cw + CH2=C R-C-CH2-C
I I I I
R R R R

2
Geometric shape The carbocation takes up the more stable s·p configuration with the vacant 2p orbital a
2
right angles to the plane of the sp orbitals.
Stereochemical effect The vacant 2p orbital can be attacked from either side of the plane of the ion by an
electron-rich species. This may result in the formation of both the optical isomers in suitable substrates.

R R,
x-c~R' R'-c-x
'R.' R"/
(0) (l)
 THE BREAKING AND MAKING OF BONDS 25

(iii) tarbanion
An ion In which the cafbon bears the negative charge 19 called a carbon anion or carbanlon. They are formed
6y heterolysis when a group departs ftom a molecule without the bonding pair of electrons.
tirHetiidhs may Be formed by the following methods:
(ii) When a group or afgf'fl departs from a carbon atom without its bonding pair.
n
R ~CH2-H
e
--+ R-OHt
@ n
+ f'I ; R-c(~
ho 6 e
___. R + C02
oe
(b) When a negative ien attacks on a multiple bond

n
-O=C-
~e
+ !X __.,. -C-C-
e~
1 I I I

Reactions of carbanions They Undergo two types of reactions-displacement and addition.

(i) Displacement reaction .

e e
where R =CH (COOR)2 , CH3CO CHCOOR, etc .

(ii) Addition reactions-Add to carbonyl groups and to suitably activated carbon-carbon double bonds.

0 ~ o-..... 0 08
II '?.. .~ II-' 11 I
H-C-CH2 + C-R _____.. H-C-CH2-C-R
I I
H G H
PhCH=CHCOOEt + CH (COOR)2 ~ Ph-CH-CH2COOEI
I
CH (COOR)2

Geometric shape Since in the formation of a carbanion, only an atom or a group departs without the bonding
pair of electrons, the unbonded electron pair continues to remain in the same orbital as in tr.e molecule, i.e.,
the hybridization of the carbanionic carbon is unaltered.
Stabilities of carbanions and carbocations The ionic intermediates are considered as carrying their charges
on a carbon atom. However, the ions to some extent are stabilized by delocalization of the charge on other
carbon atoms or other elements.

Inductive effect and hyperconjugation also stabilize the carbocations by dispersal of the charge. These effects
26 REACTIONS, REARRANGEMENTS ANO REAGENTS

Ql
are additive, hence the stability order of carbocations Is 3° > 2° > 1° > CH3 .

The order is reversed in case of carbanlons due to repulsion between like charges.
As resonance effect ls stronger than other effects, allyl and benzyl carbocations are more stable
than 3° carbocations.
Change in the hybridization of the carbon bearing the charge on going sp ~ sp ~ sp progressive~
2 3

decreases the stability of carbanions. This is due to the greater s charater (50%} in sp orbital and least (25%)
3 3
in sp orbital, I.e., the electrons of sp orbital are more firmly held by the positive nucleus than those of sp
orbital with consequent stability.
e e e
Hence the stability order of alkyl, vinyl and acetyllde carbanions is RC = C > RCH =CH > RCH 2. There
are other transient intermediates such as carbenes, R2C:, chlorocarbenes, :CCl2 , nitrenes RN and arynes.

REAGENTS
Majority of organic reactions are ionic and we will be interested in the reagents for ionic reactions. The
classical rule of physics-like charges repel and unlike charges attract-operates in ionic reactions.
The electronic imbalance (i.e., dipolarity) created in the molecules due to one or the other structural
features or by the approach of the two reactants results in the attraction of oppositely charged species in an
ionic raction. In an ionic reaction, therefore, one reactant donates and the other accepts an electron pair. The
reactant which has greater energy takes the aggressive role in the electron transfer and is called the reagent.
In a reaction between an organic and an inorganic reactants, it is considered that the organic molecule isthe
substrate and the inorganic molecule is the reagent, e.g.,
R - X + NaOH ~ R - OH + NaX
substrate reagent
In a reaction between two organic molecules, it is difficult to specify the reagent and the substrate. Ordinarily,
however, the one with full blown charge is more reactive and may be considered as the [Link],
e
C2 H50 is the reagent in the reaction given below.
e 6l
A - X + C2H50Na ~ C2H50A + NaX
substrate reagent
Broadly, [Link] are of two types. The one which attacks the positive site in the molecule is called
the nucleophile or nucleophilic reagent and the one which attacks the negative site in the molecule is calle
the electrophile or electrophilic reagents.
Electrophilic reagents A species which can accept a pair of electrons (i.e., Lewis acid} is called an
electrophilic (electron-seeking) reagent. Electrophlle seeks an electron-rich (negatively charg~d) site 1n a
molecule for attack. It may be positively charged ion or electron-deficient molecule (molecule having an atom
with sextet). Common electrophiles are:
6l ID 6l 6l e ID e e
(a) Positively charged lons-H, H30, X, N02 , NO, S03 H, C8H5 N2 , R3C, etc.
 ENERGETICS OF REACTIONS 27

(b) Electron-deficient ft10l@dUlel}-BF3 , AIX 3, S03, C02, ICI, SnCl2. FeCl3, etc.
[Link] rnpnts A species which can donate an unshared electron pair (lewis base) is called a
hueleopllilie (fn.1~1ebl9"SHklng) reagent or nucleophile. Nucleophile seeks an electron-deficient site for the
attaek. It may be a Hegatively ghargdd Ion or a molecule having an unshared electron pair. Some common
nueledphlles are:
a ee a e e ee e
(a) Negatively charged lon-H, HO, CN, RO, RS, RC= C. RCOO, NH2, CH(COORh, etc.
(B) eteetren-ri~h molecules-H 20, R - 6 .. H, R - NH 2, NH 3, Ri~. RMgBr, Ali, etc.

ENERGETICS OF REACTIONS
An organie reaetien is a prE>E:ess 6f bgne breaking and bond making. Since a bond is associated with energy,
a eHemical reaction essentiaity involves the energy change of the system. Every system seeks to attain the
state of minimum energy. A chemical reaction attains equilibrium when the energy change in the system is
btiriipl~te. If the products haiJe fmmH lower energy tliaM the rtactants, a large amount of products will be
fottned before the equilibrium is attained. lfl OtHer words, the energy difference between the reactants and
products (usually denoted by 6.H) and the position of eciuHlt;rlum are directly related.
The energies of molecules are depellaent on structural features. It !lome structural feature stabilizes one
molecule over the other, however small, tfie equillt"1urn wlll Shift towards the more stable molecule.

RATE OF REACTION AND TRANSITION STAtE

Wood, paper, etc., when burnt in air are converted into C02, H20, etc., I.e., the organic molecules (cellulose)
react with oxygen and pass to more stable stat@~ (Q0 2 , H20, etc.). Although the energy difference between
the reactants and products is fairly large, yet it Is tafely observed that wood or paper spontaneously burns in
the pr~sence of oxygen.
In most chemical reactions increase in temperature result§ In Increase ln the reaction rate. Frequency
of collision increases with the molecular motion .which in turn increases with temperature. Arrhenius postulated
that even though there is a net gain of energy in a reaction, yet some extra amount of energy has to be
supplied to bring about the reaction. This indicates that without the supply of extra energy, the collision
between the reactants is not stJfficient to result in the products. The extra amount of energy which must be
supplied by collision for a reaction to occur is known as the energy of activation (Eac1) . Eact Is essential for most
re~ctions. It forms the energy barrier between the reactants and the products. It is this er.o,·gy barrier which
protects us from being burnt out in air.
Reasons for re~uirement of the extra amount of energy (E'ac1} for reactions:
(i) The energy gained in the process of bond making (in the intermediates and products) is [Link]
available for bond breaking in the reactants.
(Ii) Reactant particles do not move with the same speed. Those moving slowly bounce apart on collision
without any effect. Those moving fast can bring home the effect (reaction) on collision.
(iii) The reacting particles having enough energy may not react on collision if they are not properly
orientea.
~ '/--
HO: - c - x : -:oH
<?.
.. I .. --
Effective Non-effective
collision collision
 28 REACTIONS, REARRANGEMENTS AND REAGENTS

Moreover, if the Eact• which increases the amplitude of the fundamental vibrations of the particles, results in
stretching the wrong bond, it will not assist the reaction. Thus, in the reaction

A A
',.
A/B-X +Y = A./._ B-Y + X
A '-.
A
t
Pl

only the stretching of B - X bond will aid the reaction. Hence, a probability factor is involved. We can
therefore, define Eact as the minimum amount of energy which must be supplied to surmount the collision a~
the probability factors, For similar types of reactions the collision and the probability factors are nearly the
same. Hence the rate is largely dependent on Eact· Lower the Eact• faster is the reaction and higher the Eaa.
slower is the reaction.
exotherr
endothermi
"8 diagrar
Transition state Therefore.
A chemical reaction is a continuous process. The reactants continuously change their geometry under the In fa
stre~s and strain of the reaction conditions and pass through an optimum state when the effective collisionhas between t~
been achieved. This state in the course of reactions is called the transition state, so called because the hlt it is a\
reactants change from one form to another after this state. The transition state, i.e., the activated complex. 1s determine~

not a real molecule, for partial bonds are formed at the site of reaction. It can be visualized as a complex Kand \H .
molecule with a temporary arrangement of atoms with transient existence and which readily passes into a
more stable arrangement as products. Transition .state Is the most important state in a chemical reaction
Transition state and Eact are interrelated.

The minimum energy necessary to fulfil all the conditions for the formation of the transition state is the
Eac1 of the reaction. Thus, the energy of the transition state is the energy of activation. Higher the energy of the F
transition state, higher is the energy barrier and slower is the rate Of reaction. In a multistage reaction, several
transition states are formed but the one with the highest energy controls the rate of the reaction. More stable
is the transition state, ·tower is its energy and more readily it is formed.
Energy diagram The energy changes of a chemical reaction are depicted by energy diagram which shows the
progress of the reaction along a path of lowest energy to products. The diagram shows the energy changes
'ft\e Eac1'
against the progre'Ss of the reaction. Attention is focused on the starting state, the transition state and the final
Wt
state.
stable P"'
In the beginning the collisior:i between the reacting particles causes their KE. to be used up in increasing product i
their PE until the transition state is formed. As the transition state collapses to form the product, the PE drops the final 1

and is converted to K!= which is given out asheat. The gr~ph starts at the left s~ing the energies of e A
reactants, gradually rises to a maximum, as it proceeds along the reaction coordinate, to show the energ minimun
the transition s~te. The graph. then' drops to indicate the final energies of the products. The highest po1n1
very low
Is less tt
the graph corresponds to the energy of the transition state.

When the products have lower energy than the reactants, the reaction is called exothermic since ener ·
is liberated. The energy difference between the reactants and products is indicated by -t::.H. When
products have higher ,energy than the reactants, the reaction proceeds by absorption of heat and is calle·
endothermic. The .energy difference !s indicated by +l:lH. For such reaction, a high-energy reagent is u e
since it is the em;1gy difference of the system which shifts the equilibrium to one direction.
 ENERGETICS OF REACTIONS 29

Transition state Transition state

t
PE
t
PE +t.H

. . tEact
- --
Progress of reaction - Progress of reaction -
Exothermic reaction Endothermic reaction

In exothermic reaction the Eact may be lower or higher than ~H. In contrast, it cannot be less than 6.H in
endothermic reaction. The endothermic reactions are slower (i.e., difficult) than exothermic reactions. From
the diagram it is clear that q reaction cannot be faster than the rate of formation of the transition state.
Therefore, the rate-determining step is the energy height of transition state, i.e., Eact·
In fact all reactions are in equilibrium. The condition for equilibrium reaction is the energy difference
between the reactants and products. When the reaction is very rapid, the EaC1 can be ignored since it is so low
that it is available from the thermal changes at room temperature. In such case only 6.H is important since it
determines the shift of the equilibrium. The reaction is then equilibrium-controlled. The equilibrium constant
Kand .A,Hare re lated .

t
PE
t
PE
t
PE

Progress - Progress- Progress-

t.H-= 0, K = 1 6H < 0, K > 1 t.H>O, K< 1
Reactants and products Products favoured Reactants favoured
equally present

Ttre Eact 1s important tor slow reactions.

When several products are formed in a reaction , the one formed at the early stage may not be the most
stable product. On prolonging the reaction , t!Je products are brought under equilibrium when the most stable
product predominates. The initially formed product in the fast step is called kinetically controlled product and
the final predominating product is called the equilibrium-controlled product.
A multistage reaction may pass through a number of transition states. In a two-step reaction the
minimum of the curve between the two transition states is the energy valley of an intermediate. If the valley is
very low, the intermediate is stable enough to be isolated. If the energy height of the adjacent transition state
is less than 20 kcal/mol, the intermediate is not isolable at room temperature .

.....................
30 REACTIONS. REARRANGEMENTS AND REAGENTS

Not l6olable
J_
t
PE

Progress-
If the Eact is low, the transition state is formed early ano its geometry will be very nearly that Of the $UbEitrate,
If the transition state is formed late (i.e., the Eact is high), its geometry will be nearly that of the product. Any
factor that assists in the stabilization of the transition state will lower its en~rQy, i.e., lower the Eact and the
reaction rate will be fast.
A catalyst is a substance which provides a reaction path of lower energy than the one in absence at the
catalyst. It increases the reaction rate by lowering the energy of the transition state.
Energy diagrams of some common reactions are given below.
Energy diagram of the reaction which proceeds-
(i) In "two steps, the first step being slowest, e.g., electrophilic addition, base-catalysed nucleophilic addition,
nucleophilic substitution (SN 1), electrophilic aromatic substitution. etc.

t
PE

Progress-
Two transiltlon states
with one intermediate

(ii) In two steps, the second step being slowest. e.g .. acid-catalysed nucleophilic addition.

t
PE

Eact

Progress-

(iii) In one step, e.g., SN2 reaction.

 ENERGETICS OF REACTIONS 31

t
PE

One transition state

with no intermediate

Energy diagram of SN 1 vs SN2-The order of hydrolysis of alkyl halides by SN 1 path is 3° > 2° > 1° and by
SN2 path Is 1° > 2° > 3° Hence . s. 1 vs S"'2 energy diagrams for 1° and 3° halides are:

t
PE t
PE

Progress- Progress-
Lower-energy path sN2 Lower-energy path SN1
for 1° halides for 3° halides

Energy diagram of electrophil1c ~ypst1tution in benzene with (a) activating subst1tuent and (b) deactivating
substituent:

( b)

N02

t
PE
t
PE
P, =@-E

Progress of reaction -
...._~~~~~~~~-~ ~-~'
Progress of reaction - e
Lower-energy path for Lower-energy path for
p-substitutlon (also for o-posltlon) m-substltutlon

~"tfl\Y dlilgr-am of sulphonation Sulphonation unlike other electrophilic aromatic substitution is reversible.
Henee, the carbocation formed on attack of S03 can lose S0 3 to revert tO benzene. Therefore, the energy
barrier heights on either side of the carbocation are nearly the same.
 REACTIONS, REARRANGEMENTS AND REAGENTS

1
PE

Progress of reaction -

Energy diagram of SN 1 vs E1 for 3° halides-The reactivity order of RX Is 3° > 2° ?' 1° for SN 1 and E1. Hence,
the rate depends upon the base concentration and polarity of the solvent. .

PE
t t
PE

Progress of reaction Progress of reaction

Low base cone. Strong base in
in polar solvent nonpolar solvent
Energy diagram of S~ vs E2.
The order of hydrolysis by SN2 path is 1° > 2° > 3° halides and the order of E2 elimination is 3° > 2° > 1°.
Hence, elimination will be less and substitution will be more for 1° RX and the reverse for 3° RX.

t
PE
t
PE

Progressofreaction-- Progress of reaction-

10 Halides 30 Halides

It should be remembered that the energy diagrams do not determine the course of the reactions, insteaQ
they depict the energy paths followed in the reaction.

CLASSIFICATION OF ORGANIC REACTIONS

Organic reactions have been broadly classified into two types on the basis of bond cleavage, e.g.,
(i) free radical reactions (homolytic cleavage) and
(ii) ionic reactions (heterolytic cleavage).
A second type of yet another broad classification is on the basis of the products of the reactions. e.g ..
(a) addition reaction, (b) substitution reaction, (c) elimination reaction and (d) rearrangement.
The above two classifications do not specify the reaction type. A more satisfactory classification has
 CLASSIFICATION OF ORGANIC REACTIQNS 33

been mad~ by subclassification of the latter three types of reactions (a), (b) and (c) on the basis of the
rea~ents involved in the rate-determining step, i.e. , the slowest step. Thus,
1. Addition reactions-(i) Electrophilic (ii) Nucleophilic
2. Substilution reactions-(i) Free radical (ii) Nucleophilic-SN 1, SN2 and SNi (iii) Electrophilic
3. Elimination reactions-E1 and E2
A. Rearrarigements

1. ADDITION REACTIONS
A rea~tiori in w~ich the substrate and the reagent add up to fqrrri a [Link]!pt is called addition reaction. The
reactien gq::ur~ at th~ site of unsaturatipn in a molecule. Thus, compounds having multiple bonds such as

)c=c~ ,-c=c- ~ c=o, -c=N, etc .

. uAEiergG aEiqjtj0n re~ctiQ'l§·

The r~a~tjvity
9f the~e compeunds is due to the more exposed and easily available n electrons to the
~1ectrori-seekj11~ (electrophilic) reaqent.

(i~ ~leqrophilic addition reaction

Thi~ is a ~haracteristiP reaction of unsaturated hydrocarbons, e.g.,

CH2=CH2 + Br2 CC'4 CH2Br-CH2Bl

Ethylene Eth~ene bromide

~~lh th~ rep~t9nts add to form a single prpduc.t.

Mechanism The meoh~mi~m of tr~ reactjon is based on the following observations.
(i} When ethylene is br9minated jn aquegus solution in the wesence of sodium chloride, the product in
addition 'to ethylene dibromlde contains 1-chloro-2-bromoethane.

e e
This indicates that a carbocation formed in the first step is attacked by both Br (from Br2) and Cl (present in
solution) in the second step.
(ii) On bromination trans-2-butene gives meso-dibromide and cis-2-butene gives racemic (DL) modification.
Thi~ indicClt~s addition cf bromine atoms to the n bond from opposite sides of the plane of the ethylene
[Link]~ i.~ .. trans-addition results.
On the pasis of !~e ~bove observations, the following mechanism is suggested: On the approach of the
Jwg reactants th~ Br - Br bonq is polariz~d by the 7t electrons to form a 7t complex which breaks down to form
~ cyclic bromonium ion and the other bromine atom leaves with lh~ bonding pair of electrons in the first step.
In th~ s~cond st~p the bromide ion attacks either of the carbons (originally double-bonded) from the opposite
sid~ tq ~ornp!ete the addition. This results in trans-addition.
 REACTIONS, REARRANGEMENTS AND REAGENTS

(1 )
'·c/ o+ Ii - Slow
II - Br-Br
/c,
(a) I
Br-c-
l
-C-Br
I
Fast

(b I
-C-Br

Br-?---

On the basis of the formation of bromoniurn ion , the formation of mesp-djprom1de from trans-2-butene
and racemic pibromide from cis-2-butene on bromination caA now be explaineg.

,.,,,..,
Br
c ·
H Me
Br+H
Br /I
' c~
/H Me - sr+H
I Me
Me
M eso-dibrom ide
H
"'- ,..........er
c
Me
_ H-f-sr
H-f-sr
Me

~ls Me
'c-H M~ H
9- +Br2 Br C.-
I /I
Me-C
I ""'
Rotation
/c Br - - - - - .
J Me
H<±> Br-C-H
I / (aa)) ~Me / ' H about C- C
1/ ~a bond

'~
Me-C
4~af> ~b fr R~perpic
s:libfOIllig@
c
Me......_~
. p
'H

I
Br

;, reaction is therefore stereoselective. * Evidence tor the formation of intenn~~iate c£lrbocation in the
is provided by the formation of abnormal proquct (14) along with th~ e~pected pr~duct (15.) when
1-butene is treated with ha/ide. The abnormal product is d~e to th~ i~herent ottaracteristics of
71ent of carbocations tor stability.

tion in which only one of a set of stereolsomers is formed predominantly or exclusively is called stereoselective.
 [Link] OF ORGANIC REACTIONS 35

~ @ Rearrangement
M92CH-ctt=CH2 - - • Me2CH-CH-CH3

e 12ndstep
1st step
c20>
~I

M92CH-CH-CH3
I
(15) Cl

~ Ula bromonium ion may be considered as a resonance hybrid of the follqwing ~nonical form5,
i:f:r @fl alternative canonical form of the carbocation.

,@ I
I
Br
'
.....c-c- .,_.... .....c=c
@'
Br
/
._... -c-c
I @/
I
Br
'
=. . c--c,
,
\(±)I
B ,J·
/

The first step pf the reaction is slow due to polarisation of bonds, formation of n complex and bromonium
jon or £albooation. In pontrast, the second -step is fast due to attraction between oppositely charged ions.
~ the slowest step is initiated by electrophile and the overall reaction is addition, the reaction has been
~ssed ~ 'electrophilic addition'.
~of ~ents It is seen that a bromonium ion or a carbocation is formed in the rate-determining step.
nis 199~1 to assume that electron-donating substituents will not only increase the electron density for facile
electrophilic attack but aJ~ aig io §W>lliz~ Y,e carbocation. Thus, the activation energy for the formation of the
carbocation Is lowered so that the reaction becomes fast. The relative rates of addition of some substituted
abnesare:

~. el~qq:-wilt)drawing ~roups will have reverse effect.

~yp~v rJJI~ In case of addition of unsymmetrtcal reagents (e.g., HX) to unsymmetrical alkenes, the
~e rnoi~W (i.e., nucleophile) pf the addendum (reagent) attacks the more highly substituted carbon. This
j§ ~a~ ~~rkpynikQv rule.
TilY§, midmcm qf HBr lP propylene giv~s 2-bromopropan~ (16) ~nd not 1-bromopropane (17).

(±)
e
Br
Me-CH-CH'.\ - Me-CHBr-CH3
~ r 1
(~, (16)

Markovnikov ,µle is explainf:)d OR ttle basis of the stability of the first formed carbocation. Since 2°
~tion 1$ more staQle and hence formed rnore easily than 1~ ~rt>ocation, the product is (16). Thus, when
mc>r• than one qarbocation formation is possible, the most s~I~ of the carbocatio~~ '!Viii determine the
oneotation of th$ Qverall addition. This is seen in the addition of H I to vinyl chloride when ethylidene ·chloride
(11) and not ethylene chloride (19) is obtained.

b
 REACTIONS. REARRANGEMENTS AND REAGENTS
36

© .• © ~
CH3 -CH-?J: - CH 3 -CH=<:! : - CH3 -CHCl2
Resonance stabilized (1 8)

(f) •• ~
CH2-CH2-~!: --=-- CICH2-CH2CI
No resonance-stability (19)

The rate of addition is, however, slower (about 30 times) than with ethane due to the electron-withdrawing
effect of chlorine.
In the presence of peroxide or under cc;>nditjons of radical formation, anti-Markovnikov addition results.
The peroxide breaks dowri to a free radical which generates a bromine-free radical from HBr. The bromine
radical attacks the n electrons producing a 2° radical rather than a 1° radical for reasons of stability.

ft ~ ~ • •
R-c-o:o-c-R-2R-C-O - 2R + 2C02
.
R + H :er - RH + Br
,
Y?lff'. . .
Cl-t3-CH.!..CH2 + B r - CH3-CH-CH2Br(not CH3 -CHBr-CH2)
(2 0) (10)

.
CH3-CH-CH2Br + H:Br - CH3CH2CH2Br + Br
.

Free radical addition of HF, HI or HCI is energetically unfavourable.

Addition to conjugated dienes Co~jugated dienes, e.g., 1, 3-butadiene, undergo electrophilic addition in a
similar stepwise process. However, more than one addition product is formed.
This is due to the preferential formation of a resonance-stablllzed allylic carbocation in the first step in
which the positive charge resides on both C2 and C4 either of which can be attacked by the nucleophile in the
second step to result in 1, 2, and 1, 4-addition products.

Br2 @ (f)
Cti2=CH-CH=CH2 CH2Br-CH-CH=CH2 -cH2Br-CH=Ct1-CH2
-are
e
Br
- CH2Br-CHBr-CH=CH2 + CH2Bt-c.t1=CH-CH2Br
(1 ,2-AqditiPn) (1 ,4-Addition)

The 1, 2-product predominating at lower temperature and 1,4-product predominating at higher temperature.
This may be du~ [Link] of 1, 4-product by hyperconjugatiori,
Additio~ to alkynes Electrophilic addition to alkynes resembles those of alkene~. For example, one molecule
of brom~ne adds first to acetylene in two steps to give trans 1, 2-dibromoethylene and then another molecule
of bromine adds to give 1, 1, 2, 2-tetrabromoethane.
 CLASSIFICATION OF ORGANIC REACTIONS

Br er, "'H Br2

HC::CH --1... C=C ---"-+ Br2CH-CHBr2
H/ 'er

However, alkynes are less reactive than alkenes because the n electrons are more tightly held by the
carbons due to their relative short distance between the carbons (1.20 Afor C C and 1.34 Afor C =C). This =
Is reflected In the hydration of alkynes with sulphuric acid in which the aid of a catalyst (mercuric salt) is
necessary (20).
~g~.e Hge Hge G> H
Hg2$
H6·.:::6H
I I H I
HC::CH - H-C=C-H - H-c-c-H -H-C-CH
(20) \Jr! I II I
H
II
0
\_5>H H 0

Aromatic compounds (e.g., benzene) haven electrons which are tightly held by several nuclei. Aromatic
compounds are therefore much less reactive and undergo a few addition reactions. It is more so because
addition reaction is energetically unprofitable due to loss of resonance energy.

(ii) Nucleophilic addition reaction

We have seen that electron-releasing groups conjugated to carbon-carbon multiple bonds promote
electrophilic addition. In the same way, conjugation of electron-withdrawing groups activate the
carbon-carbon multiple bonds towards nucleophllic addition.

e 1 e e® 1 1
Nu + )c = c( - Nu-c-c( -Nu-c-c-E
I I I

The substituents reduce the n-electron density, thereby aid the attack of the nucleophile and stabilize the
carbanion formed on attack by delocalization of the negative charge (cf Michael reaction). Some common
electron-withdrawing groups are:

0 0 0
II
-C---\H > -C-R
II
> II
-C-OR > -c=N ) -N02, etc.

Polar functional groups, e.g., > C =0, - C = N, > C = N, > C = S, etc., also undergo nucleophilic
addition. The hetero atoms, like the electron-withdrawing substituents, reduce the n-electron density on the
carbonyl carbon and stabilize the anion, formed on attack of the nucleophilic, by accommodating the -ve
charge.
Ct)
e,~ 18e I
Nu+ C-0 -Nu-C-0 --Nu-C-OE
/ ~ I

However, the addition product will be stable enough to be isolated provided the carbonyl group is not
attached to a good leaving group such as OH, OR, Cl, NH 2 , etc. Carboxylic acids and their derivatives,
therefore, undergo substitution rather than addition on attack of nucleophiles.
Nucleophilic ad~ition to carbonyl group is, therefore, a characteristic reaction of aldehydes and ketones
e e e
since H, A and Ar are not good leaving groups. Considering the steric and electronic factors (inductive effect)
of the group attached to the carbonyl carbon, the reactivity of the carbonyl groups decreases in the order:
H2C =0 > RCHO > R2CO > ArCHO > Ar2CO.
 REACTIONS, REARRANGEMENtS AND REAGENTS

H2 C =0 > RCHO :::>- R2 CO > ArCHO > Ar2CO.

(a) Addition to carbonyl group--{i) HCN addition
Mechanism
The carbonyl group may be considered as a resonance hybrid of the following canonical structures:

-c=o ....... -c-o

(±) e
I I
e
The addition of the nucleophile (GN) to the carb0n will be facilitated by adding base to increase the
e e e
concentration of CN, e.g., HCN +OH~ H20 + CN or by adding acid to protohate the oxygen atom so as to
. '\ (±) 'tt)
increase the +ve character of the carbonyl carbon, e.g., .,......c=o + H - / c - o - H . Hence, the reaction is
catalysed by both acids and bases. However, base-catalysed nucleophilic addition reactions are common.
Base-catalysed-The base removes the weakly acidic protons from the reagent to generate the nucleophile
which adds to the carbonyl carbon in the first step. In the second step a fast addition of protons to the
negatively charged oxygen completes the addition.

e
HCN + OH ---+ H20 + CN
e
e Slow
'" c /oe
+ CN
/' CN
- --- -- ---.1 st step

Fast e
+ OH ------ ---2nd step

Acid-catalysed-The acid protonates the negatively charged oxygen atom in the first step. The slow attack of
the reagent to the caroonyl carbon in the second step completes the addition.

Fast
------·----1st step

'-~-OH + HCN Slow., '\.c/OH ----------·2nd step

/ / '-cN

Although acids increase the catinoid character of the carbonyl carbon it reduces the concentration of the
nucleophile, e.g.,
eCN
(±) •• (±) ffi
+ H --+ HCN ; RNH2 + H --+ RN HJ

Hence, highly acidic medium r~tards the reaction. Weak acids which can form hydrogen bond are used. In
practice the carbonyl compound is mixed with sodium cyanide and acid is added to generate HCN. T~e acid
should be insufficient to consume all the sodium cyanide so that the medium remains alkaline.
In both acid- and base-catalysed additions, the nucleophile is added in the slowest step and hence the
 CLASSIFICATION OF ORGANIC REACTIONS 39

reaction Is called nucleophilic addition .

Addition product of carbonyl compound with HCI is not isolable. The equilibrium lies far to the left since
chlorine is a good leaving group.

A number of carbonyl addition reactions follow the same mechanistic pattern of cyanohydrine formation. A few
of these are mentioned.
(ii) Alcohol addition The addition of alcohol to carbonyl group to form hem;acetal is catalysed by both base
and acid but the formation of acetal from hemiacetal is catalysed by acids only.

R\ /OH R, c/OH
R-c=o + R'OH /c.....__
I H/ 'oR'
H H HOR'
@ Hemiacetaf

R'OH R /OR'
'c
H/ 'oR'
Acetal

(iii) Bisulphite addition Aldehydes, methyl ketones or cyclic ketones add with sodium bisulphite in aqueous
medium to form crystalline adducts. The effective nucleophile is SO~ which is a strong nucleophile, and so no
catalyst is required for the addition.

(iv) Carbanion addition A large number of carbanion addition reactions are known. Addition of Grignard
reagent is given for illustration. Grignard reagent may be considered as a carbanion donor due to the polarized
S- S+
carbon-metal bond, R-MgX.
A straight forward reaction is then possible, e.g.,

'-.. () s- s+ '-. •/OMgX HJO@ ' ~ (OH

C=O + R-MgX - C ---. C
/~ / 'R / R

However, addition of MgBr2 (Lewis acid) increases the rate of addition. From this and other evidence (complex
of Mg with the carbonyl oxygen) , it is suggested that one molecule of RMgX complexes with the oxygen to
facilitate the attack of the other molecule to the carbonyl carbon.
 40 REACtlONS, REARRANGEMENTS AND REAGENTS

o+ o- o- o+ ct> o----Mgx
R\
c=o ... 2R-MgX
R•
"c/ le "c
R' OH

R'/
__.
R'/.L !)
R-MgX
-RMgX
R'/ 'R
/

(v) Addition of derivatives of ammonia (Addition-elimination) Derivatives of ammonia .add to the carbonyl
group by donating the free electron pair on nitrogen to the ca~bonyl carbon. Subsequent,a:rigration of a proton
from the nitrogen to the negatively charged oxygen gives a product which on protonation eliminates a
molecule of water. The result is replacement of oxygen and formation of a stable product Thus,
hydroxylamine, hydrazine, phenylhydrazine, semiaarbazide, etc., give respectively oxime, hydrazone,
phenylhydrazone, semicarbazone, etc. The mechanisms of the reaction are generalised as given below.

,,. o en Et) .fo___ ,, 2 Et)

'-11n 7 ? 7(t) ?H .• ~ ~ •• -H20.-H I ••
-C + :N-Q ~ -C-N-Q ~ -C-N--Q ~ .....:....c-N-0 ====~ C=NQ
I I I I I I 1.F1
H H H lH
([Link]=OH, NH2, PhNH, NHCONH2 1 etc.)

Strong nucleophiles (e.g., NH 20H) do not need acid catalysis for the first step but weaker nucleophiles need
acid to aid the attact< on carbon. Acid, however, Is necessary for the dehydration step which is slow with base.
Hence, the reactiortis are subject to general acid catalysis . Strong add, however, reduce the concentration of
. .. e ®
nucleoph1les (QNH 2 + H - ONH 3 )

Therefore, the reaction best proceeds at an optimum pH(:::::: 3-4).

Orientation of addition to carbonyl group- Since the carbon-hetero atom bond is polar, oxygen forming the
negative end of the dipol~ nucleophile is attached to the carbon and electrophile to the oxygen atom.
Stereochemistry of nucleophrlic addition to carbonyl group- The molecule is flat as the carbon is
2
sp -hybridized. Since both the sides are equivalent, the nucleophile is free to approach the earbon from either
side of the plane to produce a racemic mixture.

6 ,0 ,
Nu-c~R' R -c-Nu
'R R/
(+) (-)

When the carbonyl group of ketones has an asymmetric a-carbon, the two sides of the flat carbonyl compound
are no longer equivalent. The bulky oxyg~n atom orients itself so that it is farthest from the largest of the three
groups on the a-carbon.
M 0

s
R

Preferential nucieophilic 1 attack' then occurs from the least crowed side resulting in the formation of unequal
amounts of the diastereomers. This is the basis of Gram's rule for the prediction of the diastereomer that will
be predominantly formed. The formation of unequal amounts of diastereomers when an asymmetric centre is
-
CLASSIFICATION OF ORGANIC REACTIONS 41

created in the presence of another asymmetric centre is known as asymmetric induction.

(b) Addition to activated carbon-carbon double bond Compounds containing carbon-carbon double
bond conjugated with electron-withdrawing substituents undergo nucleophilic addition. Electron-withdrawing
substituents reduce the 1t-electron density to promote nucleophilic attack and stabilize the intermediate
carbanion by delocalization of the -ve charge. Thus, nucleophilic additions are observed in aP-unsaturated
aldehydes, ketones, esters, nitriles, etc. The reactions are often catalysed by base. The base converts the
e
nucleophile (HA) to a stronger nucleophile (A).

(i) R-CH=CH-CO-R I R-CH-CH2-CO-R I

I
NH2
0
C5H5SH II
C5H5S-CH2 -CH2 -C -OCH3
MeONa
M ethyl-~ - phenytmercapto propionate

M ethyl -~- ethoxypro pio nate

Et ON a
(iii) Ph-CH =CH-C02R + HzC (COOR)2 Ph-CH-CH2-C02R
I
CH (COOR)2

(iv) RNH2 + CH2 =CH-CN - RNH -CH2 -CH2 -CN

Mechanism
The mechanism of the nucleophilic addition of HA to the substrate - C =C - Z (where Z =CHO, GOA, COOR,
I I
CONH 2 , CN, N02 , etc.) in the presence of a base is given below:

A A H
HA I f \ (l_.
--c-C=C-OH
I I I
- I
-c-c-c=o
I I
I
I

The nucleophile attacks the ~-carbon. The negative charge in the resulting carbanion is delocalized by the
carbonyl group. Subsequent protonation completes the addition. Protonation occurs chiefly on the oxygen
because it is more negative than the carbon . Therefore, an overall 1, 4-addition occurs, which transforms into
a~-addition product. Considering the steric and electronic factors the electron-withdrawing effect decreases in
the order CHO > COR > COOR > CN > N0 2 , etc.
The most important nucleophilic addition reactions of synthetic importance are cyanoethylation and
Michael reaction.
Cyanoethylation When acrylonitrile is treated with nucleophilic reagent in the presence of a base,
2-cyanoethyl group is attached to the nucleophile. The process is known as cyanoethylation. The nucleophilic
42 REACTIONS, REARRANGEMENTS AND REAGENTS

reagent may be alcohol, phenol, 1° and 2° amines. .'.··:sf al

Base · C2H50-CH2-CH2-CN
C2HsOH + CH2 =CH - CN '·
~-Et ho xypro pio nitrite

e
The nucleophile, C 2H50, attacks the ~carbon. The -ve charge on the resulting anion is stabilized by the-cyano
group. Subsequent abstraction of proton from the solvent completes the reaction.
e0 (l e] ()
C2HsO + CH2=CH-c::N -c2HsO-CH2-CH-C::N . . . - - C2HsO-CH2-CH=C=N
1\ re
e
C2HsOH
C2HsO-CH2-CH2 -CN
-C2H50
Amines function both as nucleophile and base and so no catalyst is required for the reaction.
The utility of the reaction is the introduction of a three-carbon unit with a cyanide group which can be
manipulated for further synthetic applications.
Michael reaction A group of conjugate addition involving carbanion nucleophile is known as Michael
reaction.
0 0
II NaOEt II
( i) -CH =CH -C- + CH2 (COOR)2 -CH-CH2-C-
I
CH (COOR)2

NaOEt
CH3-CH-CH2-C02Et
I
CH2NP2
Ethyt-~-methyf-4-nitrobutyrate

The attacking nucleophile, the enolate anion, is generated by the base NaOEt from a variety of active
methylene compounds such as malonic ester, ethyl acetoacetate, ethyl cyanoacetate, nitroalkanes, etc. The
mechanism of addition follows the general mechanism given earlier.
Since a large number of different substrates and different nucleophiles can be employed, the reaction
has useful synthetic applications.
Addition of C = C vs C = O It is seen that the most common activating group is C = O which we have seen
undergoing nucleophilic addition. When C = C and C = 0 groups are conjugated it is seen that the addition is
usually to C = C. This may be explained on the stabilities of the products formed on addition to these bonds.
The product on addition to C = C has a residual C =0 while the product on addition to C =O has a
residual C = C.
(i) -b-6-b=o (i) additionto c=C
I :1 I I I
-c=c-c=o Nu E

I I I
-c=c-C-OE ( ii) addition to c=O
I
Nu

Since C := 0 is a stronger bond than C = C, the preferential·addition is to C = C.

However, steric hindrance may be an important factor. Thus, PhMgBr adds to C 0 in =
· PhCH =CH -CHO while the addition is to C =C in PhCH = CH - COCMe3 • The inductive effect of Me group
 CLASSIFICATION OF ORGANIC REACTIONS 43

may also be a factor besides steric hindrance.

2. SUBSTITUTION REACTIONS
A reaction in which one group or atom is replaced by another is called a substitution reaction. The incoming
group is bonded to the same carbon to which the leaving group was bonded. Substitution reaction has been
classified according to the nature of the substituents involved. Thus-

I. Free radical substitution • •

A:B + Q ---+ A:Q + B

fl. Nucleophilic substitution A:B

e
+:a --. A:Q +:e
e
(t) (t)
Ill. Electrophilic substitution A:a + Q ---+A:a + B
It will be seen that in all types of substitutions the displaced species belong to the same class as the
attacking species.

I. Free radical substitution

Radical substitution reactions are initiated by radicals in the gas phase or in non-polar solvents. Thus,
methane and chlorine react in the presence of sunlight or heat to give methyl chloride.

Light energy or heat causes homolytic fission of chlorine producing chlorine radicals which attack methane to
form methyl chloride.

cr:ci huor 300°C • •

Cl + Cl -----------( i)

HJC: H + Cl -
. .
R3C + HCI -----------(ii)
• •
HJC + Cl :er - H3C: Cl + Cl -----------(iii)

The mechanism is supported by the factthat no reaction occurs in the dark, and in the presence of tetraethyl
lead (0.02%) the reaction ta~es place at 140°C. Tetraethyl lead decomposes at 140°C to ethyl radical which
produces chlorine radical from chlorine for the propagation of the reaction as given above.

The reaction proceeds by the repetition of steps (ii) and (iii).

When the ratio of methane 1o chlorine is high, methyl chloride is formed predominantly and when
chlorine is in excess all the hydrogens are replaced to give carbon tetrachloride.

II. Nucleophilic substitution

('a) At saturated carbon Nucleophilic substitution reaction involves the rusplacement of a nucleophile by
·another. These reactions have great synthetic importance. A classical exampre is the hydrolysis of alkyl
halides.
e e
HO:+R:X ~ HO:R+:X
 REACTIONS, REARRANGEMENTS ANO REAGENTS

The nucleophile furnishes an electron pair to the carbon from which the leaving group departs with the
more nucteophil
bonding pair of electrons. Investigations by Ingold and co-workers indicate that nucleophilic substitution
S,fl mechanism
reaction can proceed by two different paths which have been designated by Ingold as SN 1 and SN2 depending
(Substitution M
on the nature of the substrate, the nucleophile, the leaving group and the solvent.
concentrations
Mechanism found to be of s
SN 1 mechanism Kinetic studies of the hydrolysis of t-butyl bromide indicate that the rate of the reaction is
proportional to the concentration of the alkyl halide, i.e. , rate oc [R 3CX].
Since the rate of reaction is dependent on one of the reactants, the reaction is a first-order reaction.
Nucleophilic substitution reaction which follows first-order kinetics is designated SN 1 (Substitution Since the rate-c
Nucleophilic Unimolecular).
In the direct di~
e the old C - Br t
As the rate of reaction is independent of [OH], it is interpreted that the halide undergoes slow ionization
e the reaction is
in the first step producing carbocation intermediate. In the second step a rapid attack of OH on the carbocation During tt
completes the hydrolysis.
opposite to brc
t
Me
Slow
Me 0 [Link] nee:
Me-C-Br Me-6(±) + Br -- - --------( i )
I I bond starts st1
Me Me bonded to the
Me G Me HO ... C ... Br. .
t (±) - Fast I
Me-C + OH - Me-C-oH -----------(ii) hydroxide ion
I I C-OH bond i
Me Me

The energy required for the ionization of the halide is supplied by the energy of salvation of the ions. Since a
carbocation is formed in the slowest step, the alkyl halide which can most easily form a stable carbocation will
favour hydrolysis by SN 1 path. Hence, the order of hydrolysis of alkyl halides by S 1 path is:
Allyl, Benzyl > 3° > 2° > 1° > CH3X ([Link] effect and resonance effects)
2
Stereochemistry of SN 1 reaction-Since a carbocation is flat (sp , trigonal planar) with the vacant 2p orbital In [Link]
vertical to the plane bearing the three groups, the attack of the reagent can occur from either side of the plane b1'omide to t-1
with equal probability, i.e., a racemic product should result if the alkyl halide is chiral. decreases the
bromine pro~
R
,, The steric fac
R-c-x
R"/ 0 transition sta
1l-X alkyl halides
R' R' Stereochemi
/ \
HO-C-R R-C-OH seen that th1
'R" R"/
(-) optically acti
(+)
configuration
Inversion of configuration Retention of configuration In this case ,
directions of
configuratior

Pure racemization (50/50 mixture) is rarely observed. This is because the leaving group lies close to th An ele
carbocation shielding the side from the attack till it has sufficiently moved away. Thus, more attack of th in SN2 reacti
reagent occurs from the opposite side to the leaving group. This causes more inversion than retention ° acetone to (
configuration. Stable carbocations have longer life to permit salvation from either side of the plane of the
carbocation resulting in greater proportion of racemization . Greater proportion of inversion is observed wit

• '
I
I \I\
'
I \' I'

I
 CLASSIFICATION OF ORGANIC REACTIONS 45

more nucleophilic solvent due to faster attack from the opposite side to the leaving group.
SN2 mechanism Nucleophilic substitution reactions which follow second-order kinetics is called S~
(Substitution Mlcleophilic Blmolecular) reaction. The rate of a second-order reaction depends upon the
concentrations of both the reactants. Thus, the rate of hydrolysis of methyl bromide with NaOH has been
found to be of second order, i.e.,

0
the rate ex [CH 3 Br][OH].
e
Since the rate-determining step involves both CH 3Br and OH, a collision between the two reactants resulting
e e
in the direct displacement of Br by OH occurs in such a way that while a new C - OH bond is being formed,
the old C - Br bond starts breaking, i.e., the bond formation and the bond breaking are simultaneous. Hence,
the reaction is a concerted one-step reaction without any intermediate.
During the collision an energetic hydroxide ion approaches the methyl bromide molecule from the side
e
opposite to bromine to avoid repulsion, i.e., at 180° to the leaving group-a back-side attack. When the OH is
sufficiently near the electron-deficient carbon of the substrate, it begins to form a bond with it and the C - Br
bond starts stretching. At one stage of the reaction , a state is reached when the OH and Br are partially
bonded to the central carbon and the non-participating groups lying in a plane perpendicular to the line
HO ... C ... Br. This state is called the transition state. In the transition state partial negative charge of the
hydroxide ion is transferred to bromine via the carbon atom. With further approach of hydroxide, a complete
C - OH bond is formed and bromine departs with the bonding pair of electrons.

e
-
H H
\I
H O~C-Br -
6-
H
\ /
H
6-
H 0---- ----C ----- ---·Br - HO-C
H
//H
+
8
:s r
H
I
H
I 'H
Transition state

In the transition state five groups or atoms are bonded to the a-carbon. As we go along the series from methyl
bromide to t-butyl bromide, the increasing crowding of the carbon bearing the bromine atom progressively
decreases the nucleophilic attack. Also, the increasing +I effect along the series makes the carbon bearing the
bromine progressively less positively polarised and consequently less readily attacked by the nucleophile.
The steric factor is, however, more important than the electronic factor. Hence, the E.c1 for the formation of the
transition state will be highest for 3° halides and least for methyl halides. Therefore, the rate of hydrolysis of
alkyl halides by SN2 path is CH 3 X > 1° > 2° > 3°, i.e., reverse of SN 1 path.
Stereochemistry of SN2 reaction-From the course of the direct displacement reaction as shown above, it is
seen that the molecule is turned inside out. A Walden inversion is therefore expected to take place. An
optically active halide on hydrolysis by SN2 path, therefore, should give an alcohol with inversion of
configuration. The change of configuration can be established by observing the directions of optical rotation.
In this case, however, the substrate (bromide) and the product (alcohol) are two different compounds. The
directions of rotation and the configurations of two different compounds are not usually related. Hence, the
configurations of the substrate and the product should be related to arrive at the conclusion.
An elegant method has been suggested (Huges and Ingold) to establish the Inversion of configuration
128
in SN2 reaction. The method involves the conversion of (+)2 lodooctane with potassium radlolodide (K 1) in
a
acetone to (-)2-iodooctane. The reaction was found to be bimolecular (SN2), I.e .• rate oc [C 6H, 3CHICHJ][I•).
 46 REACTIONS, REARRANGEMENTS AND REAGENTS

The exchange of ordinary iodide with the radioactive iodide was accompanied by the loss of optical activity.
This indicates the formation of(- ) isomer from the(+) isomer to result in racemization .

side since
C H C5H13 C5H13
e observed.

1c,--- ---1 -
* 8 s 13 , * s- 1 s- * 1 M + I
1 + Me/ F - 1- 1 ·-- ---- 1-c(H e
(-)
H Me H

( +)

The rate of loss of optical activity (i.e. , racemization) was found to be twice the rate of iodine exchange
(i.e., inversion)-one (+)molecule is inverted and another(+) molecule pairs with it to form a(±) modification. The over<
The above formulated mechanism of SN2 reaction is therefore established. Inversion of configuration is
always indicative of SN2 reaction.
Factors influencing SN 1 and SN2 reactions
(i) Solvent Polar solvents help in the separation and stabilization of unlike charges, i.e., aid ionization. In
SN 1 reaction ionization occurs in the rate-determining step. Hence, polar solvents promote SN 1 reaction. In
SN2 reaction , the charge brought in by the nucleophile is spread over a large part in the transition state. Hence Hence, tt
polar solvents have little effect on the transition state. However, highly polar solvents form strong solvent layer Wh
around the nucleophile. Therefore, extra energy is required to break the solvent layer for the attack. Hence
reaction~
strongly polar solvents slightly slow down the SN2 reaction.
of config1
(ii) Nucleophile In SN 1 reaction , a carbocation is attacked by the nucleophile. Hence, a low concentration of
weak nucleophile is sufficient for SN 1 reaction. A high concentration of strong nucleophile may act as base by
accepting proton from suitable carbocation resulting in the formation ot alkenes. In SN2 reaction, a
high-energy transition state has to be formed. Therefore, a high concentration of strong nucleophile is required
for SN2 reaction.
(iii) Leaving group Less basic groups are better leaving groups because a strong base has a greater
tendency for a backward direction in the reversible reaction HA ~ He + A
9
.
e e e
Strong bases such as OH, OR, R2N, etc., are not good leaving groups. Thus, alcohols are resistant to
substitution in non-acidic medium. In acidic medium. however. the hydroxyl group leaves as H20 which is a
weak base. (b) At ur
©
H
© e
Br bears a
R-OH - R-OH2 - R-Br + H20
substitu1
Increase in the ionic size of the elements of the same group in the periodic table causes decrease in the (i) Hydro
e e 0 e
basicity as the charge to size ratio decreases. The basicity order of the halogens is I < Br < Cl < F. Therefore.
the rate of hydrolysis of the alkyl halides is RI > RBr > RCI by either SN 1 or SN2 path.
SNi mechanism Nucleophilic substitution reaction which follows second-order kinetics and yet with no change
in the configuration of the product is identified as SNi which means SUbstitution [Link] Internal. Thus, the
esterification of chiral alcohols with thionyl chloride results in the retention of the configuration of the product.

Ph Ph
Me ~c -OH SOCl2 Me,\
C-CI + S02 + HCI
(ii) l=orm
H/ H/

The rate of the reaction is found to be dependent on both the reactants, i.e., rate oc [PhCH(Me)OH][SOCI l
Thionyl chloride reacts with alcohol to furnish alkyl chlorosulphite (21) which has the same configuration as (iii) Este
 CLASSIFICATION OF ORGANIC REACTIONS 47

the alcohol. There is evidence to show that the transformation of (21) to product involves an ion pair (22).
The chloride ion is then supplied by the chlorosulphite anion for the attack. The attack occurs from the front
side since the chlorosulphite anion is held from the front side. Hence, no inversion of configuration is
observed.

el J
t
Ph Ph Ph 0 Ph
Me \ -HCI Me~ /o'-s=o e~@ \ Me . . . .\
-C-OH +
/
Socl2 - /c / - /c s==O ~ /C-CI +
H H Cl H ~ H

(21) (22)

The overall reaction may be considered as an internal attack.

Hence, the reaction is designated as SNi to distinguish it from SN2·

When the reaction is carried out in the presence of pyridine, the pyridine hydrochloride formed in the
e
reaction supplies the effective nucleophile, Cl, for a back-side attack as in normal SN2 reaction with inversion
of configuration.

•• <±>
Cs Hs N + HCI __....... Cs Hs N HCI
e
Ph 0 Ph 0 Ph
8 Me,.,\ 11 I II I _....Me 8
Cl + C-0-S-CI -c1 -----c----·O-S-CI -c1-c + S02 + Cl
/ / \ '\.H
H Me H

(b) At unsaturated carbon When a carbon atom multiply bonded to hetero atom (e.g., O , N, S, etc.),
bears a good leaving group such as Cl, OH , OR, NH 2 , etc., nucleophilic attack on the carbon results in
substitution rather than addition. Some examples are given for illustration.
(i) Hydrolysis of acid chloride, acid amide and ester:

e
CH3COOC2Hs + OH __,. CH3COOH + C2HsOH

(ii) Formation of acid amide from acid chloride :

.. ..
CH3COCI + N H3 ___.. CH3CO N H2 + HCI
(iii) Ester from acid:
 REACTIONS, REARRANGEMENTS ANO REAGENTS
48

Mechanism
The general mechanism of the reactions is:

C..
o:/\..,.
llr . (:;)
~--8
:o:
I
0
II
e-
R-C + Nu - R-C-Nu - R-c-Nu + x
I /,I,
x ~ e
Nu==OH , R ~H
.. , N H3, etc.

X=CI , NH2 , OH , OR ;etc

The nucleophilic attack on the unsaturated carbon displaces an electron pair to the oxygen atom in the
transition state. When the electron pair reverts, the leaving group is displaced.
(c) Aromatic nucleophilic substitution- (i) SubstiMion of hydrogen of benzene Nucleophilic substitution
of the hydrogen of benzene is difficult because (a) the 1t-electron cloud will repel the nucleophile and (b) ~
would be difficult for the ring to accommodate the negative charge brought in by the nucleophile. However, the
presence of a strong electron-withdrawing group may overcome the difficulties and nucleophilic substitution
then is possible. Thus, nitrobenzene gives o-nitrophenol on treatment with strong NaOH in the presence of
oxidising agents such as KN03 or K3 Fe(CN)6 •

0
9 9
Since OH is a better leaving group than H , the expulsion of H is aided by oxidation.
(ii) Substitution of groups other than hydrogen Nucleophilic substitution is observed in suitably substituted
aromatic compounds. These reactions may be unimolecular (SN 1) or bimolecular (SN2).

SN 1 type-A common example of aromatic nucleophilic substitution which resembles nucleophilic substitution
at saturated carbon by SN 1 path is the decomposition of diazonium salts in polar medium and formation of
mixed products in the presence of various nucleophiles.

ihe rate of reaction is found to be dependent on the concentration of ArN: only, i.e., the reaction is
unimolecular (SN 1). Hence, it is presumed that in the first slow, rate-determining step, heterolysis of C - N
bond takes place with the formation of nitrogen and aryl cation. This is followed by a fast attack of the
nucleophile in the second step. The aryl cation is very reactive and takes up any nucleophile present, even
recombines with the eliminated N2 • Therefore, the reaction is reversible.
-
CLASSIFICATION OF ORGANIC REACTIONS 49

e
0-oH
Cl
Q-c1
eCN
0-cN
Although aryl cation is very unstable, the driving force for its formation is the elimination of very stable
nitrogen (bond energy of N = N == 226 kcal/mol).
SN2 type-Halogens activated by strong electron-withdrawing groups from o- and p-positions undergo
displacement by bimolecular mechanism .

eOH
o2 N - o - C I

e
The rate of the reaction is proportional to the concentration of both the reactants, i.e., rate oc [ArX][Nu]. The
reaction fails in the absence of the electron-withdrawing group, N02 . Hence, activation of the halogen by the
N02 group is suggested.
The carbon bearing the halogen is electron-deficient due to the electron withdrawal by the N0 2 and Cl
groups. This promotes attack by the nucleophile. The intermediate formed on attack of the nucleophile is
stabilized by delocalization of the negative charge by the N02 group. The intermediate then passes to more
stable product by expulsion of the halogen.

-
Fast

The reaction is not exactly analogous to aliphatic SN2 reaction in the following:
(a) The attack of the nucleophile occurs from the side as the back-side attack is sterically hindered by
the ring.
(b) The carbon bearing the leaving group forms four rather than five bonds as in normal SN2 reaction .
(c) The bond to the attacking nucleophile is first formed and then the bond to the leaving group breaks,
i.e., it is an addition-elimination process.
(d) An intermediate rather than a transition state is formed . Hence, the reaction is designated SN2
(aromatic).
(iii) Substitution of unactivated halogens (Benzyne mechanism) Unactivated halogens in aromatic
compounds undergo indirect nucleophilic displacement in the presence of very strong bases such as
sodamide in liquid ammonia at low temperature (-33°C) or strong NaOH at high temperature (340°C).

e liq. NH3
Cs Hs Cl + NH2 - - - · Cs Hs NH2 + Cl
e
-33 °C

e
It has been observed that NH 2 is able to remove a proton from the benzene ring. It is therefore suggested that

-
.
50 REACTIONS. REARRANGEMENTS AND REAGENTS

0 0
NH2 removes a proton from the ortho position to chlorine. This results in the simultaneous expulsion of Cl and
formation of benzyne• intermediate. Benzyne is exceedingly reactive and reacts with any nucleophile present,
in this case the solvent liquid ammonia, to form an addition product.

NH3 + Cl
e
Benzyne

The reaction is, therefore, an elimination-addition process. The symmetrical benzyne intermediate can
be attacked at either of the carbons forming the triple bond. This is observed in chlorobenzene with labelled
14
carbon ( C) bearing the chlorine.

Thus, p-chlorotoluene on treatment with strong NaOH at 340°C gives a mixture of o- and p-cresols.
This cine-substitution (aromatic nucleophilic substitution at a different position from the leaving group)
supports the formation of benzyne intermediate. Further support of the mechanism comes from the
observation that no reaction takes place when both the ortho positions are substituted.

Ill. Electrophilic (aromatic) substitution

We know that benzene is a resonance hybrid which is a flat ring with a cyclic cloud of negative charge, above
and below the plane of the ring.

Benzene ring therefore discourages nucleophilic attack and encourages electrophilic attack. Alken;s also
encourage electrophilic attack resulting in addition while the electrophilic attack on benzene results in
substitution since addition would involve loss of resonance stabilization of benzene.

* Acetylenic bond in benzyne is unlikely since the ring will be greatly deformed with accompanying strain. It has bee
suggested that the third bond is formed by the overlap of the two sp 2 orbitals vacated by hydrogen and chlorine. T
overlap of the two sp 2 orbitals will be poor and consequently benzyne will be very reactive.

~Cl

~H -
Its existence has been established by trapping experiment and spectroscopy.
 CLASSIFICATION OF ORGANIC REACTIONS 51

© '
.
... +
®
E -
©' .'
E $
+H

Hence, the typical reactions of benzene and its derivations are electrophilic substitution. Aromatic electrophilic
substitution includes a wide variety of reactions, e.g., nitration, sulphonation, halogenation, Friedel-Crafts
reactions, etc. The reaction permits the direct introduction of groups to the ring and their subsequent
transformation to various other products.

H2 S04
ArH + HN03 ArN0 2 + H20

AIC1 3
ArH + Cl 2 ArCI + HCI

S03
ArH + H2S04 ArS0 3H + H20

AICl 3
ArH +RGI ArR -t HCI

Mechanism
The various aromatic electrophilic substitutions follow the same mechanistic pattern which is generalised
below.
The reagent and the catalyst (Lewis acids or proton acids) undergo acid-base reaction to produce the
attacking electrophile which then attacks the ring to form a carbocation (cr complex) in the first slow step. In
the second step the proton from the site of attack is rapidly removed by the base to complete the reaction.

® e
E-Nu + Cal ~ E + Nu- Cal ........( I )

© 0~
® Slow
+ E
.'
a complex

~Ef"e
~ H + Cat-Nu -v
~E
Fast
+ HNu + Cal .......... (ii)

The energy gained in passing from the cr complex to the product (regain of aromaticity) provides the energy
for breaking the strong C - H bond. It may seem that the formation of cr complex would involve high energy.
This is, however, not so because the energy liberated by the formation of a C - E bond and the delocalization
of the positive charge lowers the energy of the cr complex.
The rate of reaction does not involve the breaking of C - H bond. This has been established by isotope
effect." The rates of reactions are the same on replacement of hydrogen by deuterium or tritium. Hence, the

• A difference in reaction rate due to a difference in the isotope present in the substrate is called isotope effect.
52 REACTIONS, REARRANGEMENTS AND REAGENTS

rate of the substitution reaction is determined by the slow attachment of the electrophile to the ring in the first
step. <"·:;
'

Let us now consider some of the individual substitution reactions.

(a) Nitration Nitration of benzene is effected with a mixture of concentrated nitric and sulphuric acids. In the
absence of sulphuric acid the reaction is slow. It is suggested that H2 S04 acts as a strong acid and protonates
e
HN03 to generate nitronium ion, N0 2. This has been confirmed by various methods.

HO-N02 + H2 S04 ~ H20-N02 + AS04

ffi e H2 so4 ffi ffi
H30 + N02 + 2HS04
e

m
Overall reaction is HN03 + 2H 2 so4 ~ No2 + 2Hso4 + H3o.
e ffi
The nitronium ion then attacks the benzene nng to form a carbocation in the first step.

~ @ ~N02 ~N02 ~N02 ~N02

~+ N02 ~VH r=~-H-LLd'H =~-H
e
In the second step, a fast abstraction of hydrogen from the site of attack by the base (HS04 ) completes
the reaction.

~
N02 e
fast
©JN02
••••••
H + HS04 - \••• ) + H2S04

The presence of appreciable amount of water in the acid mixture is not desirable since it reduces the nitronium
ion; hence, the use of concentrated acid mixture.

@ @ HS~
e
N02 + H20 ~ H2N03 H2S04 + HN03

Phenol, which is highly reactive due to the mesomeric effect of the OH group, is nitrated even with dilute
Ql
HN03• A small amount of phenol is oxidized to produce HN02 which with HN03 gives nitrosonium ion, NO.
The latter nitrosates the reactive phenol to yield nitrosophenol which is rapidly oxidized to nitrophenol with
HN03 and nitrous acid is produced by reduction of HN03 . With the progress of the reaction more and more
nitrous acid is produced and the reaction rate is increased.

@ e <t>
HN02 + 2HN03 ~ H3 0 + 2N03 + NO
OH OH OH OH

~O ~····\ ~03
© _.. t @ :

H NO
____.. ()·····.,
\
.... __ .....

NO
:

p-Nltrosophenol
HN03
______,. ()·····.,
t
.. ....... , ..

N02
p-Nilrophenol
: + HN02

(b) Sulphonation Benzene .on heating with concentrated or better with fuming sulphuric acid gives benzene
 CLASSIFICATION OF ORGANIC REACTIONS

>honic acid, C6H5S03H. Sufphonation can also be effected with CfS03 H.

reaction is slow with concentrated H2 S04 but rapid with ofeum or 503 in inert solvent. The electrophile is
which is present in small amount in H2 S04 •

e <±>
2 H2 504 ;;;=::!!!!: 503 + HSO,. + HJO

~lectrophile, 503 , is neutral but has a powerful electrophilic sulphur which attacks the ring .

.!e
03 1
®'S-03
I 1
03e
-e
@· 503~
1te-determining step involves the breaking of C - H bond since deuterated benzene is sulphonated more
· (isotopic effect). The reaction is reversible. On treatment with steam. S03 H group is replaced by
~en. The reversibility of the reaction has practical utility.

logenation Free halogens can attack activated benzene rings but Lewis acid catalyst is required for
ne ring.
It is suggested that probably benzene first forms an complex with the halogen molecule, e.g., Br2 • The
acid (FeBr3) then polarizes the Br - Br bond and helps in the formation of a cr complex between
ne carbon and the electrophilic end of the polarized bromine by removing the incipient bromide ion.
quent abstraction of hydrogen in the second step completes the reaction.

6+ 0-
Br-Br Br--- - Br- - --Fe Br3

~+Br2~
~
~ ~ ~ -~H+FeBr4
~~~Br
(I)
re complex G complex

,--...
H 9
Br + FeBr4 - < Q ) - e r + HBr + FeBr3 ( ii )

The order of reactivity of the halogens is F2 > Cl 2 > Br2 > 12 • Fluorine is too reactive for practical use.
ordinary condition, iodination fails. In the presence of HN03 direct iodination has been effected. The
ing electrophile le is produced by HN03 .
edel-Crafts reaction Alkylation and acylation of aromatic rings with alkyl halides and acid chlorides or
Irides respectively in the presence of Lewis acids, e.g., AICl 3 , Fe8r3, BF 3 , BCl 3 , etc. , is known as
~I-Crafts reaction.

©rCOR RCOCI
AICl3
© RCI
AICl 3
©JR
 54 REACTIONS, REARRANGEMENTS AND REAGENTS

(i) Alkylation-The function of the catalyst is to provide a real or potential carbocation for the electrophilic "!.
attack. When the alkyl group can form a stable carbocation as in case of 3° halides, the attacking species is
the real carbocation which forms an ion pair {23).

HBr + AIBr3

In other cases, a polarized complex with a potential carbocation is the attacking species.

6+ &-
R-CI + AICl 3 ~ R - Cl---AIC1 3

v~6+R-Cl-AICl3-~
T
~R &-
-H

(24)

The intermediates (23) and (24) have been isolated in some cases. It has been observed that the same alkyl
halide gives a rearranged and an unrearranged product with different Lewis acid catalysts.

Rearranged
FeCl3
Cs Hs + Me3C . CH2CI Cs HsCH2 CMe3
Unrearranged

Since AICl 3 is a stronger Lewis acid than FeCl 3 , it is presumed that the complex with AIC1 3 is so strongly
polarized that the alkyl group attains almost a free carbocation character to undergo rearrangement.

ot o- ot o-
Me3C-CH2······-Cl-·····-AICl3 ___.., Me2 C. CH2Me········Cl········AICI:;

The alkylating reagent besides alkyl halides may be aliphatic alcohols, alkenes, ethers, etc., in th
presence of strong proton acids which generate the carbocation for the electrophilic attack.
(ii) Acylation-Acylating reagents are acid chlorides or acid anhydrides in the presence of Lewi~ acid. The
electrophilic species may be (a) acyl cation as an ion pair or (b) a polarized 1 : 1 complex. Probably bot
mechanisms operate depending on conditions.
 CLASSIFICATION OF ORGANIC REACTIONS 55

® e ct> e
(i) RCOCI + AICl3 - R co + AICl4 or R co AICl4
Ion pair

© ' R~O ~c" - ~]°R AICl 4

- ©'co~ HCI ' AJCl3

6+ 6-
( ii) RCOCI + AICl 3 - R-C:.:..:O ···AICl3
I
Cl
1 :1complex

In both cases , one mole of the catalyst remains complexed with the product, ketone . Hence, slightly more than
one mole of Lewis acid is required for acylation. Acylation may be effected with acid anhydrides also. The
~

attacking species in this case may be a free RCO or RCOCI. (For further details see Friedel-Crafts reaction,
Chapter 2.)
Effect of substituents in aromatic rings In planning syntheses based on substitution of mono-substituted
benzenes, it is necessary to have prior knowledge to predict which position of the ring is most likely to be
substituted and how readily the substitution will occur.
It has been observed that the group already present influences the orientation of substitution of the
incoming group and the reactivity of the ring . Mono-substituted benzene on further substitution gives either
m·isomer predominantly or a mixture of er and ,risomers predominantly. Groups (substituents} which induce
faster electrophilic attack than on benzene are called activating and in the reverse case (i.e .• if slower) they
are called deactivating.
On the-Oasis of the above, groups have been divided into two classes, 'A' and 'B'. Thus,
'A' class of groups are o-/p-orienting with activation, e.g., NR 2• NH 2 , OH, OR, NHCOR, OCOR, etc.
Q)

'B' class of groups are m-orienting with deactivation, e.g., N02. CHO, C02H, S03 H, CN, NR 3, CN, CCl 3 , etc.
Let us now consider the electrophilic substitution in C6 H50R which has one 'A' class of groups. Benzene
derivatives containing 'A' class of groups have in common an atom, adjacent to the ring, that has at least one
electron pair. The electronic displacement by +M(mesomeric) effect of these groups increases the overall
electron density of the ring. The electron density is more marked at o- and p-positions than at m-position.

Hence. these groups cause facile (fast reaction) electrophilic substitution at o- and p-positions.
This effect of the group OR on the' rates of attack at o-, Jr and m-positions can be explained on the basis
of the stabilities of the transition states formed on attack at these positions. This, however, is usually not
possible and hence the stabilities of the cr complexes which closely resemble the transition states in energy
and structure will be examined. Thus,
 REACTIONS, REARRANGEMENTS AND REAGENTS
56

(±) theCH3 gro

OR OR OR H OR H

~H
(±)
E
- GI - ®
E
~E - (YE (X1)
o-attack

OR OR @oR OR

®
H
Q- E H
~ E
- 6 - Q®
H
(X2)
E H E
p-attack

This outwei
o-/p-substitl
In cas

ctH ®Ck -
OR OR OR Stabilize the

E
- ::-... H
E
~H (±) E
m-attack

It is seen that the cr complexes formed on attack at o- and p-positions are both stabilized by four
canonical structures relative to three for m-attack. The extra fourth structures (marked X 1 and X2) are specially
stable because all the atoms have complete octet. This factor overshadows the electron-withdrawing inductive
effect of the electronegative oxygen atom. Thus, the unshared pair of electrons on oxygen atom helps in
greater delocalization of the positive charge formed on attack at o- and p-positions. This gives added
resonance stability to the respective carbocations.
As the more stable carbocations are expected to be formed more rapidly, the substitution products are
nearl¥ completely o-/p-isomers.
Substitution in chlorobenzene Chlorine is strongly electronegative. Its electron-withdrawing inductive effect
deactivates the ring at all positions, yet chlorine aids o- and p-substitutions.
On drawing all the possible canonical forms of the cr complexes formed on attack at o-, p- and m-
positions as for C6H50R earlier, it will be seen that the extra fourth canonical forms (a) and (b) (cf X1 and X2
for C6 H50R) for the o- and p-cr complexes are specially stable since all the atoms in each have complete octet
and the delocalization of the positive charge is beyond the ring .
(±)Ci: Sllbstitution

o-attack
H
Q E
p-attack
(a) (b)
Hence, these canonical forms make great contributions t0 the respective hybrids and strongly stabilize them
relative to the cr complex for the meta-attack. Therefore, though C6 H5CI is less reactive than benzene. 11
undergoes o-/p-substitution. Substitution in C6 H5CI is, however, more difficult than in benzene due to overall
deactivation. {To draw the resonance forms of all the cr complexes for C6 H5CI, substitute Cl for OR in the
canonical forms given for C6H50R.)
Substitution in toluene Although there is no unshared pair in CH 3 group, toluenE:: undergoes o-/p-substitut1on
This is due to the +I effect in addition to hyperconjugative effect of the methyl group.
As before let us examine all the resonance forms of the cr complexes. It is seen that one of the
resonance forms in each case of attack at o- and p-positions has a positive charge on a carbon adjacent t
 CLASSIFICATION OF ORGANIC REACTIONS 57

the CH 3 group.

o-attack
6.
p-attack

These forms are specially stable being 3° carbocations. Such form is absent in case of attack at m-position.
This outweighs the stability of the o complexes formed on attack at m-position. Hence toluene undergoes
o-/p-substitution.
In case of phenyl group substituted in benzene, an electron pair of the substituent (phenyl) group may
stabilize the canonical forms of the cr complexes for o- and p-attacks.

H~@
E ~-
-

Hence, biphenyl undergoes faster electrophilic attack than benzene at o- and p-positions. It should be
remembered that the effect of either activating or deactivating groups is reflected at ortho and para positions.
Thus,

6-b-6-a6
B B B B
Activating

©-&-6-i6 Deactivating

Substitution in benzene with 'B' class of substituents All the substituents of 'B' class are strongly
electron-withdrawing due to a positively charged or positively polarized atom adjacent to the ring.

H_ence, these groups overall deactivate the ring by electron withdrawal. The deactivation is more marked at o-
and p-positions than at m-position. This can be seen from the stabilities of the cr complexes formed on attack
at these positions, e.g., in C6 H5 N02 •

eo-®-:;:::;.o
N H

-@ (;I E o·attack

( y1 ) ( High energy )
58 REACTIONS. REARRANGEMENTS ANO REAGENTS

eo,(.±).......,0 e eo, (.1)-;;:::;.o

N,_ 0...._~-;;::::.0

®Cl - Cl:
N

(t H -
E ~
H
E
(.±)
"'-attack

e0 <.t> eo....~~o 8@
'N·::::~O O,N-;;:::;.O

<±>Q-
H E ~ -a)@
H E
( Y2 )(High energy)
H E
p-attack

The canonical forms (Y 1) and (Y2 ) on attack at er and p-positions have each positive charges on adjacent
atoms. These forms are of high energy and do not contribute to the hybrid. Consequently, the delocalization
of the positive charge restricted in two canonical forms of the ring for er/p-attack is less than form-attack rn
which no such destabilizing forms are present. Thus, the N02 group does not aid the attack at any position and
specially discourages the attack at er and p-positions.
The attack at any position in C6H5N02 is therefore slower than in benzene and it is specially slow at
er/p-positions. Hence, C6 H5N02 undergoes m-substitution predominantly.
From the above it is seen that the effect of either activating or deactivating groups is reflected at ortho
and para positions while m-position remains practically unaffected.

3. ELIMINATION REACTIONS
When two groups or atoms from adjacent carbons are eliminated with the formation of unsatura ed
compounds ( alkene or alkyne), the reaction is called elimination reaction. Most commonly a nucleophile (fror
the a-carbon) and a proton from the i>-carbon are eliminated. Hence, the reaction is known as 1, 2· ,.
Ct(3-elimination or simply j)-elimination.

x
(i) -tlS~t~ -HX
I
-c=C- ; (ii) -c=c-
I I I
H

Some familiar elimination reactions are:

(i) Dehydrohalogenation of alkyl halides by base.

(ii) Dehydration of alcohols by acids.

(iii) Hofmann's degradation of quarternary bases by heat.

 CLASSIFICATION OF ORGANIC f3EACTIONS 59

The presence of at least one hydrogen on the ~-carbon is necessary for elimination. The driving forces for
elimination are (a) stability of the olefin formed and (b) the relief from steric strain due to crowding in the
substrate.
Branching at the 13-carbon (as also at the a-carbon) of the substrate produces substituted olefins
stabilized- by hyperconjugation and hence favours elimination. Thus, Me3CCI gives only 16% olefin while
Me2CH - CMe2CI gives 62% olefin.
Strain in the substrate due to crowding by the substituents can be relieved on the formation of olefin
3 2
since the bond angles increase from 109.5° in the substrate (sp -hybridized) to 120° in the product (sp -
hybridized). Hence 3° halides favour elimination most and 1° halides the least, i.e. , the order of elimination in
halides is 3° > 2° > 1°.
The eliminatiqn reactions like SN reactions may proceed by either unimolecular or bimolecular
mechanisms. These elimination reactions have been designated E1 and E2 on their resemblance to SN 1
mechanism and SN2 mechanism respectively.
(a) E1 mechanism The elimination reaction in which the rate of reaction is dependent on the concentration of
the substrate only, i.e., kinetically of the first order, is designated E1 . Since the rate of reaction is independent
of the concentration of the reagent, it is interpreted, as in SN 1, that the first step of the reaction is the slowest
step involving ionization of the substrate. This is followed by the rapid removal of a proton from the ~carbon
by the reagent in the second step. This is illustrated below.
(i) Dehydrohalogenation of alkyl halides-The rate of elimination of a halacid from t-butyl bromide in basic
medium is found to be proportional to [Me3CBr]. Therefore, the halide undergoes slow ionization in the first
step. This is followed by a rapid extraction of a proton from the carbocation by the base or solvent in the
second step.
CH3
I Slow
CH3-C-Br (i)
I
CH3

( ii )

It is seen that a carbocation is formed in the first step in both E1 and SN 1 reactions. Hence, the reagent can
attack the carbon to give substitution product and also can accept a proton to give elimination product. In
practice both alcohol (substitution product) and <.> 1kene (elimination product) are obtained on hydrolysis of
Me3CBr.
 REACTIONS. REARRANGEMENTS AND REAGENTS
60

eOH ( nucleophlle)
Substitution tl12
sin
eOH (base) CH3 '-
fro
st2
'---El-lm....;..ln_a_tlo-n"-- CH ,....c =CH2 tor
3

When more than one alkene can be formed, that alkene will predominate which has larger number of alkyl
groups on the double-bonded carbons-this is Saytzev's rule . This is understandable since the substituted
alkyl groups will stabilize the alkene by hyperconjugation.

CH 3 Cl
I I
CH3-C-C-CH3
I I
H H
Major M inor

(ii) Dehydration of alcohols-Acid-catalysed dehydration of alcohols follows E1 mechanism. The dehydration

is carried out at elevated temperature with sulphuric acid .
Alcohol is first protonated which weakens the C - 0 bond . Hence, water is eliminated from the
protonated alcohol with generation of a carbocation . The latter then expels a proton to form a stable alkene.

H2 so_. @ -H20 @
Me3C(OH) Me3C-OH2 - M93C

Me @
Ir;-..
-H
Me-C~ -
I~
H2C-H

The concentration of acid depends upon how fast the carbocatioi:i- is formed , i.e., on the stability of the
carbocation. Primary alcohols generate unstable carbocations and hence require high temperature and high
concentration of acid while 3° alcohols require lower temperature and lower concentration of acid for
dehydration. Thus,

conc.H2S04
CH3CH2 OH CH2=CH2
11o·c
CH3
20% H2S04 I
( CH3 )3 C (OH) CH3-C:CH2
go•c

E1 reaction is facilitated by
(i) branching at the a.- and p-carbons of the substrate-for stability of the olefin,
(ii) strong polar solvent-to aid ionization,
(iii) low concentration of base-the greater stability of the alkene over the carbocation makes the
extraction of proton easy.
(b) E2 mechanism When the rate of elimination reaction is dependent on both the substrate and the reagent.
i.e., rate oc [subatrate][reagent], the reaction is kinetically of the second order or bimolecular. Such bimolecular
elimination reaction is designated E2 on its similarity with SN2.
 CLASSIFICATION OF ORGANIC REACTIONS 61

Since the reaction Involves both the reactants in the rate-determining step, It Is interpreted as in SN2,
at the reaction occurs In one step in which. both the groups (proton and the leaving group) depart
multaneously through the Intermediate transition state. It is·visuallzed that as the base abstracts a proton
'm the ~carbon, simultaneous departure of the nucleophile takes place from the a-carbon. In the transition
P
ate the C - H and a C - X bonds are stretched on the attack of the reagent with the incipient 7t-bond
\r

1rmation.
GA HO,,
H0 1 •H ''H
'
-c-c-
/ ---. '---c=c/
/ ---x
/ 'x Transition state

ihe energy of the transition state will be least when the two leaving groups, the a- and ~-carbons and the
tttacking base are coplanar in the transition state. Also, the two leaving groups (H and X) should be trans to
~ach other to effect n bond.

The two leaving groups orient themselves in the trans position when a cr bond exists between the a- and
~carbons. When, however, free rotation is not allowed as in the case of double bond, elimination is difficult
when the two leaving groups are cis to each other. Thus, acetylene dicarboxylic acid is more easily formed
from chlorofumaric acid (25) than from chloromaleic acid (26).

Cl, _.....COCH
COOH
I Cl, _....COOH
c -HCI ~I -HCI c
II II
c Fast C Slow c
HOOC,.... 'H I H..... 'cooH
COOH
Leaving groups Leaving groups
trans ( 25) cis (26)

E2 reaction is facilitated by
(i) branching at a- and ~-carbons-since more stable olefin is formed,
(ii) strong base of high concentration-since a strong C - H bond has to break,
(iii) solvent of low polarity-polar solvents form a strong solvent wall around the base restricting the
attack. Hence DMF or DMSO are usually used as solvents.
(c) E1cB mechanism It may be argued that a second-order elimination reaction may as well proceed In two
steps as in E1 reaction. The first step involves a fast and reversible removal of a proton from the ~carbon with
the formation of a carbanion which then loses the leaving group in the second slow rate-determining step.

7 I
-C-C-
8-
+ Et 0
Fast 81
-C-y- + EtOH ----------( i)
I I I Br
Br

8~1 Slow I e
-c-c-
1 nr -c=c-
1
+ Br -····-·---(ii)

The overall rate of this reaction is thus dependent on the concentration of the conjugate base of the
substrate (carbanion). Hence, this mechanism has been designated as E1c8 (Elimination, Unimolecularfrom
conjugate base).
To distinguish between E2 and E1c8 mechanisms, deuterium exchange experiment was performed.
62 REACTIONS, REARRANGEMENTS AND REAGENTS

For this 2-phenylethyl bromide was treated with sodium ethoxide in EtOD. This substrate was selected
because the Ph group is expected to increase the acidity of the 13-hydrogen and also to stabilize the carbanion Elimination in<
to exist long enough for incorporation of deuterium in the starting material from the solvent EtOD. (iii) Nature of ~
decreases s,,

Et<6~H
polar solvent
I Fast 8 EtOD
+ Ph-CH-CH2-Br ~ Ph-CH-CHiBr ~ Ph-CH-CH2-Br~PhCD-CH2Br
9 Et<6 8 aprotic solver

absent. Thus
-
e
PhCD=CH2 + Br
sulphoxide). ·
Styrene (iv) Effect of
energy is rec
The reaction was interrupted before completion and analysed for deuterium content. No deuterium
incorporation was found either in the substrate or in the styrene. Hence, no reversible carbanion was formed. In gen
The reaction followed E2 path. However, the E1 cB mechanism does operate in substrates having strong solvent of /01
electron-withdrawing groups, e.g., chlorine on 13-carbon, and poor leaving groups, e.g., fluorine as in concentratio
Cl 2CH-CF3• Orientation
Elimination vs substitution Elimination reactions are usually accompanied by substitution reactions. When elimination.
the reagent is a good base, it accepts protons to yield elimination products (alkenes) and if it is a good
nucleophile• then it attacks the carbon ta give substitution products.
The proportion of elimination and substitution depends upon the following:
(i) Structure of the substrate-In general, the proportion of elimination increases with increase in the branching
of the carbon chain. In other words, the proportion of elimination increases from 1° ~ 2° - > 3° substrates. The
reason is that a~kenes formed on elimination are stabilized by hyperconjugation. Also the steric strain due to To he
3
crowding in the substrate (sp -hybridized, bond angles 109°) is relieved on the formation of alkene rule and (ii)
2
(sp -hybridized, bond angles 120q) whereas on substitution "the strain is reintroduced. Suitably substituted (i) Saytzev
groups, e.g., C = C and Ph, in the substrate that can stabilize the developing alkene favqur elimination. Thus. predominar
ethyl bromide gives about 1% alkene while 2-phenylethyl bromide gives about 99% styrene. In E1
(ii) Nature of the base-Strong bases promote elimination over ~ubstitution in general, and fn particular E2 elimination
over E1. In low base concentration and in polar solvents SN 1 is favoured over E1. Higher concentration of orientation
base in non-polar solvents favours E2 over S~. Hence, alcoholic KOH favours elimination and aqueous KOH
favours substitution. Strong nucleophiles but weak bases promote substitution over elimination whereas
strong bases but weak nucleophiles promote elimination over substitution.-Though pyridine and R3 N are not
strong bases they are poor nucleophiles because the branching at the nitrogen atom causes steric hindrance
to nucleophilic attack on carbon. Hence, they act as base to accept the more exposed hydrogens of the
substituent groups to afford alkene. A similar steric effect is observed with the size of the base or nucleophile. In suitable
steric reas1
• Nucleophilicity-Any species having an unshared electron pair (whether neutral or negatively charged) may act as
nucleophile. In SN 1 reaction, the nucleophile is not involved in the rate-determining step and so the SN 1 reaction is
independent of the identity of nucleophile. The rates of. S~ reactions are, however, influenced by the strengths of
riucleophiles.
The identity "of nucleophiles may be examined on th~ basis of the following. A negatively charged species is stronger
nucleophile than its conjugated acid, e.g., 0 9 H and ~H~ are stronger nucleophiles than H20 and NH3 respectively The
approximate .order of nucleophilicity is ~H 2 > R09 > 0 H > R2 NH > NH3 > ~ > H20.
Going down the periodic table, nucleophilicity increases with the decreasing basicity of the elements. e.g. 1h
nucleophilicity order of the halides is ,- > Br- > er> F -. This is due to increasing charge to size ratios as we go along
The olefin
the series with progressive increase of the solvent layer by hydrogen bonding in protic solvents. This restncrs
olefinic bo
nucleophilc attack on the substrate.
The order is reversed in aprotic solvents in which the solvent layer is absent. Thus, in DMF or DMSO the thereby lo•
nucleophilicity order is Cr > Br-> 1-. will be inc
 CLASSIFICATION OF ORGANIC REACTIONS 63

Elimination increases with increase in the size of the nucleophile.

(iii) Nature of solvent-For most reactions, increasing solvent polarity increases the rate of SN 1 reactions and
decreases SN2 reactions. Hence, the pathway can be changed with changing polarity of the solvent. A less
polar solvent not only favours bimolecular reactions but also E2 over SN2. Change of hydroxylic solvents to
aprotic solvents increases the base strength as the solvent layer around the base by hydrogen bonding is
e e e
absent. Thus, Cl, OH, OR, etc., are very strong bases in DMF (dimethylformamide) or DMSO (dimethyl
sulphoxide). The use of aprotic solvents may sometimes change the pathway from E1 to E2.
(iv) Effect of temperature- In elimination reaction a strong C - H bond has to break, hence a high-activation
energy is required for elimination reaction rather than for substitution reaction.
In general, the proportion of elimination increases on using a strong base of high concentration and a
solvent of low polarity. On the other hand the proportion of substitution increases by using a weak base of low
concentration and a solvent of high polarity.
Orientation in elimination reactions Substrates having alternative ~-hydrogens give a mixture of olefins on
elimination.

8 H' Br H" 8
Et O I I I EtO
Me-CH=CH-CH3 - Me-CH-CH-CH 2 Me-CH2-CH=CH2
-H' -H"
81% 19%

To help in forecasting the major product of elimination (alkene), there are two empirical rules: (i) Saytzev
rule and (ii) Hofmann rule.
(i} Saytzev rule-The rule states that neutral substrates (alkyl halides, alkyl toluenesulphonates) lead
predominantly to that alkene which is more highly substituted on the carbons of the double bond.
In E1 mechanism the leaving group is gone before the abstraction of proton. Hence the direction of
elimination depends wholly on the relative stabilities of the olefins. Therefore, Saytzev rule governs the
orientation of E1 reaction.

CH3 @ H' CH2-H "@ Me

I -H' I I -H" I
Me-CH=C-CH3 - Me-CH-C-Me ___. Me-CH2-C=CH2
\ @
( 82 % ) ( 17%)

In suitable substrates the rearrangement of the carbocation before elimination may give different alkenes. For
steric reasons the non-Saytzev product may be the major product in suitable substrates.

Me
(a) I o
H Me 8 H Me - < : M e3C-CH2-C =CH2 ( 80 Yo)
I I I I
Me3C-C-C-Br Et 0 Me3C-C-C-CH2 Me
I I I (±} I (b) I
H Me H H M03C-CH=C-CH3 ( 19%)
+ e+ .
(b)\.Et6J(a) (Me candCH3are cis)
3

The olefin obtained through path (b) is minor due to steric hindrance. In E2, it is suggested that the incipient
olefinlc bond formation in the transition state is being stabilized by the inductive effect of the alkyl groups,
thereby lowering the energy of the transition state. Therefore, with the increasing number of alkyl groups there
will be increasing stability of the transition state with progressive lowering of energy of the transition state.
 REACTIONS, REARRANGEMENTS AND REAGENTS
64

e
H·-·Et 0

Me-CH 2 -~H=CH 2 -
! E2
Me-CH2- CH=CH2
: Minor
Br
Stabilization by one
alkyl group

0
H---Et 0
! E2
Me-CH=CH-CH 3 -Me-CH=CH-CH3
l Major
Br
Stabilization by two
alkyl groups

(ii) Hofmann rule-When a quaternary ammonium hydroxide is strongly heated (<125°C) it decomposes to
yield a tertiary amine . water and alkene .
@
M9JN-CH2-CH2-CH30H
e 6
- + M9JN: + CH2=CH-CH3 + H20

This is known as Hofmann elimination or (3-elimination. The reaction involves abstraction of a proton from
(3-carbon with the simultaneous expulsion of the leaving group.

@I 7~e
Me3NjCH2\:'.'CH-CH3 OH Me3N: + CH2=CH-CH3 + H 20

When there are alternative 13-hydrogens in the quaternary ammonium salts, a mixture of alkenes is formed.
Hofmann rule states that in case of alternative (3-hydrogens in the charged substrates (quaternaty
ammonium and sulphonium salts), the least substituted alkene is predominantly formed.
Thus, 2-butylquaternary ammonium hydroxide undergoes Hofmann elimination to give 1-butene as the
major product.
( b) r-.~-
e ;) (a )
f 'oH (a)
7()
CH3 -CH-CH-CH 2
~7 --CCH3CH2-CH=CH2
Major ( 95 % )
"A ~
11
NM93"
A' (b)
@ CH3 -CH =CH -CH 3
Minor (5%)

a>
To explain, it has been suggested that the strong electron-withdrawing effect of Me3 N group makes the
hydrogens of the (3-carbons more acidic for facile abstraction by the base and stabilizes the Incipient
carbanion formation in the transition state on gradual stretching of the f3 C - H bond. In this particular
compound with alternative 13-hydrogens, the 13''-hydrogens are less acidic due to +I effect of the adjacent
methyl group. Hence, W-hydrogen which is relatively more acidic Is removed to give predominantly I-butene.
Hofmann product Increases on Increasing branching In the base. Sterle effect due to crowding In the
leaving group or in the substrate promotes Hofmann ellmlnatlon.
 CLASSIFICATION OF ORGANIC REACTIONS 65

In general the proton acidity and for that matter the inductive effect .is t~e more import~nt fa~tor for
Hofmann elimination. Whatever be the conditions, that alkene is formed in which its double bond 1s coniugated
with Ph or C = C groups, e:g.,

'+'Ml e
\;?;I
8 150 °C
Ph CH2 CH2-N -CH2 -CH3 OH PhCH =CH2 + M e2NEt
~e Styrene(93%)

Hofmann elimination has been very useful in the degradation of nitrogeneous heterocyclics for structure
determination . Thus,

O"··~c. 0
Pyridine
N,N-Dimethylpiperi-
Piperldlne dinium iodide

H~~~
~a
~-~m 3
()
1,4-Pentadlene
+ ~3N

Stereochemistry of E2 Elimination results in n-bond formation. In E2 reaction the p orbitals which develop on
the a- and p-carbons with the departure of the leaving groups should be parallel for maximum overlap. For this
both the leaving groups and the carbons bearing them should be in one plane.
When the two leaving groups are planar there can be two extreme conformations: (a) anti-periplanar
(27), i.e., the two groups are in trans position and (b) syn-periplanar (28) , i.e., the two groups are in cis
position.
The elimination then may proceed as given below.

XR R~HB~'
R I

B~
R~'~
::
R
L
R' --HL

(27) (27a)

B:'°" R

·~
R
R
R'
R' - R
R ~ R'
R'
-HL
-
·~·· R'
(28) (28a)

From the Newman projections of the trans and cis conformations the elimination is expected to be more facile
from the trans conformation (27a) than from the cis conformation (28a) . This is because (i) in (27a) the
attacking base approaches from the farthest side of the leaving group while in (28a) the [Link] from the
same side of the leaving group which causes repulsion, (ii) the developing charge on the p-carbon displaces
the leaving group with its bonding pair from the back side (as in SN2), a path of least energy, and what is most
66 REACTIONS, REARRANGEMENTS AND REAGENTS

important is (iii) the elimination ·occurs tram the lower-energy staggered conformation (27a) than from the
higher-energy eclipsed conformation (28a) .
Hence, the transition state and consequently the pathway for elimination is of lower energy when the
leaving groups are trans (27) than when they are cis (28).
Therefore, most E2 reactions proceed faster when the leaving groups are trans (25) than when they are
cis.(26) . The ~-isomer of hexachlorocyclohexane has all the six chlorines in the equatorial bonds so that they
are all trans to each other and no hydrogen is available in the trans position. The result is that the elimination
of HCI is slower by 7000-24000 times in ~-isomer than in other isomers.

Cl Vii
fOI
Cl
pa
hY
~-isomer
H to
ex
4. MOLECULAR REARRANGEMENTS
be
In most organic reactions the functional group of the substrate undergoes structural change without affecting
bri
the carbon skeleton of the molecule. There are however many other organic reactions in which atoms, groups
(alkyl or aryl), double bonds or functional groups migrate within the molecule. The latter types of reactions are
known as rearrangement reactions or molecular rearrangement. Thus, molecular rearrangement involves K«
modification in the sequence of atoms or groups in a molecule resulting in a new structure. Cc
Migration1of atoms or groups occurs from one atom to another (usually adjacent) within the same SU
molecule by Whitmore 1, 2-shift. (iii
M M to
I I f0 1
A-B-A-8
cti
ca
The atom A is called the migration origin and the atom B is called the migration terminus. The shift of Mfrom thi
A to B is called 1, 2-shift. When M is hydrogen, alkyl or aryl group, it is called 1, 2-hydride shift, 1, 2-afkyl shift
or 1, 2-aryl shift respectively. The migrating group may move with its bonding pair of electrons (anionotropic).
without the bonding pair (cationotropic) or with a single electron (free radical). This means that rearrangement
may take place through intermediates that are cations, anions or free radicals.
A large number of molecular rearrangements involve anionotropic migration of a group to an adjacent
atom with ,incomplete octet (i.e., electron-deficient). The rearrangements involving electron-deficient species Tt
are more common.
•
Rearrangement due to migration to electron-deficient atoms (C, N, O)
During a reaction an electronegative group may depart with its bonding pair of electrons leaving behind an
electron-deficient atom with six electrons. This results in the migration (1, 2-shitt) of a group with its bonding
pair from the adjacent atom to the electron-deficient atom. The migrating group may be hydrogen, carbon.
nitrogen, oxygen, sulphur or halogens.
The migrating group may either (i) detach from the migration origin and then form bond with the
migration terminus (electron-deficient atom) or (ii) may remain partly bonded to both migration origin and
terminus to form a briqged ion intermediate or transition state. The general mechanistic possibilities by 1,
2-shift are given below.
 CLASSIFICATION OF ORGANIC REACTIONS 67

L M M

-c-c- ENu I f N~ -c-c

I I __,,..--c-c---c-c--
I $ I I
I I -Le I I e I I I
M M Nu
Open ion Rearranged Product
open ion
or
L
I I I I
-c-c- -c-c-
\&'
1 I fl'/
M M (29)
Bridged ion

When M is a hetero atom, besides crossover experiments there is stereochemical evidence that (29) is
formed. The nonbonding electrons of the hetero atom are said to be involved in the neighbouring group
participation in forming (29) since the rate of reaction is increased by anchimeric* assistance. Alkyl group or
hydrogen has no non-bonding electrons. It is quite possible that those groups first leave the migration origin
to form open ion and then form the bridged ion because the rearrangements do not show the increased rate
expected from anchimeric assistance.
The corresponding rearrangements with radical and anion intermediates are seldom encountered
because of unfavourable distribution of electrons in the molecular orbital encompassing the three atoms in the
bridged ion. Rearrangements to electron-deficient carbon, nitrogen and oxygen will be separately studied.

Rearrangements to electron-deficient carbon (Carbocation rearrangement)

Carbocation intermediates are generated in the course of various types of reactions, e.g., (i) solvolytic
substitution and elimination reactions (ii) protonation of alcohols, ethers, alkenes, alkynes, etc.,
(iii) decomposition of diazonium salts, etc. If the carbocation generated in a reaction is unstable, it rearranges
to a more stable carbocation by 1,2 shift so that rearrangement is observed in the product. Thus, the driving
force of the rearrangement is the stability of the carbocation which depends on the dispersal of the positive
charge on the carbon. The dispersal of the charge increases with increased substituents on the cationic
carbon by inductive and hyperconjugative effects. Conjugation of cationic carbon with n electrons increases
the stability further. This may reverse the rearrangement, e.g.,

Thus, the stability order of carbocations is:

• When a group with an unshared electron pair and 13 to the leaving group is present, the rate of substitution Is greater than
expected. This is due to neighbouring group participation. The first step is intramolecular nucleophilic substitution by the
neighbouring group forming a bridged ion. In the second step the external nucleophile pushes out the neighbouring
group, i.e., the molecule undergoes two SN2 substitutions, so that the configuration is retained. Thus, the neighbouring
group aids the nucleophilic attack and consequently Increases the rate.

e i_/e a-c-
I
-X
~~/ _v -C-Y
1
I I
 M Nf

1 n ~'n t ~ r arr ng d arbocat1on may unde rgo various sub st1tut1on and elim1na 10
r.:l l r du ts with o r w ithout the change in the carbon skeleton . This is illustrated below
~ • )l"I ~'"'·'"~K'4lt without dlange in the carbo11 skeleton (i) On diazotisation , 1-amino buta e
tl i 1· hlch r rranges to 2-butyl cation (2°). Both 1° and 2° carbocations under
nderg 1b titution nd limination to give alcohol s and alkene.

e cations m dd to the lkene fo rmed to give newer carbocations which may again undergo
reactions. Thus, a plethora of products may be formed .
H20
M eCH2CH2CH20H
e 1-Butanol
x
MeCH2CH2CH2X
@
-H
Rearr8ngement MeCH2CH=CH2

H20
MeCH2CH (OH) CH3
ex 2-Butanol
M eCH2CHXCH3
@
-H
MeCH=CHCH3
+ MeCH2CH=CH2
No change in the carbon skeletons in the products is observed. Since stable carbocations have longer life, the
yields of the products formed through 2° carbocation (2-butyl) are higher than those from the less stable
initiany formed 1° carbocation (1-butyl). This is reflected in the higher percentage yields of 2-butanol over
1-butanol.
(ii) Allylic rearrangement-Another most widely recognized example of this class of rearrangement occurs in
the substitution at the allylic position in which the double bond migrates from one position to an adjacent
position with consequent rearrangement of the carbocation. Thus, solvolysis of 3-chlorobut-1 -ene (30) in
EtOH by SN1 path gives two isomeric ethers, (31) and (31 a) .

Wit~ NaOEt in high concentration . the reaction follows SN2 path with no rearrangement.

e""\V
Et 0 + CH-CH :CH2--. EtO-CH-CH =CH2
I I
Me Me
When, however, the alpha carbon is substituted with bulky groups, direct SN2 displacement with allylic
rearrangement is observed.
 CLASSIFICATION OF ORGANIC REACTIONS 69

er-t ~ 0
EtO + CH2=CH-yHTX .___. EtO-CH2-CH=CHR
R

Bimolecular displacement reaction with allylic rearrangements are designated SN2'.

(b) Carbocation rearrangement with change in the carbon skeleton 0) Hydrocarbon rearrangement-During
the cracking of petroleum hydrocarbons in the presence of Lewis acids, carbocations are generated from
straight-chain hydrocarbons. These carbocations undergo rearrangements to form branched-chain products.
The process has been commercially utilized for producing anti-knock fuels for automobiles.

AIBr3
( i ) CH3 CH2 CH2 CH3 ( CH3 )3 CH
( 20 %) (150oC) ( 80 %)

Another example is the interconversion of methylcyclopentane and cyclohel<ane.

( 12.5 %}
0
( 87.5 %)

In the presence of acids, carbocations generated from alkenes readily undergo rearrangement to form
products with change in the carbon skeleton .

Me
I H
Me-C-CH=CH2 ~Me-C-CH-CH3
+
Me 4'
I W
1 2- h·ft
, S I
Me Me
I I -H
<±>
.. Me-c.,-c-CH3 ---+ /c=.c
Me
\ <
Me

I /.'._ 1 <±>v~ Me Me
Me ~

In the Friedel-Crafts alkylatior:i. the alkyl cations rearrange before attacking.

AICl3 <±> <±> Cs Hs

CH 3 -CH 2 -CH2-CI •CH3 -CH -CH2 - + CH3-CH-CH3 ___. C5 Hs. CH ( CH3 )2

cu
Dienone-phenol conversion involves carbocation rearrangement (see Chapter 2).
(ii) Neopentyt . rearrangement-Hydrolysis of neopentyl bromide (32) under SN 1 conditions gives
2-methyl-butane-2-ol (33) instead of the expected neopentyl alcohol (34) .

Me Me Me
Me-t-CH2 Me ~ 2
H 0 Me-t-CH2 Br v H2 0. Me-h-cH20H
I SN1 I A SN1 I
QH Me Me
( 33) ( 32) ( 34)

Along with (33), 2-methylbutene-2 (36) is also obtained. This is explained due to the rearrangement of the first
formed 1° carbocation to 3° carbocation (35).
70 REACTIONS, REARRANGEMENTS AND REAGENTS

Me
I
Me Me Me H 2 0~ Me-C-CH2 Me
I SN 1 I (±) Rearrg . I ,,....,, (±) I
Me-C-CH 2 Br__.Me-C-CH 2 Me-c-CHM~H OH (33)
1 /. 1• _ 1 <±> ~
Me ~
( 35) Me-9=cH Me ( 36)
Me

Reaction under SN2 conditions is slow due to steric factors. However, (32) forms neopentyl ethyl ether (37) by
SN2 path on treatment with sodium ethoxide without rearrangement.

EtO
e
Me3C-CH2Br S Me3C-CH20Et
N2
(37)

Hence, in the absence of other information rearrangement is often taken as an evidence of SN 1 reaction and
for that matter carbocation formation. However, the phenyl analogue (38) of neopentyl-type bromide does not
rearrange due to the greater stability of the benzyl cation (39) over 3° carbocation .

, . - - - - to products
Rearrangement @ ~e
20 Me2 C-CHPh
( 39)
(30)

-·
(iii) Pinacol-pinacolone rearrangement-Acid-catalysed conversion of 1, 2-diols (e.g., pinacol) to ketones
(e.g., pinacolone) is another example of the rearrangement of carbocation with change in the carbon skeleton.
The rearrangement involves 1, 2-methyl shift.

MeMe @ Me Me ~Me '+' Me Me

I I H I I -H20 ~ ~ I "9 I I
Me-C-C-Me ~Me-C-C-Me ~ Me-C-C-Me-Me-C-C-Me......,Me-C-C-Me
6H bH 6H (bH2 6H @ 6H ~e @gH ~e
\@.../ (40) (41) u-cr:
Me-C-CMe:J
II
0

The 3° carbocation (40) rearranges to (41) due to the extra stabilization conferred by the oxygen atom. (For
further details see Chapter 2).
(iv) Rearrangements of the alicyclic ring systems-Demjanov rearrangement-The rearrangements of the
carbocations generated during the deamination of alicyclic primary amines is known as Demjanov
rearrangement. The rearrangement results in substitution, elimination and ring contraction or expansion.
Thus, cyclobutylamine (42) on treatment with nitrous acid gives a mixture of cyclobutanol (43) and
cyclopropylcarbinol (44), the latter with ring contraction .

CTNH2 HN02 LJOH

HCI
(42) (43)

~$-
 CLASSIFICATION OF ORGANIC REACTIONS 71

If cyclobutyl methylamine (45) is treated with nitrous acid, four products are obtained, viz., cyclobutylcarbinol
(46), cyclopentanol (47), methylene cyclobutene (48) and cyclopentene (49) in which ring expansion is
observed in (47) and (49) .

®
ITCH2NH2 HN02 CTCH2 -~ • CTCH2
L._j HCI
(45) 4B)
\ H 0 C I T C H OH
2 • L___J 2

(46)

-HD
@

-Q(49) OH

2.-H® b
(47)

It will be seen that when the positive charge is on the alicyclic ring, the migration of ring methylene group
causes ring contraction (44). When the positive charge is placed on the carbon a to the alicyclic ring,
expansion of the ring occurs (47) & (49).
By this rearrangement, seven- and eight-membered rings may be prepared.
(v) Wolff rearrangement-This rearrangement does not involve carbocations. It involves rearrangement to
electron-deficient carbon but without any charge on the carbon, i.e., a carbene. Thus, a-diazoketones
rearrange to ketenes with loss of nitrogen in the presence ot solid Ag 20 or on irradiation or heating.
Ag20
RC OCH N2 R -CH =C =O + N2

Ketenes are very reaGtive and react with the nucleophiles present. Thus, the reaction in the presence of water,
alcohols or amines gives acids and their derivatives.
Mechanism The reaction involves migration of the group, A, to the adjacent electron-deficient carbon (but
uncharged) formed on the departure of nitrogen molecule. This has been suggested on the observation that
the isotopically labelled carbonyl carbon of the a-diazoketone is found to be present in the carboxyl carbon of
the resulting acid when the reaction is carried out in the presence of water.

~ ®G ~G~AO
R-C-C=N=N .... R-C-CH\N:N 92
0
II~c H--.o=c =CHR *
* I
H
* -N2 Ketene
11-Diazoketone !H20
o~*
~C-CH2R
HO/

Splitting of nitrogen and migration of A may be concerted. The group A migrates with retention of
configuration if A is chiral. This has been confirmed. (See Chapter 2.)
Stereochemistry of carbocation rearrangements We have seen that the migrating group remains joined to
both the migration origin and the terminus during the migration. This has been confirmed by the crossover
experiments with two similar substrates with different migrating groups in the same reaction mixture when no
 1
72 REACTIONS, REARRANGEMENTS ANO REAGENTS

crossover products were obtained. In case of hydrogen migration, the reaction was conducted in 0 20 or EtOO
but no deuterium was incorporated in the product. The rearrangement Is therefore intramolecular. He~
when the migrating group is chiral, we can expect no change In configuration of the migrating group. ·
There is evidence to indicate that Inversion of configuration occurs at both migration origin and migra&n
terminus. This is explained on the basis of bridged ion intermediate as in the case of trans-addition to alker1e3
through the brominium ion intermediate. {See p. 34)

R*
R''
R' R~R''
- YR''
Nu *
where R is chiral

It was, however, found that the inversion was not 100% and a small amount of mirror-image compound was
obtained. This may be due to rotation about the C - C bond through the open-ion intermediate.

Rearrangements to electron-deficient nitrogen

Similar to the electron-deficient carbons such as carbocation and carbene intermediates, electron-deficient
e
nitrogen species are known in which the nitrogen bears a positive charge, A 2 N: (cf carbocation) or the nitrogen
has an open sextet of electrons, A~: a nitrene (cf. carbene). Hence, as in the case of electron-deficient
carbons, migration of alkyl or ary groups with their bonding pair of electrons takes place to the
electron-deficient nitrogen with consequent rearrangement.
Some well-known examples of rearrangements to electron-deficient nitrogen are Hofmann, Curtius.
Schmidt, Beckmann rearrangements, etc. The general pattern of the rearrangement of this group of reactions
is shown below:

o"e
11, .. . ..
@:c... ~fx--.o=C=N-R
Beckmann rearrangement involves the conversion of ketoximes to amides while the rest involves the
transfonnation of acids info an amine with one carbon less than the starting acid. Thus:

@
OH2
H2 o.. R-6=N Ph

1, NH2 NH2
RCOOEt-----j-.
2 , HNOz ore
lly ··~ CHCl3
@
H3 0
or
R~-~ N=N --""'•..,R-N=C=O
-N2 -CO:z
 CLASSIFICATION OF ORGANIC REACTIONS 73

HQfmann 0 Br O Br 8 8
RCONH2
NaOB r II f 0 H II
R-C-N-H--R-C-N:
I 8 -B r
•
~_flt].
~N:
..
___.., R-N=c=o
( 82 + NaOH) ••

Schmidt

H20
RNH2 + C02

The configuration of the migrating group is retained in all the rearrangements of electron-deficient
nitrogen. This has been confirmed by correlating the configurations of the chiral acid and the resulting chiral
amine in Hofmann rearrangement. Both have the same relative configurations.

( -)-1-P henytmethytamine
( +)-2-Phenytpropionic acid

Rearrangements to electron-deficient oxygen

From the foregoing rearrangements to electron-deficient carbons and nitrogens, it is logical to expect similar
rearrangements to electron-deficient oxygen. Such rearrangements are indeed observed in Baeyer-Villiger
oxidation and hydroperoxide rearrangement.
(i) Baeyer-Villiger oxidation-The reaction involves the oxidation of ketones to esters by reaction with
hydrogen peroxide or peracids

Cyclic ketones are ~onverted to lactones with ring expansion.

Mechanism Acid-catalysed addition of peracid to ketones gives an adduct, peroxide intermediate (50). The
adduct then undergoes loss of carboxylate anion and migration of a group to the electron-deficient oxygen to
give the protonated ester.

(±) OH
0
II oH re o e OH <±) 0
R-C :Q ....!::!.. R -t@ R'C-0-0H R-6-oto-g-R' -R'COO I -H II
R-C-OR ----. R -C-OR
@
R
I I
R -H ~ (50) <±>
Adduct

The key step of the reaction is the heterolytic fission of the 0 - 0 bond of the adduct to generate an
electron-deficient oxygen to which the migration occurs.
Electron-releasing substituents in the migrating group, A, and electron-withdrawing substituents in A'
e
group of the acid promote the reaction. Hence, the loss of R'COO and migration of A is concerted. It has been
found that the labelled oxygen of the ketone is entirely present as the carbonyl oxygen of the ester which
supports the mechanism.
 74 REACTIONS, REARRANGEMENTS AND REAGENTS

180 180
1
fl R C03H II
R-C-R R-C-OR

(Ii) Hydroperoxide rearrangement-A similar rearrangement is obseNed in the acid-catalysed decompoomon

of hydroperoxides. Hydroperoxides are prepared by air oxidation of hydrocarbons or by sulphuric acid indUCl;<j
addition of hydrogen peroxide to double bonds.
Thus, acid-catalysed decomposition of cumene hydroperoxide occurs in the following steps .

Me @ Me ~ Me Me @ M e l.h
I H I ~ -H20 I H20 I H I W
Me-C-0-0H --+Me-C-0 OH 2 - - - Me-C-OPh Me-C-OPh-.. Me-C -OPh
I
Ph
/l.. t
~
4'
\;!;/
-H@
OH
I I
OH
H
@ Me
-H I
"'Me-C + PnoH
II
0

This method is utilized for the industrial preparation of acetone and phenol.

Rearrangements to aromatic nucleus

These rearrangements involve the migration of a group, X, from a substituted hetero atom Z to the activated
positions of the aromatic nucleus. e.g .. ortho and para positions of benzene ring.

~ZH ~ZH
o-z-~ ~x + xfi)
The rearrangements may be classified on the basis of hetero atoms bearing the migrating groups.
(a) Rearrangements of phenol derivatives Claisen and Fries rearrangements are examples of this class of
rearrangements (see Chapter 2).
(i) Claisen rearrangement-The reaction involves the migration of allyl group from oxygen to the ortho
position . When both the ortho positions are substituted . migration occurs at the para position .
•

M•&M• Me*Me
O-CH2 -CH =CH2 ,OH
•
(C='Mc )
A

CH2-CH=CH2
Phenyl ally! ether o-Allylphenol p -All)4-2 ,4-dimeth)4phenol

Studies with labelled carbon indicates end-interchange during ortho migration. During para migration the
end-interchange occurs twice so that there is no rearrangement in the final product.

CH2
0,--- ---'•~CH
/ ' C:. 0
o~---!!i!L_ ~CH2-CH=CH2 -
Aro matliatio n

(TS)

Similar rearrangement is observed in aliphatic allyl ethers.

=ries rearrangement-Phenolic esters on he~ting in the presence of AICl 3 give o- and p-acyl
rrangement involv.e s migration of acyl group from the oxygen to the aromatic ring, i.e., the rea
lation . e 0
~Cl3 ~-CH 3 ~2 OAICl2 OH

v
hOCH3
AICl3 " 0 @ -HCI " 0 COCH3 +
Q Ho
2 ~
&COCH3
I ~
+
~
COCH3

Rearrangement of aniline derivatives A group of rearrangements involves the migration o

·ogen to the aromatic ring on treatment wiith mineral acids. These rearrangements are either i
intermolecular. Thus-
ramolecular rearrangement:

Hydrazobenzene Para migration Benzidin

Ort ho migration

· examples are the conversion of phenylnitramine to o- and p-nitroanilines and phenylsulpha

~nilic acid and orthanilic acid.
101ecular rearrangement:

©CINCOCH3

HCI.,
©
HNCOCH3

+Cl2 __.. &Cl+ ¢

NHCOCH3 NHCOCH3

Cl
n-chloroacetanlllde o- and p-chloroacetanllldM

=imp/es of intermolecula r rearrangements are the conversion of

Diazoaminobenzene to p-aminoazobenzene
V-methyl-N-nitrosoaniline to p-nitroso-N-methylaniline
 Chapter 2

Reactions and Rearrangements

Introduction
There are quite a large number of organic reactions and molecular rearrangements which are of wide
synthetic importance and application and hence are associated with the names of their discoverers.
These reactions illustrate the applications of the various types of basic organic reactions, e.g., addition,
substitution, elimination, rearrangement, etc., given in Chapter 1.
By the dext_erous application of these named reactions and rearrangements, it has been possible to
produce useful materials for civil and military use-medicines, fuels, lubricants, paints, fabrics, polymers,
building materials, explosives, etc.
Some of these reactions are of such great importance for their varied and useful applications that their
discoverers have been awarded Nobel prizes.
There exist a number of excellent treatises on the organic reactions and their mechanisms written by
eminent authors. Many of those, however, are very wide in their coverage and cite detailed evidence in
support of the accepted mechanisms. In the present treatise which is mainly intended for graduate course
students, accepted mechanisms have been taken for granted without going too deep in the logic as to how the
mechanisms were arrived at.

76
 ACYLOIN CONDENSATION n

ACYLOIN CONDENSATION
When carboxylic acid esters are refluxed with metallic sodium in aprotic solvents such as ether, benzene,
toluene or xylene . free from oxygen , a-hydroxy ketones called acyloins are formed . This is called acyloin
condensation .
0
2R -C-OC2Hs Na, Xylene R-C=O 2Na R-C-ONa R-C=O
I II I
or toluene, t::. R-C=O R-C-ONa R-C-OH
I
H
Acyloin

The yield of acyloin is good when R =alkyl group. With diesters, cyclic acyloins have been prepared.
Mechanism
The mechanism of the condensation is not clearly known but it is suggested that the reaction proceeds
through a diketone intermediate, since diketone has been isolated in small amounts as a side product.
As the reaction occurs in the presence of metallic sodium, a direct transfer of electron, i.e., a radical
mechanism is suggested.
The metallic sodium donates its electron to the carbonyl carbon to give (I) which subsequently dimerizes
to yield (II). Loss of both the alkoxy groups from (II) produc~s 1, 2-diketone (Ill) . Further reduction gives
sodium salt of enedlol (IV) . Finally, addition of acid yields 1, 2-diol which tautomerizes to the stable
acyloin (V).

R-c=o
I
OC2 Hs
+ 2Na• - - + °t•
9@
R-C-ONa
I
OC2H5
- R-C=O
I
R-C=O
R-~-ONa

~II
. R-C-ONa

(I} (Ill) (IV)

0..
R-C-OH

II):: -
R-C-OH
._ - R-c::o
I
Ri-C-OH
I
H
N)

Small traces of oxygen reduce the yield. Hence the reaction is carried out in an atmosphere of
oxygen-free nitrogen.

Applications
The condensation has considerable preparative value.
1. Preparation of cyclic acyloins The condensation has been employed with great success for the
preparation 6t cyclic acyloins. Long-chain dicarboxylic esters have been converted to large-ring compounds
without high dilution technique. The method is the best for closing rings of ten members or more.
 78 REACTIONS. REARRANGEMENTS AND REAGENTS

f°"c=o
(CH2)n ) • where n = 10 to 20 or more
~CHOH

The yields are as hrgh as 60- 95% for 1O to 20 membered rings.

To account for the ready formation of large rings, it is suggested that the two ends of the ester are
adsorbed, albeit weakly, to nearby sites on the surface of the sodium metal. Thus, the reactive ends are not
available for intermolecular coupling to compete with cyclisation.

I (CH2~--, H@ I (CH2~ I
2RONa I I
RO-C C-OR - - - - cI cI - - · o=c CHOH
"• "•
0
. .
0 ON a ON a

I: NaNa
. :. : • Na:
Na •1
Sodium surface

2. Preparation of catenane An interesting and unique compound called catenane, a compound with
·interlocking rings, was formed when acyloin condensation was employed for ring closure with ester of
34-carbon dicarboxylic acid.

(CH2)
I COOCH3
Na C~C=O
l (CH2)32 32 } +
f°"c=o
(CH2)32 I
32
HO-CH CH-OH ~CHOH
LCOOCH3

(Less than 1-2%) Acyloin

Catenane

The compound has a great prospect as polymer. Unfortunately, the amount formed is very low. It is, in
fact, a chance product depending upon the possibility of threading of diester molecule through the acyloin ring
before it closed.

ALDOL CONDENSATION
Aldehydes having a-hydrogen(s) undergo self-condensation on warming with dilute or mild base to give
fl-hydroxy aldehydes, called aldols (aldehyde + [Link]). This reaction is known as aldol condensation.
A typical example is the reaction of acetaldehyde with base under mild condition.
eOH
CH3CH(OH)CH2 CHO
Acetaldol

Various basic reagents such as dilute sodium hydroxide, aqueous alkali carbonate, alkali metal alkoxides,
etc., may be used. The reaction is not favourable for ketones.
Aldol condensation has broad scope. It can occur between
 ALOOL CONDENSATION 79

(i) two identical or different aldehydes,

(ii) two identical or different ketones and
(iii) an aldehyde and a ketone.
When the condensation is between two different carbonyl compounds, it is called crossed aldol condensation.

Mechanism
The first step involves the formation of a resonance-stabilized enolate anion by the removal of an a-hydrogen
from the aldehyde by the base. In the second step the enolate anion attacks the carbonyl carbon of the second
molecule of the aldehyde to form an alkoxide ion. The latter then takes up a proton from the solvent to yield
aldol in the third step.

e
e ~o - e ~o /0
OH+ H_._CH2~c, - H20 + CH2-G._. .__. CH2=c,
H H H
e
0 H2 o OH
I I
CH3 -9-cH2CHO =e=~ CH3-9-cH2CHO
H -OH H

Thus. the overall reaction is an addition of enolate anion to the carbonyl double bond. [Recall that Michael
reaction involves addition to an activated carbon-carbon double bond.]
Usually aldol as such is not isolated. e.g .. acetaldol is isolated as a cyclic hemiacetal..

/Cf=t2-CH-OH
-cH3-CH "'-o
"-o-c~ I
CH3
Cyclic hemiacetal

Aldol is isolated under reasonable mild condition, i.e., using aqueous K2C03 as base.
The reaction between two ketones is not very successful. The equilibrium is not favourable and lies far to the
left
e
- OH
2CH3COCH3 - - CH3-C(OH)-CH2-CO-CH3
I
CH3

This is because the carbonyl carbon of ketone is less positive (due to +I effect) and more sterically hindered
relative to aldehydes. This reduces the nucleophilic attack on the carbonyl carbon. However. it is possible to
prepare diacetone alcohol in reasonable good yield by boiling acetone with solid Ba(OH)2 in a specially
devised apparatus.

~Jient features of aldol condensation

(a) AJdots are easily dehydrated to a , ~-unsaturated compounds on heating alone or with acid or base.
IO REACTIONS. REARRANGEMENTS AND REAGENTS

Cf> e
HorOH
CH3 -CH (OH)-CH2CHO CH3-CH=CH-CHO
A
JS-Hydroxy butyraidehyde Crotonaldehyde
Cf> e
HorOH
(CH3)2C(OH)CH2COCH3 (CH3)2C =SH -CO-CH3
A
Di:acetone ak:ohoC Mesityl oxide

(b} When aJdol condensation is carried out in the presence of strong alkali, repeated condensation and
dehydration results in the formation of resins.

CH3 -CH =CH-CHO CH3 -CH =CH-CH =CH-CHO--• Resin

{c) The condensation is promoted by~ effect and reduced by +I effect on the carbonyl carbon.
(d) The reaction equiribrium is favourable for aldehydes but much less favourable for ketones.

Crossed aldol condensation

When the condensation is between two cflfferent carbonyl compounds, it is caJled crossed aldol condensation.
(i) Crossed aldol condensation between two different aldehydes When both the aldehydes have
a-hydrogen(s) ooth can form carbanions and also can act as carbanion acceptors. Hence a mixture of four
products are formed which has little synthetic use. If one of the aldehydes has no a-hydrogen then it can act
only as a carbaruon acceptor. In such case two products are formed, e.g.,

e
(a) R3C-CHO + CH3CHO ...Q!!... RJC-CH(OH)-CH2-CHO
Crossed product
e
OH
(b) CH3CHO + CH3CHO _ . . . CH3CH(OH)CH2CHO
Simple product (nonnal)

.ltrlMff:l!Ver, a good yield of the crossed product is obtained by slowly adding the aldehyde having a-hydrogen
a mixture of the aldehyde having no a-hydrogen and the catalyst. e.g ..

~~ + OH
e CH3CHO CsHs·CH =CH-CHO
Cinnamaldelyde

FonnaJdehyde havtng no a-hydrogen is a reactive carbanion acceptor due to the absence of steric hindrance
and +I effect Hence. when acetaJdehyde is treated with excess of formaldehyde in the presence of
Ca(OH)21 crossed aldol condensation continues (three times) until trihydroxymethyl acetaldehyde,
(HOCHmCCHO (I) is formed. The latter having no a-hydrogen undergo_es crossed Cannizzaro reaction to
form peotaerythritol.
 ALDOL CONDENSATION
81

e e
CH3CHO +OH ::::;;;:::=~ CH2 CHO + H20
e
[Link]"h e
H-c•+ CH2CH0 =~ H c-o
Ho
2 1) OH 2)CH 20 3) H2o 9H20H
2 • H2C - O H - - - - - - - - HOH2C-C-CHO
I I
H CH2CHO CH 2CHO (Twice) CH 20H
(I)
CHzOH
I OH
0 yH20H e
HOH2C-C-CHO + CH20 - - - - - - - . HOH2C-C-CH20H + HCOO
' Crossed Cannizzaro I

CH20H reaction CH20H

Pentaerylhritol

(ii) Crossed aldol condensation between two different ketones Due to poor reactivity of carbonyl carbons (+I
effect and crowding) of ketones, a poor yield is obtained and so it is rarely attempted.
(iii) Crossed aldol condensation between an aldehyde and a ketone (a) When an aldehyde and a ketone both
having ex-hydrogens are condensed, two products are obtained. This is because ketones are poor carbanion
acceptors and so cannot undergo self-condensation. Aldehydes being more reactive than ketones act as
carbanion acceptors and the ketones provide the carbanions.

e
OH
CH3CHO + CH3COCH3 ~ CH3 -CH(OH)-CH2-COCH3
4-Hydroxypentan-2-one(crossed product)
e
OH
CH3CHO + CH3CHO ~ CH3-CH(OH)-CH2-CHO
Acetaldol (normal product}

Usually, the crossed product is the predominant product. The formation of acetaldol can be minimized by
slowly adding the aldehyde to the mixture of ketone and the catalyst base.
(b) When the addition is between a ketone and an aldehyde with no a-hydrogen, only one product is
obtained. This is because the ketones are less reactive and cannot undergo self-condensation and the
aldehyde does not undergo Cannizaro reaction which is slower than aldol condensation. Hence the ketone
provides the carbanion and the aldehyde acts as the carbanion acceptor. Thus,

e
-OH
C5H5-CH=CH-CO-CH3
Benzylideneacetone
e
OH
(ii) CsHsCHO + CH3COC5H5 - - · CsH5-CH =CH-CO-C5H5
Benzylideneacetophenone
e
OH
(ill) CH3COCH3 + HCHO CH3-CO-CH2-CH20H
4-Hydroxybutanone-2

ihe reaction (iii) is difficult to stop at this stage and proceeds further till all the hydrogens of the ketone have
 82 REACTIONS, REARRANGEMENTS AND REAGENTS

been replaced by hydroxymethyl group to give (HOCH2 )JC-CO-C(CH2 0Hh.

Dehydration of aldols
Aldols can be easily dehydrated to a , P-unsaturated compounds in the acidic or basic medium and sometimes
on simple heating.

Acid-catalysed: @
@
OH
I
H
I H
_,.. ~H 2 ~ -H20
CH;r-C -C-CHO CH3 -~ --9-cHO @ " CH3 -CH =CH-CHO
I I
H H H~H -H

Base-catalysed:
OH H
I I OH
9
\..9H~
CH3-C-C-CHO ---+ CH3 -C-CH-CHO - - • CH3-CH =CH-CHO
.2H
H H -H20 H
I

Applications
Several synthetic preparations are based on simple and crossed afdol condensations. Saturated and
unsaturated aldehydes, ketones and alcohols of synthetic importance may be prepared.

e
OH .6 H2/Ni
(i)2CH3CHO _ _ . CH3CH(OH)CH2CHO ---+ CH3CH=CHCHO ___. CH3CH2CH2CH 2 0H
-H20 Crotonaldehyde n-Butanot
e
(ii) 2 C3H.,CH20H
2~~·c 2C3H.,CHO OH

C3H.,CHiCH(C2Hs)CH20H
2-Ethythexanol-1

(iii) The intermediate P-ionone required for the synthesis of vitamin A is prepared by the condensation of citral
with acetone and subsequent treatment with born trifluoride.

a
0
II
CH~ ,.,c, BF3
CH CH3 ~
AcOH
Citral 'lf·lonone P-lonone

(iv) Aldol condensation is also effected in the presence of acid. Acetone with dry hydrochloric acid gas slowly
gives mesityl oxide and phorone.
Ory HCI gas C~COCH3
2CH3COCH3 (CH3)2C=CHCOCH3 HCI gas (CH3)iC:CH-CO-CH:C(CH 3)2
Mesityl oxide Photone

Mesitylene is obtained on distilling acetone with sulphuric acid.

(v) Aldol condensation of glycolaldehyde gives monosaccharides.
 ALL YLIC REARRANGEMENT

Na OH
3CH20HCHO - - - CaH120a
Glycol aldehyde formose

(vi) Pyridine and quinoline having methyl groups at pos1t1ons - 2 and - 4 undergo aldol type of condr;n ation
with aldehydes. The process forms the basis for the preparation of an important class of dye . e.g., cyarnne
dyes (photographic sensitisers).

G.J_CH
N 3
Plperidine
G.J_CH=CH-o-~
N9 -
NR2
18 I -
Me1 Mel
a·Picoline ~-Dlalkylam i no Cyanine dye
methiodide benzaldehyde

(vii) A number of compounds which have acidic C- H bonds undergo aldoHype condensation with aldehyde
and ketones to produce valuable synthetic intermediates.
Thus, condensation of acetylene with aldehydes or ketones gives acetylenic alcohol , a valuable
commercial product.
Cu2C2
2CH20 + HC =cH HOH2C -c =c-CH20H
2-Butyne-1, 4-diol.

The process is known as ethynylation.

Pentaerythritol (see above) is a valuable chemical. It is a medicine for heart trouble . Its nitroderivative .
penterythritol tetra nitrate (PENT) is a valuable explosive. It is also used as a surface-coating agent. Reactions
closely related to aldol condensation are: Perkin, Claisen , Knoevenagel, Dieckmann, Doebner, etc.

ALLYLIC REARRANGEMENT
Allylic compounds are those which have a functional group on a carbon atom a to an olefinic bond, e.g.,
I I
-c=c-c-x
I I

The double bond (and the functional group) in these compounds undergo acid- or base-catalyzed
migration to form a new compound .

I I
®
H or OH
e I I I
R-C=C-C-OH - - - - • R -C-C :c-
l I OH
Examples:
@
CH3
I H
(a) CH2 =CH -C -OH - - •
I
CH3
2-Methyl-3-butenol-2 3-Methyl-2-butenol-1
 ALLYLIC REARRANGEMENT 85

Generally the SN2 reaction is much faster than the SN2' reaction.
However, the SN2' reaction may proceed concurrently with SN2 or even to the exclusion of SN2 wben the
ex-carbon is crowded with substituents. The crowding in the a-carbon restricts the direct approach of the
nucleophile to the a-carbon so that SN2' reaction becomes significant.
Thus, a-chloroallyl chloride with sodium ethoxide in ethanol gives a normal SN2 product and a
rearranged SN2' product as well.

Cl ,.-... SN2
(I) CH 2 =CH-CH ~Cl ~ CH 2 =cH·-cH(OEt)CI (Normal SN2 product)
C~oe a-Ethoxyallyl chloride 30 %

~i) EtO
e~ n9 1 \Cl
+ CH =CH-CH ~s2·
N ... Et0-CH 2 -CH :CHCI (Rearranged SN2' product)
2
1-Chloro-3-ethoxypropene-1 60%

With highly substituted a-carbon, the SN2 attack is completely inhibited and only the rearranged product is
obtained (SN2').

<t> e
(a) (CH3)3DcH2QCHc; - I
(CH3)JN-CH2-CH =CHCH3 + Cl
CH3
Cl
I
(b) CsHsSNa + CH2=CH-C(CH3)2 _ _ . C5H5S-CH2-CH=C(CH3)2 +NaCl

(c) c6 H 5
'"-:'5c2H5
O ___.

The SN2' reaction is stereospecific. The nucleophile [Link] from the same side of the molecule as the
leaving group producing the same stereoisomer.

~~(£
rrL-0
:Nu trans
Nu
trans
+x
e

SNi type. Asuitably substituted allyl alcohol on treatmen~ with SOCl2 gives two halides.

CH3 -CH -CH :CH2

I -HCl,-S~
OH
Crotyl chloride
a-Methylallyl alcohol a-Methylallyl chloride
(1°hallde)
(2°alcohol) (2°halide)
 86 REACTIONS, REARRANGEMENTS AND REAGENTS

The formation of 2° halide with retention of configuration indicates a normal SNi reaction. The formation of 10
halide can be explained on the basis of the internal attack of Cl on the y-carbon with consequent shift of the
double bond.

SOCl2
CH3CH(OH)-CH=CH2 -HCI

Since the reaction is analogous to SNi, but the attack occurring at the y-carbon instead of the ex-carbon, the
reaction has been designated SNi',

Application
Allylic rearrangement has been utilized in the course of synthesis of many natural products such as terpenes
(citral, cx-irone), diterpenes (phytol),sesquiterpenes (farnesol), vitamin A, etc.

ARNDT-EISTERT REACTION
The reaction consists in increasing the length of the carbon chain by one methylene group in carboxylic acids.

The reaction involves the following steps:

The acid is first converted to acid chloride which reacts with excess of diazomethane to form diazoketone. The
latter on irradiation with light or h~ating with Ag 20 in the presence of water splits off nitrogen and rearranges
to ketene (this rearrangemen of diazoketone to ketene is known as Wolff rearrangement). The ketene then
reacts with water to form a higher homologue of the starting acid.

RCOOH _s_oc_r_
2• 2 __2_N__
RCOCI - -C_H 2_ RCOCHN2 Ag 20 R-CH=C=O
-CH3Cl,-N2

Excess of d1azomethane is used to consume the liberated hydrochloric acid .

RCOCI + CH2N2 ~ RCOCHN2 + HCI

CH2N2 + HCI ~ CH3CI + N2

In absence of excess diazomethane . d1azoketone is lost in reacting with HCI to form chloromethyl ketone.
RCOCHN2 + HCI - + RCOCH2CI + N2

If alcohol, ammonia or amine is present 1n place of water then ester. amide or substituted amide respectively
is formed.
R'OH RCH2COOR'

RCOCHN2 - Ag2 01:,~~ 2 : • RCH2CONH2

\(...__- --: RCH2CONHR'

Besides Ag 2 0, the reaction is catalysed by colloidal platinum, silver, copper, etc., and sometimes heat.
The group A may be alkyl, aryl, heterocyclic or alicyclic and may contain reducible groups which remain
 ARNOT-ElSTERT REACTION
87

unaffected. Acidic groups react with diazomethane and diazoketone.

Mechanism
Nucleophilic attack of diazomethane on the carbonyl carbon of the acid chloride gives an intermediate (i)
which eliminates a molecule of HCI to give diazoketone (ii). Diazoketone then splits off a molecule of nitrogen
to form a carbene (iii) which rearranges to ketene. The highly reactive ketene readily reacts with the
nucleophile present (H 2 0 ) to form the next higher acid.

~ct>(9 e <t>
CH2-N=N: .. 4 • CH2-N:N:

~o e) (~~ (?(! ~.
II~
Cl-CI
R
+
@
CHz-Ni:N

0
-ec:H-N:Nl ?
I
R H
I

(i)
@ -HCI

(ii)
@_.
R-C-CH-N:N• - R-C=CH~~N.

A910 ~'f°:. H20

R -CH R-CH :C :O - - - R-CH2 -COOH
-N2
Ketene
(tii)

The presence of carbene (iii) has not been detected and therefore the two steps-splitting of nitrogen and
migration of R group-may be concerted.
The mechanism has been supported by the fact that ketenes have been isolated or trapped. Further,
isotopic labelling experiment has ~wn that the carbonyl carbon of diazoketone is present in the resulting
acid as the carboxyl carbon.
13
RCOCHN2

The group A migrates with retention of configuration, for an optically active acid on conversion to its higher
homologue and StJ9sequent Barbier-Weiland degradation gives the original acid with the same configuration.
Mild reaction co~ permit this synthesis without affecting complex or reducible groups in the
substrate. The yield is ·high. It has, theretor:e. many synthetic applications, especially in the field of natural
products.

Applications
COOH
1.
00 Diazo-«-acetonaphthone a -Naphthylacetic acid
(80%)

CH3
I
2. CH3CH2-C-CH2CH2COOH
I
CsHs
4-Methyt-4-phenylcaproic acid
 SACTIO"lS. REARRANGEMENTS ANO REAGENTS

3. rArNQi

~CH2COOH
2-N"rtropheny1acetic acid

5.
/0-cOC/ri
s
1S0C'22. CH~2
3. A920. H20
IO-cH2COOH
s
2-Thienylacetic acid

6_Synthesis of ho era oyl c londe. a 1 termed1ate for papaverine synthesis.

1 SOC'2 2. CH2N2

3. A920. H20
r¢i::, _s_oc_1i_
r¢i::~,
OCH3 OCH3
Homoveratroyl chloride

7. Synthesis of mescaline.

8. Diazoketones on treatment with aqueous formic acid give hydroxy ketones.

Probably in the absence of the catalyst. the species (iii) behaves as a carbocation and combines with the
nucieophile, H20 to form hydroxy ketone. 0
II .. - ~ ~
R-C-CH + H20: ___. R-C-C-OH
I
H
 BAEYER-VILLIGER REARRANGEMENT
89

BAEYER-VILLIGER REARRANGEMENT
-
Baeyer-Villiger rearrangement is an example of the migration of a group from carbon to electron-deficient
oxygen.
The reaction involves the oxidation 'of ketones to esters by the treatment with peracids such as peracetic
acid, perbenzoic· acid, pertrifluoroacetic acid. permonosulphuric acid, etc.
0 0
II CF3COOOH II
R-C-R' R-C-OR' + CF3COOH

-
Cyclic ketones are converted to lactones with ring 'expansion .

6
Cyclopentanone Lactone

The overall reaction is an insertion of oxygen atom between the carbonyl group and the adjacent carbon
in ketone. Organic solvents which are inert under the conditions of reaction may be used. The choice of
solvent depends upon the solubility of the reactants. Commonly used solvents are glacial acetic acid and
chloroform.

Mechanism
Nucleophilic attack of the peracid on the protonated ketone gives an intermediate peroxide (i). The peroxide
then undergoes loss of carboxylate anion and migration of a group from carbon to electron deficient oxygen
to yield the protonated ester (ii) . Finally the loss of proton gives the ester.

0
II I
@
H oH
I
"
1 R C03H
oH
I
oII II
"
- R - C-0
oH
I
'+'
~
[ oH
I I
Re @oH
II I
]
R-C-R ~ R-C-R - - " ' - - • R-C-0-0-C-R - - - - - . R-C-0-... R-C-OR ..___. R--C-OR
@ (i) RI \.'] @ (ii) <!!)
@ 0
H II I
- R-C-OR where R' is equal to CH3, C5H 5, CF3 . etc.

The reaction is catalysed by acids. Electron-releasing groups in the ketone and electron-withdrawing
groups in peracids promote the reaction rate. Pertrifluoroacetic acid is very effective because trifluoroacetate
ion is a good leaving group.
The mechanism is supported by Ahe fact that the labelled oxygen atom of the ketone is entirely present
in the carbonyl oxygen of the ester.
18Q " 180
II I R C03H I I
R-C-R R-C-OR

The loss of carboxylate anion and the migration of the group may be concerted. Syrkln has suggested ·
that the peroxide (i) transforms into products by a cyclic mechanism, which shows that the last three steps
may be concerted.
90 A AC TIONS, ARRAN M N ANO

0
~o'.)/g'" "
~c" 'o 'R"--• R - C - OR
1
+ R'!.c - OH
R "~'o-
~H (I) 0"

The migrating group retains its conl1guration s 111 other concerted reactions. For acyllc compoundslhe
migrating group, A' must be 2°, 3° or vinyllc. However, migration of 1° alkyl group may be brought about bit
using CF3C0 3H or BF3- H20 2 as reagent.
Baeyer-Villiger oxidation can be brought about with H20 2 and base also In some cases.
In unsymmetrical ketones, that group migrates which Is more electron-releaslng. Thus, the migratory
aptitude of alkyl groups is in the order 3° > 2° > 1° > C~. Electron-releasing substltuents In the aryl group
facilitate migration. The migratory order of aryi groups is p-anlsyl > p-tolyl > phenyl > p-chlorophenyl >
p-nitrophenyl, etc. In case of alkyl aryl ketones, it is the aryl group which migrates (except in case of /·bul~
group).

Applications
The reaction has valuable synthetic applications.
1. Esters Esters which are difficult to synthesize can be prepared by this method.
0
CF3C03H II
(a) CsH5-CO-CH3 - - - • CH3-C-OC5H5
Acetophenone Phenylacetate
0
CF3C03H II
(b) CH3-CO-C(CH3)3 CH3 -C-OC(CH3)J
Plnacolone t-Butylacetate

2. Anhydrides When 1, 2-diketones or o-qulnones are subjected to Baeyer-Villiger rearrangement,

anhydrides are produced.
0 0 0II 0II
II II RC03H
(a) CH3 -C -C-CH3 ., CH3 -C -0-C -CH3
Olacetyl Acetic anhydride
0
0
~ORC03H 0

(b) ~
a-Naphthaquinone

The products can be converted to various types of compounds.

3. Lactones Cyclic ketones are. converted tc;> lactones with ring expansion.

v
Cyclohexanone
0 RC03H 00
-Caprol~tone

Long-chain hydroxyesters can be prepared from large ring-size ketones.

 BECKMANN REARRANGEMENT

With some condensed cyclic ketones, two lactones in varying proportions are formed. For eYiaJTlple,
camphor gives two tactones (I) and (II) .

I {75%) II (25%)

Lactone (I) is the normal product formed by the migration of the tertiary bridgehead carbon wh'le lactone
(II) has been formed by the migr9tion of the methylene group. The reason for the formation of two lactooes ·
different proportions is steric factor.
4. Elucidation of structure The ester obtained as a result of the rearrangement may be hydrolysed to acid
and alcohol from which the structure of the substrate can be determined.
The reaction is not successful with aldehydes . Aliphatic aldehydes are oxidized to acids by the migra1ion
of the hydrogen.
R R"COJH
R-C-H - - - + R-C-OH
0
II

A few aromatic ald~hydes have been converted to formates by the migration of the ary1 group.
0
II
H-C-OAr
Aryl formate

BECKMANN REARRANGEMENT
The acid-catalyzed conversion of ketoximes to N-substituted amides is known as Beckmann rearrangement
The reaction is catalysed by acidic reagents such as, H2S04 , SOCl2, S03 , P20 5 , PCl 5, C6H5S02Ct, etc.
The reaction involves the migration of a group from carbon to electron-deficient nitrogen.
@
H
RR I C =NOH .---. RCONHR ' or R' CONHR

Some aldoximes undergo the rearrangement in the presence of polyphosphoric acid (PPA) but the
reaction is not a general one. The migration of the group depends not on the migrational aptitude but upon the
Orientation of the group in relation to the OH group. It is found that the migrating group is always anti (i.e.,
trans) to the hydroxyl group. Thus. the reaction is stereospecific.
1
R /OH @ R R
' H , I •• ,
C=N /C:N ~ RCONHR
R'' •• HO ••
 92 REACTIONS, REARRANGEMENTS AND REAGENTS

That it is always the antigroup which migrates has been confirmed by the rearrangements of the two
isomeric oximes of 2-bromo-5-nitroacetophenone. The structures of the two isomeric oximes were first
determined by an elegant method as given below.
On treatment with cold NaOH solution , one isomer (I) was cyclized to 3-methyl-5-nitrophenyl isooxazole
(Ill) while the other isomer (II) remained unaffected even under drastic conditions .
Me
02N'©C
Cold
Na OH
0 J 0
No react ion

(Ill)

Obviously, the OH and Br groups in isomer (I) are close enough for reaction and cyclization. Hence, the
Me and OH groups are anti (i.e. , trans) to each other. In isomer (II), the OH and Br groups are far apart for
reaction, i.e., the Me and OH groups are syn (i.e. , cis) to each other. Thus, the structures of isomers (I) and
(II) are confirmed.
Now, on subjecting the two isomers to Beckmann rearrangement it is found that (a) isomer (I) gives
N-methyl-2-bromo-5-nitrobenzamide (IV) indicating the migration of the antigroup Me to the nitrogen atom and
(b) isomer (II) gives N-( 2-bromo-5-nitrophenyl)- acetamide (V) due to the migration of the anti-aryl group to the
nitrogen atom.

Isomer( I) ---- 2N 0
Beckmann
rearrangement
0 --©:CONHMe

Br
(IV)

Isomer( II) -rearrangement

_B_e_ck_m_a_nn~• Q
02 N--©:NHCOMe
Br
(V)

Oxime esters and ethers also undergo Beckmann rearrangement. The acidic reagents convert the OH
group to a better leaving group-acids convert OH to H2 0, other reagents convert OH to an ester-leaving
group, e.g., OPC14 from PCl5 , OS02 C6 H5 from CsHsS02 CI, etc. The reaction is facilitated by heat, polar
solvents or an increase in the acid strength.
18
That direct interchange of the migrating group and OH does not occur is proved by the fact that 0 is
incorporated I in the product 1n
•
the presence of H 180 . 2

H2<) 18 0 1a
1 II t
RA C:NOH R-C-NHA
®
H

Mechanism
The mechanism of the reaction has been suggested as given below.

@ @ @
A, • H A, .. -H2<) ~ .. @ @ _,R H2') H2", -H HO
1 /C=N, ----. 1 C=N~ • \_'./(C=N
1
_,. c-N --· C=NR _____.... 'c=NR
R OH A" ( ?1.H2 R/ R'/ - R'/ R 1"
O @ (VI)
_,11
- R-C-NHR
 BECKMANN REARRANGEMENT 93

h other acidic reagents. e.g .. PhS0 2CI. the same intermediate (VI} is obtained .

PhS~I
e
R, •• -PhSO:P A...._ •• a:.
C=N C=Nw
1/ 'OH -HCI A'/
R
(VI)

In strong acids, the reaction proceeds with the protonation of the OH group of the oxime with
1sequent loss of water to yield the species (vi) with electron-deficient nitrogen which is also obtained with
er acidic reagents by the loss of ester group. The migration of A then gives a carbocation. The attack of
er molecule on the carbon followed by the loss of proton gives the amide.
The migrating group retains its configuration and hence the migrating group does not become
1pletely free during the migration, otherwise the reaction cannot be stereospecific. Thus, the migration and
breaking of N-0 bond may be concerted or at least very rapid. This has been supported by crossover
1eriments.

plications
:onfiguration of ketoximes can be assigned A ketoxime gives an amide on Beckmann rearrangement.
m the products of hydrolysis of the amide, the structure of the amide is known and for that matter, the
1figuratidn of the oxime is known.
Thus,
@
H I HiQ I
RR 'CNOH ___.,. A CONHR • RNH2 + R COOH

mation of RNH 2 indicates the migration of the group A to the nitrogen atom. The groups A and OH are,
refore, antito each other, i.e., the structure of the oxime is
1
R, ,OH
..
R 1C=N

·ynthcsis of isoquinoline

H, /OH
C=N P2')5 CH,
©-CH=CH" -H.p
OC CH
~
Cinnamaldehyde oxime lsoquinoline

ynthesis of lactams Al icyclic ketones of all ring sizes undergo the Beckmann rearrangement of their
nes to yield lactams.
A product of considerable industrial importance is perlon (valuable textile polymer) which is prepared
n CJJ·caprolactam. This is obtained by the Beckmann rearrangement of cyclohexanone oxime It is
thesized from phenol as below .

© 6
OH

H>'NI ..
H OH
Cu. 250°C
6
0
c5-H_@_._6.~ C)o :e.t. f8-NH(CHV1
Per1oo
Cyclohexanol Cyclohexanone Cyclohexanone oxlme e-Caprolactam
94 REACTIONS, REARRANGEMENTS AND REAGENTS

Similarly, cyctopentanone oxlme gives 2-piperidone under Beckmann condition. Aldoximes under the
Beckmann reaction conditions undergo dehydration to nitrites. 0
rT

Benzaldoxime Benzonitrile
(Phenyl cyanide)

BENZ1LIC ACID REARRANGEMENT

The addition of a strong base to a carbonyl group results in the formation of an anion. The reversal of the
anionic charge may cause expulsion of the attached group, X, e.g.,

x
'~
e fx
HO~/
C=o- c --c //
0 a
/ - / \OH ' OH

([Link] of esters when X =OR)

However, in a 1:2-diketone the group X may migrate to the adjacent electron-deficient carbonyl carton
forming ex-hydroxy acid.
Thus, benzil on treatment with a strong base forms benzilic acid (salt), whence the name benzilic acid
rearrangement.
00 0
e0 OH 0
11 11 NaOH 1 // 1 //
C5H5-C-C-C5H5 - - • C5H5-C-C - C5H5-C-c..__ 8 @
1 'OH 1 ONa
C5H5 C5H5
Benzil Sodium salt of benzilic acid

Barium and thallous hydroxides are more effective than sodium or potassium hydroxides. Alkoxide ions
(methoxide, t-butoxide, etc.) in place of hydroxide ion give the corresponding esters.
CH30Na
C5H5 ·CO-CO-C5H5 (C5Hs)2C(OH)COOCH3
Benzilic acid methyl ester

Phenoxide ions are too weak a nucleophile to attack. Besides aromatic 1, 2-diketones, aliphatic and
heterocyclic diketones as also o-quinones undergo this rearrangement.

Mechanism
It has been seen that the rate of reaction is proportional to the concentrations of benzil and the hydroxide ion.
i.e., rate oc [C6 H 5 COCOC6 Hs)[OH ]
18
It has also been found that when the reaction is carried out In the presence of H2 0, benzil exchanges
18
0 faster than it rearranges.
 BENZILIC ACID A AA ANG M I IT

On the basis of the above observations, it has been suggested that a fa t mvor itJle nur;lr: rJh1 Hr.. Gi t ;,,c k
ccurs at the carbonyl carbon in the first step . The second step I the rate -d ,termini g tl.::p rr vtw,h he;
1igration occurs . Finally . a rapid proton transfer completes the pro ,e

e
o(o !?-'I (R ~ 0 0 01 1
Ph-C
11 "'# ... :=;,
fast
C +OH -----
'
Ph - Ph-C-C-OH

~
~
low I prol/Jn
II I
Ph-C-C-OH - - - Ph - - C-
I
Ph
tran for 1
Ph
II

The rearrangement 1s analogous to intramolecular Cannizzaro reaction of glyoxal.

The carbonyl group which is attached to the l~ss eleGtron releasing of the two aryl group i relatively
more positively charged and, hence, is attacked by OH. Consequently, the less electron-donating aryl group
migrates to the other carbonyl group

0 ~
H3C
-0-
o11 oII
C-C-C5H5 ~
eOH
~" 9,1
H 3 C~C-C-OH
low -0-'~
11
- · H 'j c~ 9 - c -OH
0
H
@

an£> er
fast
~ C~H~
0H 011 0
-0-
I
H3c 9-c -o
C0Hs
(;r Tolyl group 1s more electron-releasing than phenyl group)

Applications
The reaction is a general one and can take place with aromatic, heterocyclic, alicyclic, and aliphatic
1, 2-diketones as also 1, 2-quinones.

(i) ao 0
1. NaOH
@
2. H
O<COOH
OH

Cyclohexane Cyclopentanol
-1 , 2-dione -1-carboxylic acid

(ii)
1. NaOH
@
2. H

Phenanthraquinone 9-Hydroxyfluorene-9-
carboxyhc acid

(iii) OH
<>-c-c-<>
0
0 0

0
1. NaOH
@
2. H
<>-~-O COOH
Furil Funl1c acid
 REACTIONS, REARRANGEMENTS AND REAGENTS
9G

(iv) OH
RR 1. NaOH
HOOC-CH2 -C-CH2COOH
I

HOOC-CH2-C-C-CH2-COOH @ I
2. H COOH
Ketopinlc acid Citric acid

(v) Similar benzilic acid rearrangement is observed when cx-haloketones not having ex-hydrogens are
treated with alkoxides.
R' R
I I RO
9 t;.\ R
\....L 11
R
I
C-C-R - RO-C-C-R - RO-C-C-R
11 I c-+. Co-
I II I 1
0 Cl 'eO ~ 0 R

This reaction is known as semibenzilic rearrangement.

BIRCH REDUCTION
When aromatic rings are reduced with sodium, potassium or lithium in liquid ammonia or amine in the
presence of alcohol, addition of hydrogen takes place at positions-1 and -4 to give an unconjugated diene.
This is known as Birch reduction.
Thus, benzene gives 1. 4-dihydro cyclohexadiene and naphthalene gives 1. 4-dihydronaphthalene.

Liquid ammonia serves as so1vent. Primary amines may also be used as solvent with advantage, since it
permits higher temperature of reaction. (b.p. of ethyl amine is 19°C and b.p. of liquid ammonia is -33°C.)

Mechanism
The accepted mechanism of reduction involves the following sequential steps: The metal transfers one
electron to the benzene ring to produce a resonance-stabilized anion radical {la-le) which accepts a proton
from the alcohol to form a radical (II). The addition of an electron from the metal to the radical produces an
anion (Ill) which subsequently takes up a proton from the alcohol to give the dihydro product.

R
v· r, -c7 Q•LQ -0 ·0~0~0~0
@H H H H H 9 H H

~ HG H H H H H H
(la) (lb) (le) (II) (111)

The repulsion between the anionic and radical centres is minimum in (lb) which, therefore. adds a
proton to give (II) and subsequently a 1, 4-dihydro and not 1,2-dihydro product is formed.
At higher temperatures (50-120°C), ammonia becomes the proton source and alcohol need not be
used. The amide ion thus formed is a strong base and isomerizes the 1. 4-dihydro product to 1,2-dihydro
product.
~1 ,

ANNI Ano R A TION 97

---.. p~-'OH NH3 . (j<

Th 1. ..ctihydro pr con1ug" t d dOlrblo bond nnd hence undergoes further reduction to form a
t tmh dro d riv tiv ,

e
HYl H
~H
Cyclohexene has single olet1nic bond which 1s unaffected by the reagent. The presence of
electron-withdrawing groµps in the aromatic rings makes the rings more electron-accepting and hence the
reaction is facilitated. The presence of electron-releasing groups have the reverse effect.
With substituted benzene the electron-donating group remains on the unsaturated carbon and the
electron-withdrawing 9rOL1p remain~ on th saturat d carbon In the products
OMe COOH

6 6
HOCOOH
. '7 I L ' liq NH3
~ C2H50H

This is because, calcul t1ons oy mo1 cular orbital method rndrcate that 1n the anion-radical
(a) the electron density is the greatest at the ortho or meta positions with respect to the electron-releasing
substituent in benzene and
(b) the electron density is the greatest at the para position with respect to the electron-withdrawing substituent
in benzene.

6 ~ •6e •6 6
OMe OMe OMe OMe

ROH• 1. LI
- LI@ ~ •• ~ 2. ROH ~

COOH

6 ~ -
COOH OCOOH_ _ _ HOCOOH

@
- LI O
e
ROH 1. Li
2,ROH

Phenols and isolated double bonds are not reduced by this method.

CANNIZZARO REACTION
In the presence of a strong base, aldehydes without cx.-hydrogens, i.e., nonaldolizable aldehydes undergo
self-oxidation-reduction i.e., disproportionation reaction, This is known as Cannizzaro reaction . Thus,
aromatic aldehydes <ArCHO), formaldehyde (HCHO), trialkyl acetaldehydes (R 3CCHO). heterocyclic

aldehydes. ~CHO . etc., undergo Cannizzaro reaction, e.g.,

0
'tffff f')''W) rn

REACTIONS, REARRANGEMENTS AND REAGENTS

98

2CsHsCHO + NaOH _.4 C5H5CH20H + C5H5COONa

Benzyl alcohol Sodium benzoa1e

2HCHO + NaOH _A.. CH 30H + HCOONa

Methyl alcohol Sodium forma1e

fhe reaction best proceeds with aromatic aldehydes . Although the reaction is characteristic of
aldehydes without a-hydrogen . a few aldehydes with <X-hydrogen are known which undergo Cannizzaro
reaction.
2(CH3)2CHCHO + NaOH 2oo·c + (CH3)zCHCOONa fviC
Dime1hyl acetaldelyde 2-Me1hylpropanol-1 . Sodium-2-methyl propanoate
(i)
oC [i
The reaction can also occur between two different aldehydes having no a-hydrogens when it is called crossed ano
Cannizzaro reaction.
NaOH
CsHsCHO + HCHO /:;. bOtl

When formaldehyde undergoes crossed Cannizzaro reaction with other aldehydes without a-hydrogens, it is anc
seen that formaldehyde is oxidized and the other is reduced. This is because the nucleophilic attack occurs
fii)
more readily on formaldehyde than on other aldehydes.
be<
de1
Mechanism
e
Rapid addition of OH to one molecule of aldehyde results in the formation of a hydroxy alkoxide ion which like wh
aluminium-isopropoxide acts as a hydride-ion donor to the second molecule of aldehyde. In the final step of
the reaction, the acid and the alkoxide ion exchange proton for reasons of stability.

e
<:~~
C5H5-C +OH
0
I

I ~ C5H5-C-OH
I
H H
Si1
o~
e
Coe
c6Hs- c' -OH +
II~
C -c 6H5 -
slow
o
II
C5H5-C-OH + H-C-C5H5
0
I proton exchange

(L/H H
I (fast)

In_the pres~nce 0~ a very strong concentration of alkali, aldehyde first fonns a doubly charged anion (1) Cc
~rom which a hydride anion is transferred to the second molecule of the aldehyde to fonn acid and an alkoxide fo
ion. Subsequently, the alkoxide ion acquires a proton from the solvent.
 CANNIZZARO REACTION 99

e e e e
0
II OH 9 ~H 9
R-C ::;w=::::!!: R -C - H ::;w=::::!!: R -C -H
I I I
H OH O (I)
e
Go Rn 80
l~l\l I ~ e
R-CfH +·c=o - R-C + H-C-0
I I II I
( 0 H 0 H
e
e

Evidence in support of the mechanism

(I) The reaction follows third-order law (second order in aldehyde and first order in base), i.e., rate
2
" [AldJ [0H ]. This suggests the reaction between the first-formed anion (from base and aldehyde) and
another molecule of aldehyde in the rate-determining step.
In the presence of a high concentration of base . the reaction follows fourth-order law (second order in
e
both the aldehyde and base), i.e., rate o- [Aldf [OHf

This suggests the reaction between the doubly charged anion (formed from one molecule of aldehyde
and two molecules of base) and another molecule of aldehyde.
(ii) That the hydride ion is directly transferred from one molecule of the aldehyde to the other, and does not
become free in solution has been proved by the observation that the recovered alcohol does not contain
deuterium when the reaction is performed in the presence of 0 2 0.

It is seen that the reaction depends on the nucleophilic attack on the carbonyl carbon. Hence, factors
which reduce the positive charge of the carbonyl carbon retard the reaction. In extreme cases the reaction
may not occur, e.g., J:rdimethylaminobenzaldehyde does not undergo Cannizzaro reaction .

<t> e
Me,--~~
....-N
,,_,o _ MMe ,....-N ~c,....o
C, ....._
Me - · H e - H

Similarly, sterically hindered aldehydes do not undergo the reaction.

Applications
1. Crossed Cannizzaro reaction One of the most important applications is the crossed Cannizzaro reaction
between formaldehyde and other aldehydes having a-hydrogens.

During the reaction, the a-hydrogens are replaced by hydroxymethyl groups -CH 20H through aldol
condensation and then the product, f3-hydroxyaldehyde undergoes crossed Cannizzaro reaction with
formaldehyde.
Thus, aldehydes containing one, two or three a-hydrogens react as given below.
100 REACTIONS. REARRANGEMENTS AND REAGENTS

/CH 20H NaOH + HCHO

NaOH /CH20H
(i) (CH 3)2CHCHO· + HCHO----~ (CH3)2C, (CH3)2C ....._ + HCOONn
Aldol cond . CHO Crossed Cannizzaro CH 20H
reaction
Subsllluted trlmethylone
glycol
CH20H CH20H
2HCHO + NaOH / HCHO + NaOH /
(ii) CH3CH2CHO - - - - - - - CH3-C-CH20H - - - - - - • CH3 -C -CH20H
Aldol cond. 'cHO Crossed Cannizzaro 'cH20H
reaction
1, 1, 1 -Trlhydroxymethyl
ethane
9H20H HCHO + NaOH CH20H
3HCHO +Ca(OH)2 I
(iii) CH3CHO ------'---=• HOH 2 c-9-cHO Crossed Cannizzaro HOH2C -C -CH20H
I
Aldol cond .
CH20H reaction CH20H
Trihydroxymethyl Tetramethylol melhane
acetaldehyde (Pentaerythrltol)
Pentaerythntol 1s an important industrial product. Its ester with polybas1c acids gives resin polymers
used for surface coating. Its tetranitro derivative (PETN) is a useful explosive.
2. lntramolecular Cannizzaro reaction Dialdehydes and a.-keto aldehydes undergo intramolecular
Canniz zaro reaction giving various valuable products .

•. ti\ 0 0 9
e e
OH
II II 9~
(i) CsHs-C-C-H - - - • C5H5-C-C-OH -
CR 9R lntramolecular
OH
I
CsHs-C-C-OH C5H5-C-C02Na
Phenyl glycol U) H proton transfer
H
I

Sod. salt of
mandelic acid

0 0 OH 0
II 1. NaOH
II I ~
(II} H-C-C-H H-C-C
2 . H@ I 'OH
H
Glycol Glycolic acid

. Svnthesis of various types of alcohols and acids

CHO Na OH CH20H COON a
(j) 2 I I + I
COOH 6 COON a COON a
Glyoxalic acid Sod. glycolate Sod. oxalate

(ii} 21:)--cHo Na OH
6 ~CH20H + ~COONa
Furfural Furfuryl alcohol 2-Furoic acid (sod. salt)

CHO
.
COCH

(iii) 2 ©cl OH
Na OH
6
©cl OH
+ &~ OH
2-lodo-3-hydroxy 2-lodo-3-hydroxy 2-lodo-3-hydroxy
benzaldehyde benzoic acid benzyl alcohol

The reaction is useful for the preparation of substituted benzoic acid and benzyl alcohol.
~~~~
--- ··--
....

CLAISEN CONDENSATION 101

CLAlSEN CONDENSATION
Esters having a-hydrogen on treatment with a strong base, e.g .. C2H50Na, undergo self-condensation to
produce ~-ketoesters

2 CH3COOC2Hs , .c 2HsONa CH3COCH2COOC2Hs

2. ~ Ethyl acetoacetate

1
1
2 R CH2COOC2Hs .C 2HsONa
@ R ' CH2COCH (R ' )COOC2Hs
2. H

This reaction is called Claisen condensation although there are several closely related reactions which
follow the same mechanistic pattern.
Mixed or crossed Claisen condensation also occurs between two different esters or between an ester and a
ketone.

Mechanism
The ethoxide ion abstracts a proton from the a-carbon of the ester to produce the anion (of the ester) which is
a powerful nucleophile (1st step) . The nucleophilic attack of the anion on the carbonyl carbon of a second
molecule of ester produces an oxonium ion (llnd step) , which eliminates an ethoxide ion to give the
~-ketoester (lllrd step). The 13-ketoester having an active methylene group is acidic and reacts with sodium
ethoxide to form enolate salt (IVth step). Subsequent acidification with acetic acid (1 : 1) regen&rates the
~-ketoester.

e e ... (I)
C2H50 + H-CH2COOC 2 Hs ~ C 2 H 5 QH + 1 CH 2COOC2H s

e
- 0
'
CH3 -C-CH2COOC2H
I
OC2Hs
s ... (II)

••• (111)
 102 REACTIONS. REARRANGEMENTS AND REAGENTS

The first three steps are in unfavourable equilibrium state . Hence, excess sodium ethox1de 1s used to
force the equilibrium to shift in the forward direction by the formation of a resonance-stabilized enolate anion
(IVth step). This is substantiated by the fact that esters having only one a-hydrogen do not undergo Claisen
condensation with C2H50Na. This is because the ketoester formed (analogous to step Ill) cannot be converted
to its enolate anion due to the absence of a second a-hydrogen, with the result that the equilibrium does not
shift to the right.
However, in the presence of a very strong base such as triphenylmethyl sodium, such esters, e.g., ethyl
isobutyrate, undergo Claisen condensation to give P-ketoesters. This is because the very strong base,
(C 6H5)JCNa acts in two ways.
(i) It withdraws the weakly acidic r1.-hydrogen irreversibly from the ester (analogous step I is highly
reversible).
~H3
CH3-CH-COOC2Hs
Ethyl isobutyrate
+ (CsHshC
6
--
(ii) It completely removes one of the equilibrium products, i.e., ethyl alcohol, so that the equilibrium shifts
to the right. (Compare step Ill.)

e
./ 2 (CH3)2CH-COOC2H5
(CsHsbC
0 CH3
II I
(CH3)2CH-C-C-COOC2Hs + C2H50H
I
Ethyl isobutyrate CH3
Ethyl isobutyrylisobutyrate

-- (CsHsbCH + C2H50Na

Applications
Simple and crossed Claisen condensations have been extensively used in the synthesis of a wide variety of
organic compounds, e.g., vitamins, sex hormones, alkaloids, terpenes, flavones, etc.
Crossed Claisen condensations between two different esters (both having a-hydrogens) have little
synthetic value, for a mixture of four products are obtained. However, if one of the esters has no a-hydrogen,
it acts as a carbanion acceptor and the self-condensation of the other ester is minimized. Commonly used
esters with no a-hydrogen are ethylbenzoate, ethyl formate, ethyloxalate, ethyl carbonate, etc. These esters
are good carbanion acceptors.
Ketones are generally more acidic than esters and the rate of their base-catalyzed condensation {aldol)
is very slow. Hence, ketones serve as nucleophiles in mixed Claisen condensation to give a large variety of
products.
Some of the examples of crossed Claisen condensation and their applications are given below.
1. Condensation with ethyl benzoate

(a) tC2H 50Na

C5H5COOC2Hs + CH3COOC2Hs ® C5H5COCH2COOC2H5 + C2H50H
Ethyl benzoate 2. H Ethyl benzoylacetate

(b) Synthesis of ftavones {chrysin}

sd
 CLAISEN CONDENSATION 103

(c) Synthesis ot nicotine from ethyl n 1cotinate.

~co J: J-;_e-~e
llN~ o N
1
....
r:_1-•
steps
o-9
N Me
Ethyl nicotlnate N·Methylpyrrolidone Me Nicoline

2. Condensation with (.'thvl form.1tc

CHO
(a) Formylation tC2H50Na 1
C5HsCH2COOC2Hs + HCOOC2H5 @ "' CGH5-CH-COOC2Hs + C2H 5 0H
Erhyl phenylacetate 2. H Ethyl formylphenylacetate

The reaction is utilized for formylation during the synthesis of various natural products, e.g., equilenine,
thiamin (vitamin B 1), isoflavones, etc.
(b) Synthesis of daidzein (isoflavone)

HO
CO ..........
OH
*
H2C~OH + HCOOC2Hs
t C2 H5 0Na
2 H
0

2-4-Dlhydroxypheny-p-hydroxy benzyt
ketone

~ ~co,TI-Q-oH
HO~o-CH
Oaldzein(isoflavone)

3. Condensation with diethyl oxalate (a) Ketones and esters condense with diethyl oxalate to give oxalyl
derivatives which have synthetic utility since they lose carbon monoxide on heating to give malonic ester
derivatives which may be used for the preparation of aryl-substltuted dibasic acid derivatives and ~- keto acids.
0 0 0

(a)
cooc
'
H
2 s +
COOC2Hs 6 tC2HsONa
@
2.H Cr
COCOOC2H s

2-(Ethyl oxalyl)·cyclohexanone
1so•c
CrCOOC2H5

Dlelhyl-cx·oxalylphenyl Diethyl phenylmalonate

acetate

...
r
..

104 REACTIONS, REARRANGEMENTS AND REAGENT

Phenyl-substituted malonic ester has important synthetic applications, e.g., P

prepared. Diethyl- a-oxalylphenylacetate on hydrolysis and heating gives (l,·keto acid.

CsH5CH2COCOOH
Phenylpyru 1ic acid

(b) Camphoric acid may be [Link]

+
H2C-COOC2H5

/
\
C(CH3)2
.
.. s~.. .
Sew:raf VP
' O'"*
H2C-COOC2Hs C;,r~;(A'I('.. ?.A
Diethyl-p,Jl-dimethyl Diethyl diketoapo-
glutarate camphorate

4. Condensation with diethyl carbonate Esters condense with diethyl carbonate to tom
derivatives which can be further transformed into various compounds.

·-··
I 1 H'.2<)
I CH~y -cC01
2. A Cc.
u~jl;i(v,..,cnc
aod

5. A very important product of Claisen condensation is the ~-ketoester, ethyl acetoacetate ~.A). CG: . _
easily alkylated. Ethyl acetoacetate and its alkyl derivatives under different conditions unoergo ke z.-c
acidic hydrolysis to yield ketones and acids respectively.

R
I
CH3COCHCOOC2H5 + C2HsOH + NaX

DilalcKOH ,A Cone. ale. KOH

CH3COCH(R)COOC2Hs - - - - - - - RCH2CC>On
(Ketonic hydrolysis) A (Acidic hydrolysis)

...
This reaction has been employed for the synthesis of a large variety of ketones, acids and many he'e
compounds. lntramolecular Claisen condensation in dibasic esters of six to eight carbons is caJled
reaction . The product is a cyclic ketone derivative.
Claisen condensation is very similar to aldol condensation. The only difference is that, in aJdol ~
no group is lost while in Claisen condensation the group C2 H56 is lost because it is a good leaving g

?H 9
CH3-C-CH 2CHO + :B (Aldol condensation)
I
H
 .,
CLAI.. CN n AnnAN Ml NI I or.

CLAISEN REARRAN M -N r
Clalsen rearrangement Involves the shift of a group from oxygon to ca rhon . hu , wh n uryl llyl ethers are
heated (ca 200°C) they rearrang to O·allylph nols.
a II y
0-CH -CH :C H2 011

0AR 200°c
~(Yl
V CH 2-
(II) (lt )
11 : ,lit<

The group migrates to the ortho position, although ome para product has been obtained in some
cases. In general, when both ortho positions are free , the product Is ortho compound and when both ortho
positions are occupied. the product Is para compound.
a ~ y
O-CH2-CH:CHR
H3C -6-CH3 2oo•c

When both ortho positions and the para position are occupied, there Is no reaction. Migration to the m·position
has not been observed.
During the ortho migration, the allyl group undergoes allyllc shift, I.e., the carbon atom a · to the oxygen
atom in the substrate becomes y· to the ring in the product. However, In the para migration no change of
14
attachment of the allyl group In the product is observed. This has been confirmed by C labelling In the allyl
group.
No catalyst is required , for the reaction follows first·order kinetics, i.e., one molecule is Involved in the
rearrangement Further. when a mixture of allyl ethers is heated. no crossover products ore form ed

~CH2-C~=CH~CH2-CH:CHR

Therefore, the allyl group never separates during the reaction, 1.e., the reaction rs inlramolecular
rearrangement. This indicates that the reaction proceeds through a cyclic transition state in which the breaking
of oxygen·allyl bond and the formation of carbon-carbon bond with the ring are concerted.
On the basis of the above considerations, the following mechanism of the rearrangement has been
suggested:

6
____.
Slow O · ': \
R
I
0 .. •CH

~CH
•••• !I
cH 2
Transition stale
-
aH
~O

I~ CH ~ -CH =CHR -

Dlenone (I) Intermediate

~~ 6-
I
OH

~
h-
CH2-CH=CHR

The cyclohexadienone (I) intermediate is converted rapidly into phenol for reasons of aromatic stability
106 REACTIONS, REARRANGEMENTS AND REAGENTS

Para-migration Even when the ortho positions are substituted, the migration still occurs at the ortho position Ther
to form otho-substituted dienone (II). However, the absence of hydrogen at the ortho position prevents 3. Sy
enolization, i.e., aromatization . Hence the allyl group undergoes a second migration through a similar cyclic prep
transition state to form a dienone (Ill) which aromatizes to a phenol with allyl group at position-4.
•
R )t
0-CHR'
CH slow
II
CH2
-1 ~
0

R~f'"'\•
h.
CH2-CH=CHR'
- R~R
O'

IJ I -
fast

• I
R7
YR
~
OH

I
•
(""1erec=-Wc1abelled carbo n)

Dienone(ll) H CHR -CH =CH2 • ,

CHR -CH=CH2
Dienone(lll)
Vari1
Since the ally! group undergoes double inversion, it is not rearranged in the final product. This has been
confirmed by isotopically labelled carbon.
There are enough evidence in support of this mechanism. The double inversion of the ally! group is
proved by trapping the dienone (II) intermediate with maleic anhydride in a Diels-Alder reaction. Further, the
dienone (II) prepared separately was found to give rapidly the para product on heating.
The reaction rate is unaffected by the presence or absence of substituents in the aromatic ring. since
the reaction is not ionic.
Wh•
Extension and Applications reac
1. The rearrangement is not restricted to aromatic ring systems only (a) Allyl ethers of enols, e.g.. allyl vinyl
ethers also undergo Claisen rearrangement.

O-CH2~CH2 A ~
f~-' J' - 1
R-C-CR 2-CH2-CH=CH2
R-C~ a-h
con
The product does not enolize (even when R or R' = H) because ketones are more stable than enols. ald1
(b) The 0-allyl acetoacetic esters also rearrange similarly.

o-cH 2 ~CHR A o . c HR-CH=CH2

l~,r---'
CH 3 -C =CH -COOC 2 Hs
- 11
CH3 -C-CH-COOC2Hs
1

2. Out-of-ring Claisen rearrangement Several examples of out-of-ring Claisen rearrangements are known of
the type given below.

R
I

O-CH2-CH:CHR 0 ( ~C:..>CH 2 C:. O rJ 9H 2 -cH=CHR

Me~CH=CH-CH 3 Me~CH=CH-CH3 Me~CH-C-CH3
~ ~ y - y (.,~
Me Me Me

~ cH 2 -CH=CHR
- Me y CH=i:-cH,
be

M
Me Tt
ke
Tt
 107
CLAISEN- SCHMIDT REACTION

Ositi 011
events There is no rearrangement of the allylic group in the final product due to double inversion.
CYCiic 3. Synthetic applications Since aryl allyl ethers can be easily prepared, the rearrangement is employed to
prepare various kinds of compounds, e.g..

OH

M•0-6-CH2 -CH =CH2

o-eugenol

been Vanous such derivatives may be prepared.

Allyl aryl thioethers, e.g.. ArSCH 2-CH=CH 2 , do not ordinarily give orthoallyl thiophenols.
up is
" the

ince CLAISEN-SCHMIDT REACTION

When aromatic aldehydes react with aliphatic aldehydes or ketones in the presence of a strong base, three
reactions are possible, e.g ..
rinyl (i) Cannizzaro reaction of the aldehyde having no ex-hydrogen,
(ii) aldol condensation of the aliphatic aldehyde or ketone and
(iii) crossed aldol condensation between the aromatic aldehyde and the aliphatic aldehyde or ketone.
However, when aromatic aldehydes or ketones react with aliphatic aldehydes, ketones or esters having
a·hydrogens under mild conditions, i.e., weak base (10% NaOH) and low temperature, a crossed aldol
condensation with subsequent dehydration occurs predominantly, with the formation of ex, p-unsaturated
aldehydes, ketones or esters. This is known as Claisen-Schmidt reaction or simply Claisen reaction.

10% NaOH , room temp.

C&HsCHO + CH3CHO C&HsCH :CH-CHO
8-10 days
Cinnamaldehvde

10% NaOH, 3o•c

+
of C&HsCHO CH3COCH3
2-3 days
C&HsCH =CHCOCH3
Benzylidene acetone .;
'

10% NaOH
CsHsCHO + CH3COC5H5 C5H5CH =CHCOCsHs
Below30°C Benzylidene acetophenone

10% NaOH
C&HsCHO + CH3COOC2Hs C&HsCH =CH-COOC2Hs
3o•c
Ethyl cinnamat11

The concentration of alkali is important, for in the presence of a strong base, Cannizzaro reaction may
be significant.

Mechanism
The mechanism is similar to that of aldol condensation. In the presence of the base, an anion of the aldehyde,
ketone or ester is formed which attacks the carbonyl carbon of the aromatic aldehyde to form an oxonium ion.
The latter takes up a proton from the solvent to form aldol (I) which subsequently eliminates a molecule of

.· '
.; .,
108 REACTIONS, REARRANGEMENTS AND REAGENTS

water to form a., ~-unsaturated aldehyde, ketone or ester.

e e
HO + HCH2 -CHO ....-.. CH2CHO + H20 ~

(~~ 9e H20 9H 9 -H20 ~~

C6Hs-~ ~ CH~HO . . . . C6H5-9-cH2CHO ~ CeH5-9-cH2-CHO +OH • CeHs""'y-CH-Cl-iO
H H H (I) H

-OH
e
_ . C5H5-CH=CH-CHO
(fl)

The aliphatic aldehyde may also undergo aldol condensation and dehydration but {II) predominates. This is
because the aldol (I) loses water irreversibly due to conjugation of the double bond with the benzene ring.

Electron-releasing groups in the aromatic ring at <> and p-positions to the carbonyl group retard the
reaction by reducing the positive charge on the carbonyl carbon which is the point of attack of the carbanion.
Electron-withdrawing groups have opposite effect.

Applications
(1) The a, !>-unsaturated carbonyl compounds obtained by this reaction are useful commercial products,
e.g., cinnamaldehyde and benzylidene acetone are used in perfumery.
(2) This reaction has been utilized in the synthesis of various natural products, e.g., ~-ionone, piperine,
flavones, flavonols, etc.
(i) In the synthesis of ~-ionone

~r.'CHO ~r.-CH=CH-CO-CH3 @

µ
Citral
NaOC H
+ CH3COCH3 orBa(OH)2
2 5
u
Pseudoionone
H (BF3 + CH3COOH)
or H2 S04 + gtycerol

X - c H =cHCOCH3 @ XcH=CHCOCH 3
__.~ -=H+l_)L
~-lonone

(ii) In the synthesis of flavones

COCH3 ©:CO-cH ©(CO~cH

OH
+ CsHsCHO NaOH Q
OH
CHC5H5 1. Ac20
2. Br2
CO-cHBr
BrCHCsHs ale. KOH
OAc
0 II
o,...ccsHs
Flavone

(3) The reaction has also been used in the preparation of long-chain conjugated aldehydes, which are
useful dye intermediates.
 CLEMMENSEN REDUCTION 109

Piperidine acetate
CsHsCH=CH-CHO + CH3CH=CH-CHO C5H5-(CH=CH)3-CHO + C5H5-{CH=CH)5-CHO
+Alcohol
Clnnamaldehyde Crotonaldehyde 7-Phenyl heptatrienal 11-Phenyl undecapentenal

(4) A technical route fo ~!~mimic acid is the oxidation of benzal~cetone with sodium hypochlorite.
10 % NaOH NaOCI
- - - • C5H5CH =CHCOOH
3o•c

(5) Test for the presence of -CH 2CO- group

The reaction has been used to detect the presence of -CH 2CO- group in the natural products, for only
if a compound contains -CH 2CO- group. it will undergo ttie condensation .

~---------..,
eOH
C5H5-CHFO + H2lC-CO-CH3 - - - CsH5CH=CHCOCH3
~- - -·--·---' I
H

CLEMMENSEN REDUCTION
The reduction of carbonyl groups of aldehydes and ketones to methylene groups with amalgamated zinc and
concentrated hydrochloric acid is known as Clemmensen reduction .
Zn-Hg, HCI
C5H5COCH3 CsHsCH2CH3
Reflux
Acetophenone Ethyl benzene

The reduction consists in refluxing the carbonyl compounds with amalgamated zinc and excess of
concentrated hydrochloric acid. The reduction i s useful especially for ketones containing phenolic or
carboxylic groups which remain unaffected. Ketones are reduced more often than aldehydes. Such reduction
is also observed in Wolff-Kishner reduction but Clemmensen reduction is easier to perform. The reduction,
however, fails with acid-sensitive and high molecular weight substrates. The a., ~-unsaturated ketones
undergo reduction of both the olefin!c and carbonyl groups. However, the reduction is specific for carbonyl
groups of aldehydes }ind ketones1containing other functional and reducible groups.

Mechanism
Various mechanisms have been suggested which are so contradictory that no conclusion can be drawn. A
mechanism suggesting the intermediate formation of alcohol was rejected since the reagent fails to reduce
most alcohols to hydrocarbons.
Nakabayaski has suggested a mechanism on the assumption that the reduction under acid condition
involves protonated carbonyl group to which electrons are transferred from the metal.

H@ @ '+'
~
·z
• n •• e @ H~
, -H20 H• :zn
R-C =O ______. R -C :QH _ . R -C-OH - - R -C-OH ~R-C1 OH2--R-c@-
I +2
R
I
R
I I
R 7 ~+2
- ...... ,
I
R R R -Zn
H
,e @
H
H
,
R - C: - - R-C-H
I I
R R

Certain types of aldehydes and ketones do not give the normal reduction products alone. Thus,
 110 REACTIONS, REARRANGEMENTS AND REAGENTS

a-hydroxy ketones give either ketones through hydrogenolysis• of OH group or olefins and 1, 3-diketones give
exclusively monoketones with rearrangement.

0 0 Clemmensen
ff "
CH3-C-CH2-C-CH3
reduction

Certain cyclic 1 , 3-diketones give under Clemmensen reduction a fully reduced product along with a
monoketone with ring contraction .

Zn-Hg
HCI

5, 5-Dimethyl 1, 1-Dimethyl 2, 4, 4-Trimethyl

cyclohexane-1,3-dione cyclohexane cyclopentanone

The latter probably is formed through a d1rad1cal with subsequent intramolecular C-C bond formation and
pinacol-type rearrangement.

Applications
The reduction has important synthetic applications.
1. Reduction of aliphatic and mixed aliphatic-aromatic carbonyl compounds.

(a) Zn-Hg
I CH3-~CH2)s-CHO CH3-(CH2)5-CH3
n-Heptaldehyde HCI n-Heptane

Zn-Hg
(b) CsHsCOC3H7 CsHsCH2C3H7
HCI
n-Propylphenyl n-Butyl benzene
ketone

The reaction is useful for introducing straight-chain (without rearrangement) alkyl groups in aromatic rings by
acylation and subsequent reduction.
2. Reduction of keto acids

Zn-Hg, HCI
CsHsCOCH 2CH2COOH - - - - - • C5H~H2CH2CH2COOH
~-Benzoyl propionic acid rPhenyl butanoic acid

a- and ~-keto acids are generally not reduced.

3. Reduction of phenolic carbonyl compounds

• Cleavage of carbon-hetero atom bond by catalytic hydrogenation.

 CLEMMENSEN REDUCTION 111

Zn-Hg

HCI

Sallcylaldehyde o-Cresol

4. Reduction of cyclic ketones

(a)
©rCH2
©Q
AICl3 Zn-Hg
'9H2
COCI HCI
Jl-Phenyl propionyl 0 lndane
chloride a-Hydrindone

(b) In tt)e synthesis of naphthalene

CO-cH2 1. Zn -Hg, HCI CH2-cH2

rA(l tZn-Hg,HCI
,CH2
2.SOCl2
CH2
I ~ [Link].~
COOH COCI
~-Benzoyl proplonic rPhenyl butanoyl 0 Naphthalene
acid chloride a-Tetralone

5. Reduction with ring expansion

Zn-Hg

HCI O-C2Hs
YCOC2Hs I
CH3 CH3
1-Methyl-2-propionyl pyrrolidine 2-Ethyl-1-methylpiperidine

6. Reduction with ring contraction

HCI

5, .5-Dimethyl cyclohexane-1, 3-dione 2, 4, 4-Trfmethyl cyclopentanone

7. Synthesis of cycloparaffins

Zn-Hg
HCI 0
Cydohexane
Cyclohexanone
 REACTIONS, REARRANGEMENTS AND REAGENTS
112

CURTIUS REACTION
Curtius rearrangement involves the decomposition of acyl azides in an inert solvent (e.g., chloroforrn
benzene, etc.,) by gentle heat to isocyanate. Good yields of isocyanates have been obtained. '
.

If the reaction is carried out in alcoholic or aqueous medium, the isocyanate further reacts to form urethane,
amine or substituted urea.
1
R'OH RNHCOOR
~ ~OH Urethane
---+ R-N=C=O RNH2 + C02
- N2 RNH2
RNHCONHR
Substituted urea

The conversion of acy~ azides to isocyanates involves Curtius rearrangement while Curtius reaction involves
the conversion of acids to amines, urethanes and substituted urea via Curtius rearrangement.
Acyl azide required for the reaction is prepared as below.

(a) RCOCI + NaN3 ---+ RCON3 + NaCl

Sodium azide Acyl azide

HN02
RCONHNH2
Acyl hydrazide

Mechanism
The mechanism of the rearrangement is very similar to Hofmann's rearrangement t,o isocyanate. The driving
force of the rearrangement is the electron-deficient nitrogen formed on elimination of nitrogen molecule on
heating.
o,, ~e
•• d;f •• oe~
11 •• @ •• A, c 6 H6 o11 ( ; . ••
R-C-N=N:N: - R-C-N N::N: e:s;N:---. R-N=C=O
•• - N2 Isocyanate

Since there is no evidence for the formation of nitrene, all the steps may be concer:ted.

Reactions of isocyanate
(a) With alcohols
0
II I

R-N=C=O
• H __.... R-NH -C-OR
+ RO
Urethane

(b) With water

 113
CUATIUS REACTION

R-N:C:O + HOH -
f)Rf2
R-NH-C-OH---+ RNH2 + C~
Carbamlc acid

acted isocyanate may further react with the amine to yield derivative of urea.

0
II t
+ R NH2 ~
1
R-N=c=o R-NH-C-NHR
Alkyl-substituted urea

eactlon is a general one and can be applied to aliphatic, aromatic, heterocyclic and unsaturated acids.
9 acids may contain different functional groups which remaih unaffected.

ications
;imple one-step and mild reaction affords an important and easy preparative method for primary amines,
ino acids, aldehydes, urethanes, etc.
1. Preparation ot primary amines-Primary amines, free from secondary and tertiary amines can be
prepared, e.g.,

CsHsCH2NH2
Benzylamine

CH30~NH2
Ethyl anlsate p-Anlsidine

Similarly, ethyl adipate gives tetramethylenediamine.

2. Preparation of a-amino acids

CN CN COOH COOH COOH

I 1. NaOEt I I fl I HCI I
R-CH
CH2
2. RX
R-CH R-C~ C2H50H - - - - R-CH
\
COOR
Cyanoacellc ester
\COOR CON3
Acy! azide
' NHCOOC2Hs
'
a-Amino acid
NH2

Many important a-amino acids may be conveniently prepared.

3. Preparation of aldehydes

Ct)
1. C2H50H, H
2. NH2NH2 _c...::2;._H~50_H;._
• _... CH3CH(OH)-NHCOOC2Hs
CH3CH(OH)COOH - - - - - CH3CH(OH)CON3 fl
Lactic acid 3 · HN02

Similarly, benzylmalonic acid gives phenylacetaldehyde .

 4

114 REACTIONS, REARRANGEMENTS AND REAGENTS

1 C2H50H
CsH5CH2CH(COOR)2 C5H5CH2CH(CON3)2 2. NaOH
Benzylmalonic ester

4. Curt1us reaction may be used tor stepping down the acid series.
1. NH2NH2
RCH2COOC2Hs 2. NH02

Oxdn.

DIECKMANN REACTION
lntramolecular Claisen condensation in dibasicacid esters is called Dieckmann reaction. The resulting
products are invariably cyclic P-ketone derivatives. The condensing bases may be sodium, sodium ethoxide,
sodium hydride, potassium t-butoxide, etc.

The reaction best proceeds with dibasicacid esters having 6, 7 or 8 carbon atoms which give stable rings with
5, 6, or 7 carbons. Yields for rings of 9 to 12 carbons are very low. High-dilution technique is used for the
formation of large-size rings.

Mechanism
The mechanism of the reaction is similar to that of Claisen condensation.
The base abstracts a proton from one of the a-carbons. The resulting carbanion then attacks the
carbonyl carbon of the other ester group. Subsequent expulsion of the alkoxide ion gives the cyclic ketone
derivative.

The compound on hydrolysis and decarboxylation gives cyclic ketone.

Esters of acids lower than adipic acid undergo more of intermolecular condensation with subsequent
cyclisation. Thµs, ethyl succinate gives cyclohexandione derivative. This may be due to reasons of stability of
six-membered rings.
,_i!l f- -
115
DIECKMANN REACTION

OC2H 5
o=c(
<?H2
CH2COOC2H5

0
II
/c'-..
c 2 Hs(>OC-9H 9H2
CH2 CHCOOC2Hs
'-c/
II
0
Cyclohexan-2 ,5-dione-1,4-dicarboxyfic ester

Hect of experimental condition on the ring size has been observed in some compounds.
0
)lycooR
NaH, Benzene

ROOCI (COOR
(AproUc solvent) UcooR
0
~COOR
(Proue solvent) ROOC-rrCOOR

\pplications and extension

Ille reaction affords a useful route for the synthesis of cyclopentanone and cyclohexanone derivatives. Some
ixamples are given for illustration.
1. The reaction has been used to build up five- or six-membered rings in the synthesis of various natural
products. The general process is given below.
Synthesis of steroid

2. Preparation of heterocyclic ketoesters

(a) Piperidone derivative

1-Ethy1-4-p1pendone

(b)Thiophene derivatives-Depending on the conditions of the reaction , two isomers are obtained.
 REACTIONS, REARRANGEMENTS ANO REAGENTS
118

Oiels-Ald
six-memb
3. Extension of the reaction by Lewis
(a) Intermolecular condensation between two lower acid esters has been effected to obtain different
Eth
products.

H2q-cooR
CH2
o~ ,...cH-COOR
c
I
\
CH2
@OD
1. HJO
2.-co2 O
H2C-COOR ....:c /
o:i' 'cH-COOR CycJopentane-1 , 2-dione

Above synthesis was u1111zed tor the synt h~s 1 s of camphonc acid. Electron-1
promote 1

0~CH3 COOR
1. Na
2. CH3I CH3-C-CH3
0 COOR
Olalkyl dlketocamphorale

The reac

Se•eral •lep• ~3COOH reaction

1, [Link]

~~~OH Tri1

Camphoric acid ~
cI
This, Incidentally, elucidates the structure of camphor. ~
(b) Ziegler applied Dieckmann reaction on dinitriles to obtain large-size rings using lithium ethyl
anilide and high dilution technique.• Since tt

Besides
may be '

' On dilution the intermolecular distance of the reacting groups is greater than the intramolecular distance so that
intermolecular condensation is minimized.

. '" ·
-
DIELS- ALDEA REACTION 117

DIELS-ALDER REACTION
)iels-Alder reaction involves the 1, 4-addltlon of an alkene to a conjugated dlene to form an adduct of
iix-membered ring . The double bond compound Is called the dlenophlle. The reaction Is Initiated thermally or
lY Lewis acid catalyst with or without the use of solvents.
Ethylene and simple oleflns give poor yields even at high temperature.

200°c ~
Cyclohexene(20%)

Electron-withdrawing substituents in the dienophile, such as >C=O, -CHO, - COOR, -CN, -N02 , etc.,
promote the reaction .

CHO
I
CH 100°c
II
CH2

The reaction . rate is also accelerated by the presence of electron-releasing groups in the dienes. Thus, the
reaction between 2-methyl-1, 3-butadlene (lsoprene) and acraldehyde is faste( than that between
1, [Link] and acraldehyde.
Triple bond compounds . allenes and benzyne may also function as dienophiles

Since the reaction involves uniting of n orbitals, all carbon skeleton is not necessary In the dienophile, e.g.,

: COOR aN-COOR

0 +11
N
'cooR
__. I
N-COOR
C-CN
Ill
N
340°c
0- N
CN

2-Cyanopyridlne

Besides acylic hydrocarbons, dienes may be alicyclic hydrocarbons, in which the conjugated double bonds
may be wholly or partly inside the ring, some heterocyclic and some aromatic hydrocarbons.

oo-oU All cyclic

0 0
Heterocycllc Aroma tic

Benzene, r:'aphthalene and phenanthrene are quite unreactive but anthracene responds readily.
 118 REACTIONS, REARRANOEMENTS AND n AOLN r

H 0
Endo onlhroconll mnlnlo onhydrldo

Benzyno Trlplycono
Th~ ;;r,(, ~- d ··
~ ~-tr;,,.- "') I C::"-:'
The reaction occurs with the clsoid form (s·cis conformation) of the diene. Cyclic dlenes are naturally ro
clsoid form and so react more rapidly than the acyclic dlenes which normally exis1 In 1he more stable tranwt<J
forms (s·trans conforma11on).

-- (
/

\
5 kcol

cyclic dlene s-lrana 8 •ci8

When both the dlene and dlenophile are unsymmetrical, 1wo products are possible. However, the 1. 2·
and 1, 4-products predominate.
Th' ~ [Link]
!or g eater accu

Major Minor Minor Major

e r~ac

Mechanism sy % 1z.e ma l - !
a diagno · tes c
There is little evidence in favour of stepwise polar or free radical mechanism. The other possibility is a
rf:ac-iants ca be de
concerted mechanism. Both 1he mechanisms are discussed. However, see note below. 1
-'~ -te. Some
(i) Stepwise polar and free radical mechanism The mechanism envisages 1ha1 1he bonds between the 1· Oeterminat in n of,
reactants are formed consecu1ively, i.e., one bond is formed followed by the other. The first bond gives a diion
(a) or a diradical (b) which then forms the second bond .
(a) Polar reaction

· Synth~is o l quint
2
(b) Free radical reaction
(9 1~
~·IB -(J-0
The mechanism assumes that the second bond is formed more rapidly than the rotation about the
 DIELS-ALDER REACTION 19

c-C bond, as otherwise a mixture of cis and trans products (nonstereospecific) would be obtained with
substituted reactants, which is contrary to observation. The reaction is strictly stereospecific. The orientation
of the groups (i.e., cis or trans) in the reactant remain unaltered in the product. Hence the mechanism is not
favourable.
(ii) loncerted mechanism The mechanism visualises a process in which there is simultaneous (not
consecutive) breaking and making of bonds through a six-centred transition state with no intermediate. It is a
4n + 2n cycloaddition and stereospecifically cis with respect to both reactants .

~~
H R GH R R
~+
~ R'
- ~=(-r1Y
H R
1
ll__..AR,
H Transition state

The addition of the dienophile is a1ways c1s so that the groups c1s 1n the olefin remain cis in the adduct.
The addition is therefore stereospecific.
There are two possible modes of addition, (a) exo and (b) endo. When the greater part of the d1enophile
is under the diene ring in the adduct. it is called endo and in the reverse case. 1t 1s called exo. The endo adduct
is more stable.

Endo Exo

This is because the cyclic transition state has further stabilization through secondary n-orbital overlaps
for greater accumulation of double bonds in the endo adduct.

Applications
The reaction has proved of great value. Due to its high stereospecific nature, the reaction has been used to
synthesize many natural products which otherwise would be ditticult to prepare. The reaction can be used as
a diagnostic test for conjugation in a system. Since the reaction is stereospecific, the configurations of the
reactants can be determined by studying the adduct. The reaction has also been used to trap benzyne
intermediate. Some reactions are given to illustrate its use.
1. Determination of configuration Maleic and fumaric acids c n be identified from the product

~+~
HOOC COOH
Maleic acid
~c=)
fCooH
COOH
Cis
COOH
Fumarrc acid
- tr
6

COOH
OOH

T ns

2. Synthesis oi quinones and [Link] hydrocarbons

0

( ·¢~ ct>
(i)

0 0
5. 8. 9. 10-Tellahy\lro-
1, 4-naphlhaqulnone
120 REACTIONS, REARRANGEMENTS AND REAGENTS

(ii)

(lCO
Anthracene

3. Synthesis of a~terpineol

COCH3 1. CH3M9Br
+ I( @
2. H30
lsoprene Methyl vinyl o:-Terpineol
ketone

4. In the synthesis of camphene The intermediate required in the synthesis of camphene is prepared by
Dials-Alder reaction

o + !(CHO ~ l(j(CHO Several steps

OJ(
Cyclopentadlene Acraldehyde Camphene

s. In the synthesis of cantharidine The D1els-Alder adduct from furan and acetylene dicarboxylate is the
starting product for a complicated synthesis of natural cantharidine.

~COOMe 0 ~
I( COOMe
~
A
ll,til Se~eral.,step~
COOMe COOMe ~'o
c/
Furan A~tylene dlcarboxylate CH 3 ~O
Cantharidine

The Diels-Alder adduct obtained from furan and dimethylmaleic anhyd_ride on hydrogenation gives
cantharidine which is not the same as the natural product.

JCc atco
~O

at
CH3
CH~~
'o ~
CH3
t-=='o + o 'o H2,Pt 0
~I I . I I
CH3 C~ CO co
°"O CH3 CH3
Dimethyl malek: Canlharidine
anhydride

The starting materials for the synthesis of various natural products, such as reserpine, cholesteroJ, etc.,
are the Dials-Alder adducts.

Note The concerted cycloaddition is best explained from the principle of Conservation of Orbital
Symmetry put forward by Woodward and Hoffmann. The principle states that cycloaddition
is allowed when the symmetry properties of the highest occupied molecular orbital (HOMO)
of one reactant correlates with the lowest unoccupied molecular orbital (LUMO) of the other
and vice versa.
It is seen that in the reactants in the ground state, the signs of.-1, 41obes of LUMO for 1, 3-butadiene
correlates with those of HOMp of ethylene, and hence the addition occurs smoothly on heating.
(Orbitals of the same signs, i.e., of same phase only overtap to form bonds.)
 DIENONE-PHENOL REARRANGEMENT 121

HOMO~ene: LU~oe:--~ -:YQ..

Similar correlation is observed between butadiene HOMO and ethylene LUMO.

H·~~~-0
LUMO HOMO H
The stereospecificity (i.e., cis-addition} is thus explained.

DIENONE-PHENOL REARRANGEMENT
When 4, 4-dialkyl cyclohexadienone is treated with acid, it is converted to phenol with migration of one of the
alkyl groups to the adjacent carbon. This is known .as dienone-phenol rearrangement. The dienone is
dissolved in acetic anhydride and treated with catalytic amount of sulphuric acid. The product on hydrolysis
gives the phenol.

~
0 OH
AOCH3

R
Q R ~R
R
A
~R
R

Mechanism
On protonation of the oxygen, a carbocation is generated which is stabilised by delocalization of the positive
charge.
0 OH OH

R
QL6--Q®
R R R R R

In one of the canonical structures, the positive charge is on a carbon adjacent to a highly substituted carbon.
Hence, a carbocation rearrangement occurs. Subsequent loss of a proton gives the 3, 4-disubstituted phenol.

The ease of dienone-phenol rearrangement is due to the creation of a stable aromatic system.
When one of the alkyl group forms a part of the cyclic system, either the alkyl group or tl')e ring
methylene group may migrate.
122 REACTIONS. REARRANGEMENTS ANO REAGENTS

(i) Alkyl migration

(CH3C0)20
0

(ii) Migration of ring methylene group

l}i;~
iXR
Ho· u side of the
wasobSef'
treatment ·
The course of the reaction depends on the structural or electronic factors and on the conditions of reaction. Ile~
eiltlef side
A reverse rearrangement, i.e., phenol-dienone rearrangement has been observed during the
electrophilic substitution in phenols in some cases. On
The base
.. beamgtti
er$,6,er
~
er her
-~~
[Link]
+Br: Br + HBr side of
Br Br Br

Applications
The rearrangement has useful applications. A classical example is the rearrangement of santonin to
desmotropo santonin.

rll hl
o~- HO~
HCI

o~ o~
0 0

The anthrasteroid rearrangement is closely related.

FAVORSKll REARRANGEMENT
The transformation of cx-haloketones to esters with rearranged carbon skeleton by the treatment with alkoxide
ions is called Favorskii rearrangement. Alkali hydroxides or amines in place of metal alkoxides give acids or
amides respectively.
Cyclic a-haloketones give esters with ring contraction .
e o (yCI 0
C9Hi;CH2COCH2CI -
RO II I

RO-C-CH3CH2CsHs •
•

~o -EQ. VcOOR
 AV Kii ARF\AN M NT 123

Mech nh1m
The mechanism of th r rr n m nt h b n th ubJ ct of much Investigation.
11 was observ d th t both th I om rlc k ton , (I) nd (II) g ve l·\·ph nylproplonlc acid on treatment with
hydroxide Ions.
0
e e 0
II OH OH II
C0His-CH2-C-CH2Cl ..........._. CoH11CH2CH2COOH .,.__ CoH5CH(Cl)-C-CH
(I) (II)

Thisobservation Indicates that the chlorine Is not being directly replaced by the incoming group from the other
side ot the carbonyl group, as otherwise (II) would give C6H5CH(CH 3)COOH which is not obtained. Further, it
was observed that~ cycllc ketone (2-chlorocyclohexanone) with labelled carbon bearing the chlorine atom. on
14
treatment with alkoxlde Ion gave a product in which equal amounts of C were present at the a-carbon and at
the ~·carbon. This suggests a symmetrical cyclopropanone Intermediate which opens up with equal ease on
ellher side of the carbonyl group.
On the basis of the above observations, the following mechanism has been suQgested.
The base abstracts an a-hydrogen to produce a carbanlon. lntramolecular nucleophllic attack on the carbon
bearing the chlorine displaces the chlorine atom with the formation of a transient symmetrical cyclopropanone
ring. Subsequent attack of the alkoxide ion on the carbonyl carbon opens the ring with equal ease on either
side ot the carbonyl carbon so that the product contains 50% of C at the a-position and 50% at the ~position.
14

~cl Jt e~ -3 A }t ~R
v v v dm•goof
C1-C2bond 6
14c at ~-position

l
cleavage of
C1-Cs bond
COOR

d 14c at a-poeitlon

.In case of unsymmetrical ketones, the unsymmetrical cyclopropanone ri ~g which 1s formed, opens up to give
the most stable carbanion. Thus, th~ two isomeric ketones (I) and (II) give the same cyclic intermediate (Ill)
which may open on either side of the carbonyl group to give two carbanions (IV) and (V).

R<g 8~ ~
C6 H5CH2COCH2CI - C5H5-CH CH2-tCI"'
(I) 'c/ ~
O / C5H5CH-CH2
e
RO
~eCH
Y II
CsH5-CH-CO-CH3 - CsH5-CH / 2 0
Cl
(II) ~,'\ (Ill)
~ II
0
 124 REACTIONS, REARRANGEMENTS ANO REAGENTS

The carbanion (IV) being reasonance-stabilized is preferentially formed so that the product is
C6 H5CH 2CH 2COOR. Hence, both (I) and (II) give the same product.
Although the cyclopropanone intermediate has not been isolated, it has been trapped to give an adduct
with furan in one case at least.

CeH~HCICOCH2CeH5 ---+ C9t15

eoR
'\(
0O
CeH5 ~ CeH5
f?-
0
C5H5
(Adduct)

0
The formation of cyclopropanone intermediate probably proceeds via an intramolecular 1,3-elimination
involving a backside attack of the carbanion. Thus, in nonpolar media the cyclic cx-haloketone (I) with
equatorial halogen underwent rearrangement but (II) with axial halogen did not, since the backside attack is
restricted. (Stork and Borowitz)
H
0 e
-
EtO
COO Et

(I)

H
o e
EtO
- No rearrangement

(II)
Additional evidence in support of the mechanism comes from the observation that the diastereomers (Ill) and
(IV) gave (V) and (VI) respectively indicating that the carbon atom bearing the chlorine atom underwent
inversion as is the requirement for SN2 displacement reactions . The reaction is stereospecific.*
H H
0 e
EtO EtO
-t-t3C
(Ill) COOEt M
H
0
EtO
EtoOC
O=C

For simplicity, this reaction may be represented as given below.

r--i:rocH, ri~ ~
\_Ji - \____/cooH \_floe~
Ketones not having a-hydrogen also undergo similar rearrangement in some cases. The mechanism tor this
is, in part, similar to benzilic acid rearrangement and is called semibenzilic mechanism.

• Stereospecific reaction-When a given stereomer gives one product while the other stereomer gives the opposite
product, the reaction is called stereospecific.
..
 FRIEDB.-CRAFTS REACTION 125

R" 0
' I - RO
R-C-C-R -
II I
0 Cl

Even when there is a suitably placed ct-hydrogen, the rearrangements may follow semibenzific pattern in
some compounds.
Thus, 2-bromocyclobutanone undergoes Favorskii rearrangement when treated with water as the base.
'When treated with 0 20, no deuterium is incorporated in the ring.
Cyclopropanone intermediate mechanism suggests incorporation of deuterium in the ring.
00
c{o 020
9tef°__ !S(o o2o 15P°~ E\<XD o,o K;:
Br ~
However, semibenzilic mechanism can explain the formation of the actuaJ product without deuterium in
Ille ring.

Probably, the strain in the bicyclobutanone ring restricts the operation of cycJopropanone mechanism..
Favorskii rearrangement of a,a (gem) and acx' (vie) dihaloketones produce a . 6-unsaturated esters..

Br 0 K e
I II I RO
H-C-C-C-R

-
I I
ROOC R
Br H
gem-Oihalo ketone
. ' /
e /c==c '\.
Br 0 H H H
I II I RO
H-C-C-C-R
I I
H Br
vic-Dihaloketone

The reaction is stereoselective· as it gives cis olefin.

FRIEDEL-CRAFTS REACTION
Alkylation and acylation of the aromatic compounds with alkyl halides and acid halides or anhydride:s
respectively in the presence of a metal halide (Lewis acid) catalyst, usually aluminium chk>ride, is known as
Friedel-Crafts reaction.

' Stereoselective reactio~Any reaction in which one of the stereomers is fonned c:ompaetety OI predominanlty is callMt
a stereoselective.
Conclusion-A reaction on an [Link] compound can be st~ but cannot be~
 26 REACTIONS. REARRANGEMENTS AND REAGENTS

Anhydrous AICl3
C5H5CH2CH3 + HCI
80°C Ethyl benzene

Anhy AICl3
CsH6 + CH~OCI - - - - C5HsCOCH3 + HCI
CsHsNCi Acetophenone

Anhy. A1Cl3
CsHs + (CH~0)2')

The aromatic compounds may be hydrocarbons, aryl halides, polyhydric phenols, amines, aldehydes,
quinones, certain heterocyclic compounds, etc.
The most commonly used Lewis acid catalyst is anhydrous aluminium trichloride which gives good yield but
several others have been used including proton acids such as HF, H2S04 , H3 P04 , HF- BF3 , etc. The order of
reactivity of some of the catalysts is AIBr3 > AICl3 > FeCl9 > SbCl 5 > SnCl4 > BCl3 , BF3 , etc. Th~ alkylating
agents may be alkyl halides, olefins, aliphatic alcohols, esters, ethers, etc. For active halides a less active
catalyst (e.g., ZnCl2 ) and for unreactive halides a strong catalyst (e.g., AICl3 ) are used. The acylating agents
employed are acid chlorides and acid anhydrides (open or cyclic) .
Commonly used solvents are nitrobenzene, carbon disulphide, ether, petroleum ether, methylene chloride,
etc.

Mechanism
The mechanism of the reaction is not clearly understood. The mechanisms of alkylation and acylation will be
separately discussed.
Friedel-Crafts alkylation The alkylating reagent generally used is alkyl halide.
The function of the catalyst is to furnish a real or potential carbocation for the electrophilic attack on the
ring. Since tertiary carbocations are stable, it is expected that a real carbocation is the attacking species when
the alkylating agent is a tertiary halide.

<t> e
R~X + AICl3 ____. A~ + XAICl3

However, primary and secondary carbocations are relatively unstable. Hence it is suggested that with 1° or
2° halides, a polarized complex with a potential carbocation is the attacking species.

&i- ~
[Link]! + AICl3 _ _ . CH3 -·Cl-AICl3 (Polarized complex)

~ -~ &i- ~ dH3 e
© &+
+ CH3--CI ---AICl3 _,. ~ . ~ CH3 ---c1---AICl3 ---+ ~ H + Aler.

CH3
-.... ~ + HCI + AICl3
~

It is, however, not certain whether a polarized complex or a free carbocation attacks. For example,
n-propyl chloride reacts with benzene to form both n-propyl benzene and isopropyl benzene. This indicates
 FRIEDEL-CRAFTS REACTION 1Z7

n n-propyl carbocation is first formed which may then either attack the benzene ring or rearrange by 1 ,
ride shift to form a greater stable isopropyl carbocation (2°) before attack. Thus,

AICl3 @ 9
CH~H:PHiCI CH~H~H2AICl4

+ HO + AI03

C5H5CH{CH3)2 + HCI + AICl3

Besides alkyl halides, the alkylating agents may be aliphatic alcohols, alkenes, ethers and esters also.
e in the presence of acidic catalysts, such as H 2S04 , H 3 P04 , HF, HF- BF3 , etc., afford carbocations for
lectrophilic attack on the ring.

HJP04 @ CaHs
(i) CH3 -CH =CH2 @ • CH3-CH -CH3 C5H5CH{CH3)2
{ H )
Cumene

H~04 @
C5H5
(ii) CHJCH(OH)CH3 CH3-CH-CH3 CsHs - CH{CH3)2
- H.p

HJP04
@ CsHs
(iii) CH2=CH2 @ .. CH2-CH3 CsHsCH~H3
( H ) Ethyl benzene

For alkyl halides the reactivity order is F >Cl> Br> I. Hence, FCH 2 CH 2 CH:!CI reacts with benzene to
~ CsHsCH2CH 2CH2CI in the presence of BF3 . Benzene rings with substituted haloalkyl groups have
<>rtant synthetic applications (see applications).

iitations
Polyalkylation Since the alkyl groups are activating, di- and poly-alkylations are generally observed. To
1imize polyalkylation, a large excess of the aromatic compound may be used.
Rearrangement Alkylation is frequently accompanied by rearrangement of the entering group.
lsomerization In the presence of excess catalyst and at high temperature, isomerization and
proportionation result.
CH3

A HF-BF3 HF-BF3
¥ 100°c
A

CH3
p -Xylene m-Xylene

) Effect on the reactivity of the substrates Electron-withdrawing groups inhibit the reaction while activating
oups, such as OH. OR, NH 2, etc .. react with the catalyst to retard the reaction . Naphthalene and heterocyclic
>mpounds are very reactive and react with the catalyst. Naphthalene gives poor yield and heterocyclic
lmpounds are not alkylated.
 128 REACTIONS, REARRANGEMENTS AND REAGENTS

Friedel-Crafts acylation
The acylating reagents are acid chlorides or acid anhydrides. Depending on conditions probably btro
mechanisms operate.
(i) Generation of the attacking species which may be a free acyl cation or an ion pair

'R @ e © e
R-C-CI + AICl3 - RCO + AIC'4 or RCO AICl4

~ ~coRe
O
+ @e 0-coR
......., 1 RCOAJC"___. l~:~::_,)(±)H AJCl4 -- ~ I + HCI + AJCl3

With sterically hindered acyl halides the attacking species may be the acyl cation.
(ii) Generation of 1 : 1 complex for the electrophilic attack

0
II
R-C-CI +
9'
AJCl3 ____. R ~ -O-AJCl3
e
~ae A

Cst"fs + R-C-O-AJCl3
I
Cl
<t> e -~H10
~@
C-O-AJCl3
-HCI O-c=o + AJc13

In either case, one mole of the catalyst remains complexed with the carbonyl oxygen of the ketone
formed. Hence, a little more than one mole of the catalyst is required per mole of the reagent for acylation will
acyl halides. When acid anhydride is the reagent, slightly more than two moles of the catalyst is required. This
is because one mole of the catalyst is used up in liberating acyl halide and another mole for complexing wilh
the product, ketone.

(RC0)20 + AJCl3 - RCOCI + RCOOAJCl2

AJCl3 @ 0
C6Hs + RCOCI C5H5-C-O-AJCl3
I
R

The product, ketone is liberated with ice-cold dilute acid.

Aromatic rings having activating groups, such as alkyl, alkoxy, halogen, acetamido, etc., are easily
acylated. For reasons of steric factors, acylation mainly occurs at the para position. Many heterocyclic
compounds undergo acylation with good yield. Metadirecting groups inhibit acylation. Hence, nitrobenzene Is
the favoured solvent for acylation.
Acylation differs from alkylation in the following;
(i) Acylation unlike alkylation is performed in solvents, such as nitrobenzene, carbon disulphide,
petroleum ether, methylene chloride, etc.
(ii) Acylation requires more catalyst than alkylation for complexing with the carbonyl oxygen of the
reagent.
(iii) Since acyl group is deactivating unlike alkyl group, a monosubstituted product is always obtained.
(iv) In acylation rearrangement in the substituent is not observed.
This fact has been utilized for preparing long-chain substituted arenes without rearrangement.
 FRIEDEL~RAFTS REACTION 129

Applications
The reaction is very useful for the synthesis of many classes of organic compounds. This is illustrated bek>w.
(a) Hydrocarbons

(.)
1
CaHs + CsHsCHiCI
AICl3
• CsHsCH~s
Diphenyl methane

(ii) 3C5H5 + CHCl3 AIC'3 ., (Cg-ts)JCH + 3HCI

Triphenyl methane

9. 10-Dihydro anthracene

00 Na:; . 00
co-co
(v) 00 + Cl-CO-CO-Cl AICIJ .,

Naphthalene Oxalyt chloride 7, 8-Acenaphthaquinone Acenaphthene

(b) ketones

AICl3
(i) Ct;Hs + RCOCI CsHf;COR + HCt
PhN°'l

AICl3
(ii) CsH& + CsHsCH~OCI ., CsHsCOC~s
CSi Benzyt phenyl ketone

CH3

(iii)© CH]COCI

AICl3
AoCH3

¥
COCH3
p-Totyl methyl ketone
 zq

~ ~ C 2COCIA ~ .. ©y
0
-Hydnndone

CH3COCI, AIC'3
CH2 Cl-z, O'C C~H sN02 . 95'C
OOrCOCH?
2-Naphthyl methyl ketone

c) Pofynudear hydrocarbom (cyclisation reactions) Friedel-Crafts alkylation and acytation with cyclic
........urorides have been employed to effect ring closure.

(i) ~~CH2CH2C~CI A~l:J ©C)

Tetra

~ CH3
1. 4-0imethy1 tetrali,..

+ <?H2-CO)o AICl:J rAt-CO,~H2 Na-Hg ~ 1. Cone. H2S04 ~ Se,.6

CH2-CO ~ CH 2 HCI ~ _) 2. Na-Hg+HCI ~

I COOH
COOH
~-Benzoylpropionic acid y-Phenylbutanoic acid Tetralin Naphthalene

Ptitnalic anhydride o-Benzoytbenzo1c acid

* ': 0

0
Ahthraquinone
Anth,aoeoe

(d) Acid chlorides

AICl3
CsHs + COCl2 CeH{)COCI + HCI
Phosgene Cu;iCl2

(~) Formylation Formylation with formyl chloride (HOCI) 1s not possible since it is very unstable. However.
formylation has been achieved (Gattermann-Koch) by passing dry HCI and CO through benzene containing
anhydrous AICl 3 and a little cuprous chloride. The attacking species is probably protonated carbon monoxide
@
( H-C::Q ).
 FRIES REARRANGEMENT 131

AICl3
CsHf; + CO + HCI • CU!sCHO + HCI
CIJ2C'2

FRIES REARRANGEMENT
Phenolic esters on heating with aluminium trichloride (Lewis acid) give <> and ~ acyl phenol. This is known as
Fries rearrangement.

6 '"~ ¢ A='"~tico•
0-COR OH OH

13 ©rOR + anmatic

COR

A mixture of ortho- and para-isomers 1s obtained. Electron-withdrawing groups in the substrate retard
the reaction as in the case of Friedel-Crafts reaction. In generaJ, low temperature favours the para-product
and high temperature favours the ortho-product.

MKhanism
Exact mechanism is still not clear1y understood. There is evidence for both intermolecular and intramolecular
reaction mechanisms. It is, therefore, suggested that both mechanisms are operating simultaneously.
EB
Two-step mechanism It may be taken to be Friedel-Crafts acylation in which the acylium ion, (MeCO) is
supplied by the substrate, i.e., it is self-acylation.
At first, AICl 3 complexes with the oxygen of the phenoxy group from which the acylium ion is generated.
The acylium ion then attacks the benzene ring as in the case of Friedel-Crafts reaction .

6
OAIC'2

~~
Similar attack at ~positior, gives the para-isomer.
Concerted or single-stt>p mt>chanism

Me0C @ lUCt
e @
c;.o,,.,. ~(,0-1'JC'2
"tD - -6 -6
3e r H O-AIC'2 OH

AICb ~ _ ~'• MeOC HCI MeOC H~ • MeOC

In practice, both <> and ~isomers are obtained. The amount of each isomer depends on temperature,
SOivent, amount of catalyst and on the structure of the substrate.
At low temperature (< 100°C) para-isomer is the major product while at high temperature (> 100°C)
Ortho-isomer is the major product. This is because the intermediate of ortho-isomer is stabilized by chelation
and is hence thermodynamically more stable.

b
 q

132 REACTIONS, REARRANGEMENTS AND REAGENTS

Solvent is generally not required for the reaction. N1trobenzene may be used which reduces the reaction
temperature.
Fries rearrangement has also been observed to be catalysed by light (photo Fries rearrangement). It is
suggested that the reaction In this case is intramolecular free radical process, the attacking species being
•
RCOO.

Applications
(i) This reaction is useful for the preparation of aromatic hydroxyketones since direct acylation of
phenols gives very poor yield. The effect of this rearrangement on substrates bearing methyl groups
at ortho, meta and para positions shows that when the para position is occupied, the acyl group
substitutes exclusively to the ortho position .

r&°: ¢t ©-..
NCl3
OCOIVe

NCI,
OH

©r:Me ¢ ¢-cdk
OCOMe

COIVe Major product Me Me

Major prOduct 100%

The proportions of o- and p-isomers can be varied by controlling the conditions of reaction, viz.,
temperature. solvent and the amount of catalyst. The reaction is useful because it gives both the isomers
which can be easily separated by steam distillation. The ortho-isomer having lower boiling point due to
H-bonding distills over first. followed by the para-isomer.

(ii} Esters of catechol give acyl catechols .

~= ~=
rAY"OH
NCl3
MeOC~OH
COMe
2, 3-Dihydroxy- 3, 4-Dihydroxy-
acetophenone(minor) acetophenone(major)

(iii) Oiphenyl esters also undergo Fries rearrangement predominantly in the same ring.

~ AM'b ~· +MeOC~
(Major) C~ (Minor)
'-Hydroxy-3-methoxybiphenyt 4-Hydroxy-4' -methoxybiphenyl

(iv) A very useful application is in the synthesis of (±) adrenaline which is a heart stimulant.
 GABRIEL SYNTHESIS 133

~OH
OH
OH
CICH~OCI
Pyridine
¥ [Link] ¢r0H
catechol
COCH2NHCH3 CH(OH)CHiNHCH3
(±)Adrenaline

GABRIEL SYNTHESIS
The reaction involves the preparation of primary amines free from secondary or tertiary amines by reacting
alkyl halides with alkali phthalimide alld subsequent hydrolysis.

0
11 COOK
+Rx-frcNR _KO
_ H_._
11_ r()l + RNH2
~c/ (HL>0) ~COOK
II
0

Mechanism
The alkyl halide undergoes nucleophilic displacement by the phthalimide anion (SN2 displacement) to form
N-substituted phthalimide. The latter is then hydrolysed either with acid or alkali. Usually a prolonged heating
isrequired in both the mediums. The mechanism of hydrolysis is similar to amide hydrolysis.
(a) Base-catalysed hydrolysis

CaH/
C ~c' NA ~
e e~
CsH4
,PH
/c '~
NA - CsH4
~
/C-OH
~ - Cqi4
~e
/ c -o
-
e
OH
CsH4
/
c~
~
'c/ 'c/ 'c-~ A 'c-NH R ~C~N HA
11 II \~'
0 0 oII oI I • • 9
0 OH

e
/coo
- C6H4 9 + RNH2
'coo

b
 134 REACTIONS, REARRANGEMENTS ANO REAGENTS

(b) Acid-catalysed hydrolysis

0
II

C&H,
/c'NR
'c/
II
0

/COOH Steps _ and 3

1, 2 _ C;i, / COOH
-CeH, _..;.,_
repealed
~

'COOH
'C-NHA
fl
0

When substituted phthalim1de is difficult to hydrolyse. hydrazine hydrate may be used to obtain free amine and
phthalohydrazide.
0fl 011
tAr-°'1. Nt-tiNH2- t-f2'> ~~H
~c/NR --2.-Ha---~c,.NH +RN~
fl 11
0 0
Phthalohydta:Zide

The reaction, called hydrazinolysis, proceeds under milder conditions than aJkaJine hydrolysis.
Probable mechanism for hydrazinolysis

~/NHNHi 0
II
,,...C-NHNHi
- Cfti4/c '"'
'c/
NA -Cg-t,
II
'C-NHR
II
0 0

A better solvent for Gabriej synthesis is dimethytformamide.

Applications
Gabriel synthesis is useful for the synthesis of complex ~nos because phthalimide group is fairty
unreactive and is easily separated at the end by hydrolysis. Thus,
(a) A dihalide can fonn monophthalimide which can undergo the usual reactions of a1kyt halides. RnaJty
the phthaJoyl group can be removed to obtain the free amine.
0
II

/c ' Bl1CHVn8'
C5H4 NK
'c"
II
0
 p

HEU-VOlHARD-ZEllNSKV REACTION 135

(b) Phthalimide derivative obtained by reacting with hatogeno esters can be converted to acid chlorides
which can be used in Friedel-Crafts reaction. The products on hydrolysis give amines.

(Q)--- CO(CH2) N
/~~ HCI, ~
(Q)--- CO(CH2)nNH2 + C6~"°COOH
n ............,..sH 4 'COOH
co

(c) Various amino acids can be prepared by using derivatives of malonic esters

~ 1
CsH•...........,.NK + 8rCR (COOR)2 _ . , . CE)H4
/~ NCR (COOR) 0
Cone HCI 1
"°COOH
2 R CH(NH2)COOH + CsH4
co 'Cc; 200°c a-Am no acid
'COOH

HELL-VOLHARD-ZELINSKY REACTION
Uiphatic carboxylic acids react with bromine or chlorine (but not iodine and fluorine) in the presence of small
tmOUnt of red phosphorus to give exclusively mono a-halogenated acids. This is known as Hell-Volhard-
~Onsky (HVZ) reaction. The reaction is given only by aliphatic acids having a-hydrogen. Bromine reacts smoothly.

RedP
CHJCH~OOH + Brz : - . . . CHJCHBrCOOH HBr

)llorine reacts similarly but the reaction is less specific due to some free radical chlorination.

CH3CH2COOH + Cl 2 ~ CH 3C H(Cl)COOH + CH2(C l)C H2 COOH

a-Chloroprop1onic acid P-Chloroprop1onic acid

ialogen from the catalyst does not enter the a-position of the acid, e.g.,

RCH2 COOH + Cl2 _ _.,. RCH (Cl)COOH

~echanism
)ince acylhalldes undergo halogenation without a catalyst, It is considered that red phosphorus and halogen
irst form phosphorus trihalide

mich reacts with the acid to give acid bromide.

RCH~OOH + P8r3___. RCH~OBr + POBr + HBr

rtie acid bromide then undergoes a-halogenation through Its enol form as In the case of acid-catalysed
lalogenaUon of ketones.
 136 REACTIONS, REARRANGEMENTS AND REAGENTS

0 OH
II I
R-CH2-C-Br ~ A-CH =C-Br

Finally. the interchange reaction between cx-bromo acid bromide and the acid molecule gives a-bromo
acid and regenerates acid bromide whrch continues the reaction .

A -CH(Br) -CO-Br + A-CH2-COOH _ _ . ACH(Br)COOH + RCHiCOBr

The mechanism 1s supported by the observation that anhydndes. malonic esters, mtro compounds, etc.,
which can enolise easi1y undergo a-halogenation without a catalyst.

Applications
The reaction (HVZ) is diagnostic for the presence of a-hydrogen in acids since the reaction occurs exclusively
with acids having a-hydrogen.
The reaction can be used to prepare o:-monobromo derivatives of dicarboxylic acids from their half esters.

$OC'2 CH~OCI CH(Br)COCI C2"isOH CH(Br)COOC~s

RedP I
- - • c9HVn Br2
(e H2)n
1 --• (~Hi)n
COOC2"is COOC2Hs COOC:zHs

The yield is generally very high.

The a-~logen can be easily replaced by nucleophilic reagents to give various useful substituted
products, e.g., a-amino and a-hydroxyacids which are of biochemical sign ificance.
NaOH
CH3 -CH(OH)-COOH Lactic acid

CH3-CH(NH2)COOH Alanine
@
~CN H~
~-- CH3-CH(CN)-COOH - - CH3-CH(COOH)2
a -Cyanopropionic acid Methyl malonic acid

HOFMANN REARRANGEMENT OR HOFMANN

BROMAMIDE* REACTION
The reaction involves the conversion of an amide into a primary amine with one carbon less, by the action of
alkaline hypohalite <NaOH solution + Br2 or Cl 2 ) . The overall reaction is

RCONH2 + Br2 + 4Na0H - - + RNH2 + 2Na8r + N~O;) + 2H2')

where R may be aliphatic, aromatic or heterocyclic.

• Since bromine is mostty used in the reaction and the intermediate is N-bromamide, hence the name.
p

HOFMANN REARRANGEMENT OR HOFMANN BAOMAMIOE REACTION 137

Mechanism .
jhe mechanism has been suggested on the basis of the intermediates isolated during the course of reaction.

~ NaOBr(Br2 + NaOH)
0 H
II I
o
11
e ~ -Bre
-
o
(";;;\,:,!. _r
R-C-NH2 R-C-~-Br R-C-~~r - - - - ~N:
-NaBr
N-Bromamide N-Bromamide anion Acyl nitrene

Rearrangement 9@ H;P Y'\

R-~-C=O ...__ R-N=C=O ____. R-NH-C=O ~RNH2 + COi
Isocyanate ~QH
(COi + 2NaOH - Na(!C~ + H;!O)

In the first step N-bromamide is formed by the usual reaction of hypobromite on primary amines. This
follows the removal of the acidic hydrogen from the N-atom by the base to form N-bromamide anion in the
second step. In the third step loss of bromine results in the formation of the highly reactive acylnitrene. In the
fourth step, migration of A to the electron-deficient nitrogen gives the isocyanate. The latter reacts with water
to give carbamic acid which spontaneously eliminates carbon dioxide to yield the amine.
By careful control of experimental conditions t~" intermediates, N-bromamide, its anion and isocyanate
(in aprotic solvent) have been isolated. This confirms the mechanism.
The possibility of the formation of acylnitrene, however, has been rejected, for if it is formed it would
react with water to give hydroxmic acid
0 0
II - 11
R -c -N z + H2') -----. R -C-NHOH (Hydroxamic acid)

which has not been detected.

Hence, the loss of Br and the migration of R in N-bromamide anion is suggested to be concerted.

~µ_-~
o e e- o
II
~~-tBr---+ R-~-~--+ R-N=C=O

Since no cross-over products are obtained when two different amides are rearranged, it is assumed that
the rearrangement is intramolecular and the migrating group never completely separates during the migration.
This is further confirmed by the fact that if R is chiral (asymmetric). it migrates with unchanged
configuration. Thus, camphoramidic acid (I) having the COOH and CONH 2 groups in els position undergoes
Hofmann rearrangement to give the amino acid (II) in which the COOH and NH 2 groups are also In cis
position, since it readily forms lactam.

y
~COOH
I CONH2 Br2 + KOH 1

~COOH
YNH,

(I) H H
C1s (II) Cle

bj ti to Hofmann rearrangement.
Similarly, D·cx·phenylproplonamide gives D-cx-phenylethylamlne on su ec ng
138 REACTIONS, REARRANGEMENTS AND REAGENTS

*
CH3CH(C6H5)CONH 2 ~
*
CH 3CH(C6H5)NH2
The rate of reaction increases when the migrating group is more electron-donating and decreases when
electron-withdrawing. If A is an alkyl group with more than eight carbons, low yields are obtained.
Some side products are obtained, e.g., addition of RCONH 2 to·RNCO gives RCONHCONHR and when
A is a primary group nitriles are obtained.

Applications
(1) Formation of amines It is a very useful method for the preparation of amines.
(a) Acids and amides to amines.

1. NH40H Br2 +KOH

(i) RCOOH
2.~

NaOBr
(ii) M!JCCH~ONH2 Me:JCCHzNH2
~. ~-Dimethyl butyramide Neopentyl amine

(b) Higher amides {with more than eight carbons) give nitriles which can be reduced to amines.

(c) ~~:a gives the valuable reagent hydrazine.

Br2 +KOH
HzNCO,NH2 - - - - NHzNH2
Urea

The yield of amines is poor with ~. y-unsaturated acids.

(2) Preparation of ~amino pyridine from nicotinamide

~ONH2 Br2 +KOH o-NH2

N N
Nicotinamide P-Aminopyridine

(3) Synthesis of amino acids

CH2
I
-co NaOH CH..t'QNHz
>NH--• CJ I
Br2 + KOH CHzNH2
I
CH2 -CO CH~OOH CH~OOH
Succinirnde ~-Alanine

©I. co NaOH ©r.CONH2

)NH--•
CO COOH
1.Br2 +

2.H:P
:H ©(: NH2

COOH
Phthalimide Anthranilic acid
 HOUBEN-HOESCH REACTION 139

(4) Preparation of aldehydes from hydroxyacid amides

Br2 +KOH
(I) CeHs -CH(OH)-CONH2
Mandellc acid amide

(II) Methanolic a, p-unsaturated acid amides on treatment with NaOCI give urethane which on hydrolysis with
HCI gives a good yield of aldehyde .
NaOCI HCI
R-CH=CH-CO-NH2 R-CH=CH-NHCOOCH3 - - - A-CHO
CH:PH (Hi())

N.B. This reaction is generally confused with Hofmann elimination which relates to the cleavage of
quaternary ammonium hydroxides.

HOUBEN-HOESCH REACTION
Polyhydroxy phenols, phenollc ethers and some reactive heterocyclic compounds (e.g., pyrrole) undel'.Qo
acylation with nitrile and hydrochloric acid in the presence of a Lewis acid, the most common being zinc
chloride and aluminium trichlorlde. This particular Friedel-Crafts acylation with nitriles is called
Houben-Heesch reaction.
The reaction is carried out by passing dry HCI gas through an equimolecular mixture of nitrile and
phenol in dry ether containing ZnCl 2 . The resulting ketimine chloride on hydrolysis gives the aromatic hydroxy
ketone. Thus. resorcinol gives 2. 4-dihydroxyacetophenone.
OH OH OH

HO
-© + CHY-N
ZnCt2,
HCI o·c
'
HO
--@- @ 9
y=NH~I Hi()
CH3
Ho--@-cocHa

2, 4-0lhydroxy acetophenone

The reaction is very successful with polyhydroxy phenols especially the m-polyhydroxy phenols. The
reaction, however, is not successful with phenol due to the formation of imino-ether hydrochloride as almost
the exclusive product resulting from the attack on the hydroxy oxygen.

ZnCl2, ~ <i 9
C5H50H + RCN • Cqi~ -C =NH~I
HCI

Hydrolysis gives phenyl ester.

Besides a variety of aliphatic nitriles (e.g., acetonitrile, mono- and trlchloro-aceto nitrites), aromatic
nitrlles have also been found to give good yield. Ether, chloroform, ethyl acetate, etc., may be used as solvent.

Mechanism
The mechanism of the reaction Is complex and not fully understood. The attacking species is supposed to be
the imine hydrochloride (I) . The resulting imlne salt (II) on hydrolysis gives the product.

@ e
R-C:N + 2HCI + ZnCl 2 ___. R-C=NH ·HCI + (ZnCl3}
(I)
 140
REACTIONS, REARRANGEMENTS AND REAGENTS

palymE
OH OH substn

©_ OH
+
@
R-C=NH
-- - ¢:~
R-C=NH HCI
H:P
¢-OH
R-c=o
(II)

When hydrogen cyanide is employed in place of nitrile,, aromatic aldehyde may be obtained. This modification CondE
is called Gattermann synthesis of aromatic aldehydes. By this method aldehydes of various aromatic basic
compounds have been prepared. be am
pyridir
Applications
The reaction provides a convenient method for the synthesis of polyhydroxy acetophenones and polyhydroxy
benzophenones. Many natural products of medicinal value have been synthesized by tnis reaction.
1. Synthesis of c.o-substituted acetophenones When benzyl cyanide is used, w-phenylaceto phenones are
obtained. Med
Their

¢-OH
COCH;!CsHs
The c
proto1
2. 4-Dihydroxy-w-phenyl ~-uns
acetophenone reacti

Similarly, on reacting with chloromethyl c;anide (CICH 2 CN), 2, 4-dihydroxy-w-chloroacetophenone is

obtained.
2. Synthesis of heterocydic ketones A few pyrryl ketones have been synthesized.
CH3

CH3~COCH3
N
I
H
2, 4-Dimethyl-5 acetyl pyrrole

3. Synthesis of coumarins Oxocoumarin has been synthesized from malononitrile and resorcinol.
High
OH~OH + CH2(CN)2 _z_n_c_12_._H_C-11~OH
~OH
0
/CHiCN
_H_2_0_ OH
~OH
0 9?H=O
....-CH2
~ OH'©YO
0 aid et

c~ R o less
Resorcinol Malononitrile
~NHHCI HHCI oxocournarin only,
strori
4. Synthesis of thioesters Thioester may be prepared by using thiocyanate (RSCN) .

OH OH OH OH
+ ASCN
Thiocyanate
AICl3, HCI ©t-OH
SR
H:P
©t-OH
C .. SR
c"'
II II
The
NHHCI 0 unde
Thioester
· 0 of
Mich
Fries rearrangment is not convenient for monoacylation of a polyhydroxy phenol due to the formatio
 KNOEVENAGEL REACTION 141

~rneric
· ·
aIuminrum phenoxide. Hence, Houben-Hoesch reaction Is preferred for acylatlon of such
subStrates.

KNOEVENAGEL REACTION
Condensations of aldehydes and ketones with compounds having active methylene group in the presence of
ti on
basic catalyst to form a , ~-unsaturated compounds Is called Knoevenagel reaction. The basic catalysts may
atic tie ammonia or its derivatives. Thus, primary, secondary or tertiary amines, e.g., aniline, di- or tri-alkyl amines.
pyridine, piperidine, etc. , are used.

Pyridine- 1. H20
CsHsCHO + H2C(COOR)2 _ _ _ _ C5H5CH =C(COOR)2 C5H5 -CH =CH-COOH
Malonic ester piperidine 2.6,rC02 Cinnamlc acid

ue
Mechanisrn
Theinitial stage of the reaction is base-catalysed aldol condensation with subsequent dehydration.
In the first step the base removes a proton from the active methylene group to generate a carbanion.
The carbanion then attacks the carbonyl carbon of the substrate to form an alkoxide ion which abstracts the
proton from the protonated catalyst to form a hydroxy compound. Subsequent dehydration gives the a,
~unsaturated compound which is hydrolysed and decarboxylated to obtain ex, B-unsaturated acid. The
reaction with a malonic ester is as shown :

R3N + H2C(COOR)2 ~ R3NH

@
+
e
HC(COOR)2
iS

e @
(~~ 1
? R3NH I 9H -H2<)
R'-c + CH(COOR)2 ::;;:::=!!!: R -C-CH(COOR)2 A-~-CH(COOR)2
I I
H H -R3N: H

1
1. H20 1
R -CH=C(COOR)2 R -CH=CHCOOH .
2.6.,.-C02

High reactivity of the methylene group of the active methylene compound prevents self-condensation of the
0
r aldehyde.
Both aromatic and aliphatic aldehydes give this reaction. For steric and electronic reasons ketones are
less reactive than aldehydes. Hence, ketones react with compounds having powerful active methylene group
only, e.g., ethyl acetoacetate, cyanoacetic acid and its ester but not usually with malonic ester for which
stronger bases have to be used.

/CN CH3CONH2 ,.CN 1. t+.20

(CHJ)~ =O + HzQ__ CH COOH (CH3)~ =C (CH3)~ =CHCOOH
COOR 3 ' 2.t.,-C02 . .
COOR 3·Methylcrotonic acid

The intermediate unsaturated product formed during the course of reaction with aldehydes tends further to
undergo Michael reaction especially in the presence of excess of the active methylene compound. The
Michael condensation product may be hydrolysed and decarboxylated to obtain dibasic acid.
 142
REACTIONS, REARRANGEMENTS AND REAGENTS

/CH(COOA)2
Piperidine CH2(COOA)2
CH3CHO + H2C(COOA)2 - - - - CH3-CH :C(COOA)2 Michael reac. CH3-CH

' CH(COOA)2

CH~OOH
/
CH3-CH

' CH~OOH

3·Melhylglutaric acid

Hence, Knoevenagel reaction best proceeds with aromatic afdehydes.

Applications
1. Various ex, '3-unsaturated acids such as crotonic, cinnamic, fumaric and !3-piperonyl acrylic acids can
be prepared.

CH3-CH=CH-COOH
Cr$lonic acid

Cinnamic acid

Pip I . H20
(c) HOOC-CHO + H2C(COOA)2 - - - - HOOC-CH=C(COOA)2 HOOC-CH=CH-COOH
2.~ ;-C"2
Glyoxalic acid Maleicacid

...,...O~/
(d) H~ ....._ ...._
CHO+
H2C(COOH)2
1. Pyridine-piperidine
H~ (
o~/ CH=CH-CooH
0 ...._, 2. ~ rC"2 0 ~
Piperonal f3·Piperonyl acrylic acid

2. By reacting aldehyde with active methylene compound in 1 : 2 molar proportions, various dibasic
acids and diketones can be prepared.

/COCH3 Acidic /CH~OOH

,...cocH3 ---~A-CH

H~....._ /c~ hydrolysis '

CH~OOH
COOEt Pyridine COOEt 3·Alkylglutaric acid
A-CHO + A-CH COCH
,...cOCH3 '\. / 3 /CH~OCH3
H~, CH Ketonic
A-CH
COOEt '\ hydrolysis
COOEt 'cH~OCH3
4-Alkyl·heptan-2, 6·dione
(1 ; S·Dike!one)

1
The : S-diketones may be cycfised by the treatment with alcoholic alkali to obtain cyclohexene
derivatives.
 MANNICH REACTION

3. Cyclic compounds may also be prepared from suitably selected compounds* having one active
hydrogen. The reaction proceeds up to aldol stage and then the aldol is cyclised to paraconic acid.

HOOC
\
ROOC CH~OOR ROOC CHiCOOR H O A CH-CH2
\. / Piperidine ' / 2 • I \
C + CH3CHO - - -... c CH3-CH........_ /C=O
ROOC /'H ROOC / 'cH(OH)
I
-2CQi,-H~ 0
CH3 Paraconic acid

When paraconic acid is heated to 150°C it gives f3y-unsaturated acid.

HOOC
h
H~ -I....._ )=o
1so•c
CH3 -CH =CH -CH2-COOH
0 Pent·3·enoic acid

MANNICH REACTION
The condensation of a compound containing active hydrogen with formaldehyde and ammonia or 1° or 2°
amines usually as their hydrochlorides (HCI bein·g used as catalyst) to form aminomethyl or substituted
aminomethyl derivatives is known as Mannich reaction. The base, called Mannich base, is usually isolated as
Its hydrochloride. Aryl amines do not normally respond to this reaction.
C6H5COCH3 + HCHO + (CH3)2NH'HCI- C5H5COCH2CH2N(CH3)2·HCI + H~

Thus, the overall reaction is (active hydrogens underlined):

H
I HCI I_ I
-C-H + 0 + H-N- - - c - c - N - ·HCI + H20
I - II - I I I I
H-C-H H
With ammonia or primary amines, the reaction may proceed further since the first formed Mannich base
still contains hydrogen on the nitogen atom, i.e., active hydrogen.
CH~OCH3 + HCHO + CH3NH2HCI - CH3COCH2CH2NH(CH3)·HCI + H20

HCHO
CH~OCH3 .+ CH~OCHiCH2NH(CH3)• HCI

Hence, 2° amine is preferred for the reaction.

The starting product can be prepared from malonic ester and chloroacetic ester.
ROOC CH~OOR
'/
c
ROOC / ' H
 144 REACTIONS, REARRANGEMENTS AND REAGENTS

Similarly, three successive reactions with ammonia give a 3° amine.

3CH~OCH3 + 3HCHO + NH3' HCI _ . (CH3COCH2CH2) 3 N· HCI + 3H20

Thus, with a 1° or 2J amine, the reaction may proceed further to give a 3' amine .

The compounds containing active hydrogens which react include aldehydes, ketones, esters, phenols,
nitroalkanes, ex- and y- methyl pyridines, a- and y- methyl quinolines, acetylenes, etc.
Ketones with active hydrogen are more commonly used. If the compound contains more than one active
hydrogen. all of them may be substituted by amino methyl groups.

Mechanism
It is suggested that in the first step, the amine and HCHO in the presence of cW) condense to form imminium
cation.

It is then attacked by the enolate anion of the active hydrogen compound in the second step to form the
Mannich base.
O @ OH
.. II H I
(11) R'-C-CH3 ~ R'-C=CH2

Base has also been used as catalyst.

With unsymmetrical ketones the more highly alkylated ex-carbon is substituted by the aminomethyl
group. This is due to the more acidic character of the hydrogen on the more highly alkylated carbon and tor
that matter due to more facile enolisation.
0
II
CH3-C-CH(CH3)2 + HCHO + R2NH ___. CH3COC(CH3)2CH2NR2

Applications
1. Many important natural products, especially alkaloids, have been synthesized by this reation. A
classical example is Robinson's synthesis of tropinone by a double Mannich condensation and
subsequent synthesis of atropine.
 MANNICH REACTION 145

CHO
I H HCH2
CH2 I I Double Mannich
I + N-Me +c=o
CH2 I \ condensation
\ H HCH2
CHO · ... .,.. . .
....
Sucdnaldehyde

0 t 9H •
C~HCH3
ct> ct>

C
C-H

CHO
··
+ CH3NH2 - C'H
CHO
- c CH=NHCH3

CHO
- c·
CH
NHCH3
CHO

Better yield of tropinone is obtained by the use of calcium acetone dicarboxylate in place of acetone.

$ 0 Rod"'Uon
~pH
~H
CsHsCH(CHi()H)COOH
(Tropic acid)

Tropinone Atropine

2. Decomposition to saturated and unsaturated ketones on reduclion and on healing respectively.

Ni+HI
CH3COCH2CH3
CH3COCH2CH2N(CH3) 2
CH3COCH =CH2 + (CH3)2NH

Quaternary salts give better yield of unsaturated ketones on heating. The reaction is useful for
introducing vinyl group.
3. Building up of ring system-The easy elimination of R2 NH from Mannlch base has synthetic
applications. Thus, the unsaturated ketones obtained by heating the quarternary salts may be used
for building ring systems.

CH I @ 0
(I) CH3COCH3 + HCHO + (CH3) 2 NH - CH3COCH2CH2N(CH3)
2
~ CH3COCH 2CH 2 N(CH 3lJ I
Quaternary salt

(II) (1
~0
+ ~
A 0
Michael
addition W=o o I
Aldol
condensation
~
~O
.
 140 REACTIONS. REARRANGEMENTS AND REAGENTS

4. The imminium salt, being a strong electrophile. replaces the active hydrogens of indole, phenol,
nitroalkane, etc .. e.g.,

~
~N)J Meehafl
I
H
,,,e rea<
The product may be quatemised and the amino group may be substituted by other groups. a11eoxide
$
~Hif"(CHJ>2 (CHs>2$04 ~Hif"(CH3>3 1. NaCN
~N)J @
I
I I 2. H:P
H H H
!l·lndole acetic acid (Heteroauxin)

5. Tutocaine, a commercially useful anaesthetic, is prepared as below.

An excei
(CHJ>2NHH~ CH3·COCH· CHif"(CHJ>2HCI ~CH3 -CH-CH·(CHJ)•CH2· N(CHJ)z• HCI
ketone (I
CHJCOCH~H3 + HCHO +
I I
CHJ ~
p·H2NCsH4COOH
CH3 -c;:H -CH(CHJ) -CH2 - N(CHJ)z· HCI
O-COC&H4NH2(P)
Tutocaine

6. Synthesis of tryptophan-The amino acid, tryptophan is synthesized from the quaternary salt of Thus, for
gramine (see 4 above} and acetamidomalonic ester. Th
when Al
@
H2"J(CH3)3 CzHsONa ~H2-<;:(COOCzHs)z indicate~
+ CHJCONHCH(COOCzHs)z
N -(CHa):tJ ~N)J NHCOCHJ Specifici
I I
H H
isoproxi<
@ Ali
1. OH nearty c1
@
2. H ,A causes
reaction.
as to shi

.\pplica
The red!
MEERWEIN-PONNDORF-VERLEY REDUCTION 1.
The reaction involves the reduction of aldehydes or ketones to alcohols by treatment with aluminium
isopropoxide in excess of isopropyl alcohol.

Al(OCHM &2)3 0
II
1
RCHOHR + CH3-C-CH3

The reaction is reversible. The reverse reaction, called Oppenauer oxidation, is employed for the oxidation of
alcohols, using aluminium t-butoxide as catalyst in the presence of excess acetone.
The reaction shifts in the forward direction by the removal of acetone by distillation. The reaction occurs 2.
 -
MEERWEIN-PONNDORF-VERLEY REDUCTION 147

under mild condition, is rapid , side reactions are negligible and the yield is high. The reaction is specific for
carbOnyl group, other reducible groups such as olefinic bond, N02 , etc., present in the substrate remain
unaffected. If a compound contains two carbonyl groups, one may be protected by acetal formation and the
other is then reduced. Ketones with high enol content, e.g., f3-diketones, f3-ketoesters, etc., do not give this
reaction.

Mechanism
The reaction probably involves a cyclic transition state (I) in which a hydride ion from the a.-CH bond of the
alkoxide migrates to the carbonyl carbon of ·the ketone to yield the mixed alkoxide (II).

r--~(OCHMe2)2
R \~ ( 0 Me
'II + ~./ -
1/ ~ u~ c,
R ·~ Me
(I) (II)

An excess of isopropyl alcohol is used so that it exchanges with the mixed alkoxide (II) to liberate the reduced
ketone (Ill), i.e., the desired alcohol. ·

Thus, for the reduction one hydrogen is supplied by the catalyst and the other hydrogen by the solvent.
That a hydride ion is transferred from aluminium isopropoxide to the ketone is proved by the fact that
when Al(ODCMe2)J is used, the ketone is reduced to alcohol, R2CDOH, which contains deuterium. This
indicates that the reaction is proceeding via a cyclic transition state as shown above.
Specificity of aluminium isopropoxide A number of metal alkoxides have been used but aluminium
~oproxide is found to be the best reagent.

Aluminium alkoxides are much less polar than alkali metal alkoxides since, aluminium-oxygen bond is
nearly covalent in nature. Hence, this undergoes very little dissociation to give alkoxide ions which generally
cause some polymerization of the carbonyl compounds, specially the sensitive aldehydes. Thus, the side
reactions are negligible. Its boiling point is 140-150°C (12 mm). This enables acetone to be distilled over so
astoshift the equillibrium in the forward direction.

Applications
Thereduction has many useful applications.
1. The reaction has been employed to reduce r~. B-unsaturated aldehydes to a., f3-unsaturated alcohols.

Al(OCHMe2b
CH2=CH-CHO CH2 =CH -CH20H
Acraldehyde (CH3)2CHOH Allyl alcohol

Al(OCHMe2)3
CH3-CH=CH-CHO CH3 -CH =CH -CH20H
(CH3)2CHOH Crotyl alcohol
Crotonaldehyde

2. Reduction of aromatic ketones

 G

148 REACTIONS, REARRANGEMENTS AND REAGENTS

Al(OCHMe2)3
C 6 H 5 COCH 3 CsH 5 CHOHCH3
Acetophenone Me2CHOH
a-Methyl benzylalcohol

3. Reduction of alicyclic ketones

Q=o
Al(OCHMe2)3
Me2CHOH
OOH
H
2-C~lohexene-1-0 ne 2-Cyclohexene-1-ol

4. Reduction of a-halogenated ketones

Al(OCHMe2)J
CH3COCCl3 CH3CHOHCCl3
Tricholoroacetone Me2CHOH Tricholoropropanol-2

5. Reduction of ketoesters

Al(OCHM e2)J
Me3 c·co·cooc2Hs M e3C ·CH(OH)·COOC2H5
Ethyl trimethylpyruvate Me2CHOH Ethyl [Link]

6. The reduction has been helpful during the course of synthesis of chloromycetin and oestradiol.

1Al(OCHMe2)3 1Me2CHOH
2. HCI

Al(OCHM e2)J

Me2CHOH

HO HO
Oestrone Oestradiol

MICHAEL REACTION
The base-catalysed addition of compounds having active methylene group (or relatively acidic hydrogens) to
an activated olefinic bond of the type - C = C - Z (Z = electron-withdrawing) is classified as Michael reaction.
I I

C5H5-CH =CH-COOC2Hs + H2C(COOC2Hs)2

Ethyl cinnamate Malonic ester
 MICHAEL REACTION 149

111ecompounds having an active methylene group or having relatively acidic hydrogens are called donors and
~ compounds having an activated olefinic bond are called acceptors. A large variety of donors and
acceptors are employed in Michael reaction.
!he donors include malonic ester, cyanoacetic ester, acetoacetic ester, phenylacetic acid ester,
cyanoacetamide. aliphatic nitro compounds, benzyl cyanide, sulphones, cyclopentadienes, indenes, fluorenes, etc.
The acceptors include (a) aldehydes, e.g., acraldehyde, CH 2 = CH - CHO; cinnamaldehyde,
C0H5CH = CHCHO.
(b) ketones, e.g., benzylideneacetone, C 6 H5 CH = CHCOCH 3 ; mesityloxide, (CH 3hC =CHCOCH 3 ;
quinones, etc.

(c) nitriles, e.g., acrylonitrile, CH 2=CH- CN .

(d) esters of a, 13-unsaturated acids , e.g., C 6 H 5-CH=CH- COOC 2 H5 .

Various types of basic catalysts are used. Most commonly used are alkali metal alkoxides, such as
sodium or potassium ethoxides, potassium tertiary butoxide, potassium isopropoxide, etc. Mild basic catalysts
such as 2° amines, 3° amines, piperidine and pyridine have been used with success.

Mechanism

The base generates a carban ion from the donor, malonic ester. The carbanion then adds to the 13-carbon of
lhea, ~-unsaturated ester acceptor, ethyl cinnamate to yield the anion (I) which takes up a proton from alcohol
to produce an enol. The enol then tautomerises to the more stable product, ketone.

Jl\\?H
C5H5-CH-CH=C-OC2Hs - - - - C5H5-CH-CH2-C-OC2Hs
0
II
1 I
CH(COOC2Hs)2 CH(COOC2Hs)2
(1,4-Addilion) (a, P-Addit1on)

The electron-attracting group - COOC 2H 5 (Z) facilitates the attack by stabilizing the intermediate anion (I) by
d1spersal of the charge. It is seen that although 1,4- addition occurs initially, the final result is addition to the
Cl.~·unsaturated carbons. This is because the enol reverts to the more stable ketone (recall that vinyl alcohol
isunknown). In the presence of strong base, the product may undergo cyclisation. No cyclisation occurs with
mild bases such as 2° or 3° amines and piperidine.

Compounds with two double bonds in conjugation with the electron-withdrawing group may undergo
nucleophilic attack at (3-carbon or ~-carbon to give three products. Thus:

(a) On attack at B-carbon

 150 REACTIONS. REARRANGEMENTS AND REAGENTS

o~ e e
A 11_.1 R'o ("\ <()
QH + CH 2 =CH-CH=CH-C-OR ~ CH2:CH-CH-CH:~OR +
I
Donor Q
o e
II
CH2 :CH-CH-CHz-C-CR + R'O
I
Q (I)

(b) On attack at ~rbon

Since the double bond is conjugated in (Ill), it is the most stable of the three products. Hence it is the
predominant product

Applications
The reaction is of great synthetic importance since a variety of organic compounds can be synthesized with
the help of this reaction.
1. Synthesis of polybasic acids
(a) Tricarbaltylic acids

@ CH2'COOH
CH·C~Hs
II
C2HsONa
+ H2C(COOC2Hs) 2 .....;;..~- HJO • ~H'COOH
CH"C~H5 I
CH2·COOH
Diettyl [Link] Propan-1, 2, 3-tricarboxyflc acid

Esters of tricarballylic acid are used as plasticisers.

(b) Aconitic acid

A~ acid is used in the preparation of medicines for releaving pain (analgesic) and reducing fever
(febrifuge). Its esters are used as plasticisers.
 151
MICHAEL REACTION

2. Preparation of cyano and nitro compounds

KOH
(a) HCN + (CH3)2C=CH-N02 (CH3)2C · CH2N~
I
(CH20CH3)2 CN
2-Melhyl-1-nllropropene
2, 2-Dimethyl-3-nltropropanonilrlle.
CHzNOz
I
CH3-CH-CH2-COOC2H5
Ethyl crotonate Ethyl 3-melhyl-4-nitrobutyrate

3. Building of ring system

{a) Condensed alicyclic ring

4~H 2 C iI9
+H
3
: - ocH 3
.... c
O"' 'CH3 0

This method has been employed during the synthesis of cholesterol to build the ring system.
(b) Double Michael addition for ring formation
0
II
c
HC /
11
' CH
11 + H2C(COOC2Hs)2
,.CH CH
Ph 'Ph

(c) Cyclopropane derivative-Caronic acid

Elhyl-3-methylcrotonate Ethyl cyanoacetate

CH3, /CHzCOOH tRedP+Br2 CH3 CHBr'COOC2H5 1. Na CH3 CH'COOH

/c, CHzCOOH 'c/ - -2- - - 'c/1
CH3 2. Alcohol CH3/ 'cHBr'COOC2Hs ·H 2 0 CH3/ 'cH·cooH
p, P·Dlmethyl glularic acid Caronlc acid

4. Synthesis of dimedone Dimedone is a reagent for the identification of aldehydes in the presence of
ketones.
0 /CH2COCHa
11 C2HsONa C:!HsONa
(CH3);!C =CH-C-CH3 + H~(COOC~5)2---- (CH3);!C ......._
Dieckmann
Mesityl oxide CH(COOC~5)2 reaction

1. HJO
--';..._•
2.A ,c~
@
(CH3)iC j 0

0
Dimedone

Dimedone is also employed for the separation of aldehydes from ketones because it reacts only with
 152 REACTIONS. REARRANGEMENTS AND REAGENTS

aldehydes.
exchange with
r'<,o
(CH 3 )iC\. ,;;H + t>
+
'-'. R-C-H
OH The alur
hydride ion tra

Reaction with formaldehyde is quantitative and hence, the reagent is used for the quantitative estimation of
formaldehyde. (R
5. Synthesis of amino acids

CH;iCONH COOC2Hs
C2HsONa ' C/
CH2 =CH -COOCH3 + CH;iCONHCH(COOC2Hs)2 ---"--'--- / '\.
CHJOOC -CH2 -CH2 COOC2Hs
Since the initi<
@ NH2 in cyclohexanc
1. H:P CH-COOH
2.6 ,-CO:! cH 2 -cH 2 -cooH
(Dl) Glutamic acid
Applications
1. The I
doub
Michael reaction has been employed to synthesize anthracene from naphthalene.

OPPENAUER OXIDATION
The reaction is the reverse of Meerwein-Ponndorf-Verley reduction. The reaction involves the oxidation of a
secondary alcohol with a ketone and a base to the corresponding ketone of the alcohol.
Commonly used ketones are acetone, methyl ethyl ketone and cyclohexanone. Commonly used bases
are aluminium tert-butoxide, aluminium isoporpoxide, potassuum tert-butoxide, etc.
Thus when a secondary alcohol in acetone or cyclohexanone is refluxed with aluminium tert-butoxide in
benzene or toluene solution, the secondary alcohol is dehydrogenated to a ketone and the hydrogens are 2. Prirn
transferred to acetone or cyclohexanone converting them to [Link]. acce
Al(OCM&,3) 3
R2CHOH + (CH3)2CO ===:=e
2°Alcohol Acetone Ketone 2°Alcohol (a)

Al(OCMe3) 3
R2CHOH +
0 0 RiCO + o~H
Cyciohexanone Cyclohexanol

Primary alcohols may also be oxidized to aldehydes if acetone is replaced by a better hydrogen (b) (C
a<:ceptor, e.g., p-benzoquinone. The equillibrium can be controlled by the amount of acetone, an excess of
which favours the oxidation of the alcohol.

Mechanism
The mechanism is the reverse of Meerwein-Ponndorf-Verley reaction. The alcohol and aluminium
tert-butoxide react to form aluminium derivative of the 2° alcohol. [Metal alkoxides undergo rapid acid-base
 OPPENAUER OXIDATION 153

exchange with their corresponding alcohols.]

3R2CHOH + Al(OCMe3)3 ~ (R2CHO)JAI + 3M83C(OH)

The aluminium deflvative then forms with acetone a cyclic transition state which undergoes internal
hydride ion transfer. resulting in the oxidation of the alcohol to ketone .
0
/A)··.

czq
R2C

HJC
Al(OCHR2)2

/t,
CH:J

Since the initial attack rs on the alcoholic hydroxyl group, hindered alcoholic groups react less readily. Thus,
in cyclohexanols, the axial hydroxyl groups are attacked less readily.

Applications
1. The reagent is particularly useful for oxidizing unsaturated alcohols because it does not affect the
double bonds.

Al(OCM~) 3 ~
(a) CH3 ~CH-CH =CH-CH =C-CH =CH2
' '
------a.
Acetone-benzene
CH3 -C-CH =CH -CH =C-CH =CH2
1

a:
OH CH3 CH3
6-Methyl-3, 5, 7-octatriene-2-ol. 6-Melhyl-3, 5, 7-octatriene-2-one.

(b)
CH=CH-CH(OH)-CH3
Al(OCM~) 3
Acetone-benzene
~H=CH-CO-CH3
h
a-lonol a·lonone

2. Primary unsaturated alcohols have been oxidized to aldehydes in the presence of good hydrogen
acceptors, e.g., p-benzoquinone. In some cases acetaldehyde or cinnamaldehyde have been used.

(a) 9 Al(OCM~)3+
,...,CH 20 H - -
,.,
Qninone
60°C, 3-4 hr
~ ,,,CHO
,,.,

Geraniol Citral
Al(OCM~h
(b) (CH3)2C =CH-CHz-CH~ -CH20H + C5H5-CH =CH-CHO (CH3)2C =CH -CH2 -CH2-CHO +
[Link]-4-hexene-1-ol Cinnamaldehyde [Link]-4-hexenal

CsH5-CH:CH-CH20H
Cinnamyl alcohol

The reaction is successful with low-boiling aldehydes which can be distilled off as it is formed.
(c) The terminal CH 20H group of the unsaturated side chain in Vit A 1 is oxidized to aldehyde group
by using aluminium isopropoxide in the presence of acetaldehyde and benzene and prolonged

!tn
 zq

154

heating at 700C.
3. The ~. y-unsaturated alcohols undergo oxidation with migration of double bond 10 torm a,
~unsaturated ketooes.

This reaction finds numerous appfteations in steroid chemistry.

Al(~
Acetone

HO 0
Cl'lOles te ol

4. Formates (but not acetates or benzoates) have been [Link] to ketones.

5. Alicyclic alcohols have been oxidized to alicyciic ketones.

OH 0

cO
a -Decanol
cxJ
Sensitive alcohols can be oxidized unde mild conditions by u~ng fluoreoone which is a &1r00g
hydrogen acceptor.

PERKIN REACTION
In Perkin reaction, condensation has been effected between aromatic aJdehydes and aliphatic acid
anhydrides in the presence of sodium or potassium salt of the acid corresponding to the anhydride. 10 yield
o., ~unsaturated aromatic acids.
The acid anhydride should have at least two a-hydrogens.
Al;ONa
CsHsCHO + (CH:J('O):zO Ct)H5-CH:CH -COOM + C H~
170-180cc . 5 h

Besides simple aromatic aldehydes, their vinylogs, heterocyclic aJdehydes and even phathalic anhydride (as
the carbonyl component) give this reaction.
 PERKIN REACTION 155

(a) CeH5-CH =CH -CHO (CH3CO)iO, AcONa C5H5-CH=CH-CH=CH-COOH

A 5-Phenyl-pent-2,4-dienoic acid

~
(b)
O CHO
(CH 3C0)20, AcONa
A ~CH=CH-COOH
0
3-(a-Furyl)-acryllc acid

0 CH-COOH
II II

(CH~COhO,
(c) ©r=C'
cII
. .o 6
AcONa
©J:::o II
0 0
Phthalylacetic acid

Mechanism
It ls suggested that the acetate ion abstracts a proton from the a-carbon of the anhydride producing a
carbanion (I) which then attacks the carbonyl group of the aldehyde. The product (II) then abstracts a proton
from the acid to form aldol-type compound (Ill). The latter then undergoes dehydration in the presence of hot
(ca 140°C) acetic anhydride.
On pouring the hot mixture in water. the mixed anhydride is hydrolysed to a, ~-unsaturated acid (IV).

CH3COONa ~ CH3COO + Na
e ®

e
CH3COO + H-CH2-CO-O-CO-CH3 ~
e
CH3COOH + CH2-CO-O-CO-CH3
Acetic anhydride (I)

e
CR~
CsHs-C + CH2-CO-O-COCH3 ~
0a
CsHs-C-CH2-CO-O-CO-CH3
CH3COOH
I
H H (II)

~
C5H5-C-CH-CO-O-CO-CH3
11o·c C5H5-CH=CH-CO-O-COCH 3 _H_2.... o_
He.H <111> -H20

CsH~H=CH-COOH + CH3-COOH
(IV)

Prolonged heating (about 5 h) and high temp. is required, since a weak base (acetate ion) has to react
with a weak acid (anhydride).
That the anhydride adds to the aldehyde is proved by the fact that when benzaldehyde, acetic anhydride
and trimethyl amine or pyridine are heated. cinnamic acid is obtained, but when benzaldehyde, sodium
acetate and pyridine are heated, it is not obtained. Thus, the alkali salt acts only as the catalyst.
Meta-directing groups in the aromatic ring promotes the reaction. When anhydride with one a.-H atom is
used. no dehydration is possible and an aldol-type product is isolated.
'Tl-.A ---~- - • - - - -· - - ~- - -- --"' ----i----4.:-- ! - ..~- - - - - - - -
156 REACTIONS. REARRANGEMENTS ANO REAGENTS

Applications
Perkin reaction has many useful synthetic applications.
1. Preparation of ((·Substituted unsaturated acids

CeHs-CHO + (CH:JCH~0)20 Ac~a· C&t"f5-CH=C(CH3)-cc>OH

a-Methylcinnamic acid

2. Synthesis of coumarin

rAJCHO

~OH
©C;~J -H,O ©(),.,
HO
Salicylaldehyde COumarin

3. Synthesis of carbostyril (nitrogen ana log ue of cou marin)

rAJCHO CH"
~O,AcONa 'CH FeS04 NH3
~N()i A NQi)~ =o (Aedn)
HO
~Nitrobenzaldehyde ~Nitrocinnamic acid ~Aminocinnamic acid

4. Synthesis of phenanthrene

CHO H2') -COONa CH=C-COOH CH=c~

~N()i +
o-Nitrobenzaldehyde
©
Sodium phenyl
@-NO,©
a-Phenyf-o-nitro
1. [Link]., NH3
2. NaNQi + H~4 ~
IT- - -~">()\
y
acetate cinnamic acid

Cu + H~4
A, - CQ2

5. Preparation of paraconic acid

C5H5-CH-CH-co, H20 [ Ct;Hs-yH-yH-COOH] - H20

I I /0 ~ OH /H2 A
OH CHz-CO
HOOC

6. Erlenmeyer's Azlactone synthesis

 PERKIN REACTION 157

It is believed that benzoyl or acetyl g ycine first forms a cyctic compound hot acetic anhydride. The
active methylene group of the cyclic co pou t en reacts ~ - ea de.

~ -COOH ~ --c=o k,p H2G-C::O

H-:-N ""
r:.... '.dl ~ N
I I
OH
--~..
_ 1-LJ"\
I ' o
o~
~c-- ~ ...oH ·~ ~c/
I C I
R I R
R

Azlactone on reduction followed by hydrotysis gives a-ammo aad and on SllT1ple rydrolysis gives a-keto
acid.
(i) a-am-no ac·d
H+P
Csf'is-CH:C-C:O Na Hg
I \ or -
N~ 0
~c/
I
R
Azladone

® a-keto acid

Csf"is-CH::C-C:O~C&tis-CH::C--cooH ~C
I \ I
N~ 0 '..,OH
~c/ c
I I
R R

7. Preparation of vinylogs of cinnamic acid

8. Aromatic anhydride · ace a

 158 REACTIONS, REARRANGEMENTS ANO REAGENTS

Phthalylacetic acid may be converted to different products (Michael and Gabriel), thus:

CH-COOH
II CH Na ©rco ~CH-COOH
HCl,A
©rco CO~CHi
©::> II
0 1. Cold KOH
[Link]. HCI
©::COCH,COOH
co

COOH
A
-C~
lndane-1 :~lone

©c:H3 CCX>H
o-Acetylbenzolc acid

PINACOL-PINACOLONE REARRANGEMENT
The acid-catalysed rearrangement of vie diols (1, 2-diols) to ketones or aldehydes with elimination of water is
known as pinacol or pinacoJ-pinacolone rearrangement. The name was given from the classical example of
the conversion of pinacol to pinacolone.

~ ~ H@(Oil.H~.c) ~ ~
Me -c-c-Me
I I
-------•Me
A
-c--c-Me I
OH OH Me
Pinacol Pinacolone (Methyl·t-butyl ketone)

Ph H PhH
I I I I
Ph-C-C-H Ph-C-C=o
I I I
OHOH H
2, 2·Dlphenyl -1, 2"1)1yool 2, 2·Diphenyl acetaldehyde

Elimination of water without rearrangement-the normal reaction of alcohols-may be achieved under

drastic conditions (A~03 , 450°C).

CH3 CH3 CH3 CH3

I I AJ2~ 1 45Q°C I I
CH~-C-C-CH3 ------~ CH2 =c-c =CH2 + a little pinacolone
I I
OH OH

The rearrangement has been successfully carried out with various polysubstituted glycols.

Mechanism
The reaction involves the general characteristics of carbocation rearrangement in which the driving force is the
stabilization of the resulting carbocation.
The reaction starts with the protonation of the hydroxyl group followed by elimination of water and
formation of carbocation (I). The carbocation is then stabilized by Whitmore 1, 2-shift. Finally, elimination of a
proton from the stable carbocation (II) gives the carbonyl compound.
 PINACOL- PINACOLONE REARRANGEMENT 159

Me Me
I I
@
~
Me-C-C-Me -----.... Me -C -C-Me
Me
I
Me
I G\ t'{'e 1, 2-Methyl shift @ "{'e
~
Me -9-c;,-Me - - - - - · M e -9-9-Me ...---i..
I I I @d;u
OH OH OH~ OH
I
OH Me
II
Me @ Me
Me-C-C-Me
I
-H I
Me-G-C·Me
II I II I
@OH Me c ~

The carbocation (I), though tertiary, prefers to form (II) for its resonance stability.
The mechanism is supported by the fact that any carbocation in which the positive charge is on the carbon

adjacent to the one bearing the hydroxyl group (-~-~-OH l also undergoes similar rearrangement. Thus,

Me Me @
Me Me Me
Me
1, 2-shitt, - H
I I NaN02 + HCI I I -N2 II
Me-C-C-Me Me-C-C-Me Me-C-C-Me

~
I I I
5°C
OH NH2 OH@N::N OH @

Me Me @ Me Me Me
I I Ag I I
1, 2-shitt I
Me-C-C-Me Me-C-C-Me Me-C-C-Me
I I (Ag;P) I @ @ II I
OH Cl OH -H 0 Me

The loss of water and migration of the alkyl group may be very rapid or simultaneous. Probably the migrating
group does not become completely free before it is partially bonded (Ill) to the adjacent positively charged
carbon, i.e., a type of intramolecular rearrangement is suggested.
R

" /e\ /
/ c(iii)c"-

Evidence in favour of this are (a) the migrating group retains its configuration, if chiral and (b) no cross-over
products are obtained when a mixture of two nearly similar 1, 2-diols is treated with acid.
Migratory aptitude Migration order in general is H > aryl > alkyl.

Ph H @ Ph 0 H H @ H H
I I H I II I I H I I
Ph-C-C-CH3 _ . Ph-C-C-CH3 CH3-C-C-H - CH3-C-C =0
I I I I I I
OH OH H OH OH H

As the migrating group migrates with its electron pair, the more nucleophilic group might be expected to
migrate. Thus, the order of migration amongst the aryl groups is p-anisyl > p-tolyl > phenyl > p-chlorophenyl,
etc.

¢¢
Ph-C--C-Ph
I I
OH OH
 160 REACTIONS, REARRANGEMENTS AND REAGENTS

Obviously, electron-withdrawing groups will retard the migration. The migratory aptitude amongst the alkyl
groups is Me3C > Me2CH > Me. However, the stability of the initially formed carbocation may offset the
migratory aptitude order. The initial carbocation is formed by the loss of that hydroxyl group which results in
the formation of the most stable carbocation. Thus, in the compound 1, 1-dimethyl-2, 2-diphenyl glycol, the
resonance-stabilized carbocation (IV) is formed instead of (V) and so it is the methyl group and not the phenyl
group which 'migrates. contrary to the above sequence.
Ph 0
I II
1, 2-shift Ph -C-C-Me
@ I

-H Me

Less stable than (IV)

Steric hindrance may affect the rate of migration-p-anisyl group migrates 1000 times faster than o-anisyf
group.
The migrating group attacks from the trans position (back side) to the leaving group. This has important
effect in cyclic systems. Thus, the two isomers of 1, 2-dimethyl-cyclohexane-1, 2-diol give different products
due to different orientations of the methyl and hydroxyl groups. The one (VI) in which the Me and OH groups
are trans to each other gives 2, 2-dimethylcyclohexanone by methyl shift. The other (VII) in which the Me and
OH groups are cis to each other undergoes ring methylene group shift instead of Me-shift with consequent ring
contraction to give 1-acetyl-1-methylcyclopentane (VIII).

Me

HO~ -H2')

-H
@ [Link]t
Me
(VI)

~~ -
Me
@
H Me-c·, +._ A

0
11 l-.::::::/'
OH
(VII) (VIII)

The rearrangement has interesting applications in synthesis.

Applications
1. Synthesis of carbonyl compounds from alkenes lsobutyraldehyde may be prepared on a large scale from
isobutylene.

@ CH3 H
H I I
____. CH3-C-c=o
I
H
Dimethyl acetaldehyde
(lsobutyraldehyde)

2. Ring expansion of cyclic ketones Cyclohexanone can be converted to cycloheptanone in good yield.
 REFORMATSKY REACTION 161

3. Ketones from cyclic diols Pinacol rearrangement has been employed to prepare ketones which are
otherwise inaccessible or are very difficult to synthesize.

p Ph Q

7. 8-D1phenytacenaphthene
-7, 8-diol
--H
(!)

65
r I
~
"'-=::
h-

7-0xo-8, 8-diphenylacenaphthene

(ii)
2
C)=o 1. Mg. ether
2. H20
Cyclopentanone
pinacot

REFORMATSKY REACTION
Reformatsky reaction involves the preparation of P-hydroxyesters by the treatment of a reactive organic halide e.g ..
a.-haloester or its vinylog with a carbonyl compound in the presence of zinc metal and subsequent hydrolysis.

1 . Zn + EiiO 9H
R-y=O + BrCH2COOEt @ • R-C-CH2COOEt
A' 2. H30 A'
In practice, a mixture of the carbonyl compound, a-bromoester and zinc in dry ether is cautiously heated
under reflux when zinc dissolves. Zinc may be activated by adding traces of iodine, mercuric bromide or
copper powder. The mixture is then treated with ice-cold dilute sulphuric acid and ether layer separated. Ether
is distilled off when ~-hydroxyester is obtained.
Generally used solvents for this reaction are ether, benzene, toluene, THF etc. In place of zinc,
activated indium, tin or zinc-copper couple have been used.
The aldehyde or ketone may be aliphatic, aromatic, or heterocyclic and may contain various functional
groups which remain unaffected (difference from Grignard Reagent).
Acid catalyzed dehydration of the P-hydroxyester gives a, ~-unsaturated ester.
@
OH @ 40H2
I H ~ -H20
R-C-CH2COOR ' ~ R-C-CH-COOR ' R-C=CHCOOR'
A I
A'~'H -H@ AI

Mechanism At first zinc and the a-bromoester react to form an organo-zinc intermediate (i). The zinc salt of
the enol ester then adds to the carbonyl group of the aldehyde or ketone. Subsequent hydrolysis gives
~hydroxyester.
 RE TtON REARRAN MN ANO A AG NT

6
0
StCH COOEt + zn E 1, Br~ 1~3P-oEt .__. ';':~~
Organo-Ztnc lntannoeft to

0 :~~
Ry~C-OEt- R-9-cHrC-OEt~ R-9-CH2COOEI
9ZnBr R H ~ 9H
R R R

The initial formation of the oragno-zinc intermediate (i) has been subst ntlated. Th X-ray
crystallography of the solid derived on treatment of t-butyl bromoacetate with zinc Indicates its structure to be
(ii). This structure may be seen has some characteristic semblance to (I) .
Br
Zn-CH2 OR
~' ' /

w fi R=t ·Bu~
Ao~c 'cH2-zn· ·o
' Br
(II)

Reformatsky reaction is closely related to Grignard reaction. The initially formed intermediate,
BrZnCH2COOEt is analogous to RMgX. Grignard reagent cannot be derived from a- haloesters since it reacts
with active halogens. The organo-zinc compounds are less reactive than Grlgnard reagent and do not
normally react with their own ester group. It cannot however add to sterically hindered carbonyl compounds
i.e., with too highly substituted ketones. In such case it reacts perforce with its own ester group producing a
~-ketoester.
0 OZnBr
II I HCI
2Br-Zn-CH-c- Br-Zn-CH-C-CHR'COOEI - - · R'-CH2-C-CHR '-COOEt + EtOH + 2ZnBrCI
A' OEt OEIA' (H30•)
II
0
P·Ketoester
Reformatsky reaction, therefore, best proceeds with aldehydes, methyl ketones and cyclic ketones.
Reactivity order of the a-haloesters is iodo > bromo > chloro. Zinc-copper couple may be used with
chloroesters with advantage. The~- and y-haloesters are much less reactive. However, y-bromocrotonic ester
being a vinylog of a- haloester is as much reactive.
Besides aldehydes and ketones, nitriles (Blaise reaciton) and carboxylic esters have been used as
substrates.

0 CH2COOR" CH2COOR"
Z I r4
l
II
I H 0
(ii) R-C-OA' + BrCH2COOR" --2!.... R-C-OR' ~ R-C"\OR'
I
OZnBr tiOH
C(H2COOR"
A-c=o
Normal addition in (i) and substitution in (ii) are observed though the products are the same .

.
 REFORMATSKY REACTION 163

Applications
The reaction has many valuable applications:
1. Pr~paration of ~-hydroxyesters and unsaturated esters
1. Zn 1 H2S04,~
A-CHO + R' -CH(Br)COOEt---• R-CH(OH)CHR COOEt R-CH=CR'COOEt
2. H3o
@ P-Hydroxyester - H2
0 a. [Link] ester

0-\ CHO + BrCH2COOEt

[Link] fT"V.
<(_ ;.>-CH=CH-COOEt
s @
2. H30
s
Ethyl-~·(2-thienyl)-acrylate

2. lengthening of the carbon chain

1. Zn
CsHsCOCH3 + BrCH2COOEt @ CsHs-C =cH-COOEt
2. H30 I
CH3

C5H5CH(CH3)"CH2-COOH
~-Phenylbutyric acid

By suitable selection of the reactants, unsaturated or saturated acids or esters with branching at ex- and
~-carbons can be synthesized.
3. Synthesis of arylacetic acid

a-Tetralone

a-Naphthylacetic acid

It has an important application in agriculture.

4. Synthesis of citric acid
(f)
CH2-COOH
9ooe1 Zn, Benzene yH2 -COOEI H30 I
yO + BrCH2COOEI BrZnO-C-COOEt Ho-c-COOH
I I
12 CH2-COOH
CHrCOOEt CH2-COOEt
Citric acid
Oxatacetic ester

5. Synthesis of citral

~.,. 1.H~rolysls YHO

+ ICH~OOEt

6-Methylhept-5-ene-2-one
1. Zn

2. HsO
@

9 CH2

OH
00Et k20,
-H20
b
COOC2Hs~~------_..,
2. Ca-salt+ HCOONa
Dlslil
b
Citral
 164 REACTIONS, REARRANGEMENTS AND REAGENTS

6. Synthesis of camphoronic acid

yH3
co
I
yHa
CH3-9-cH3 + BrCH2-COOEI 'fiO-C-CH~OOEt
I
COOEI CH 3 -y-CHa
Ethyl-u, a-dimethyl COOEt
acetoacetate

7. Synthesis of vitamin A1

((-60 1. Zn + BrCH2CH=CH-COOCH3

2. H36i' 3.6, - H20

OOH 1. SQC'2

2 . CH31J

~-lonone

1. Zn + BrCH2COOEt
Me
2. H20 3.6 ,- H20

CH2<)H

VrtaminA1

REIMER-TIEMANN REACTION
Formylation of phenols with chloroform in alkaline solution is known as Reimer-Tiemann reaction (RTR). The
method is applicable to phenols and some heterocyclic compounds.
A mixture of ortho- and para-isomers is obtained in which the ortho isomer predominates. If one of the
ortho positions is occupied, the para-isomer is the major product.

g~ + CHCl3 + NaOH
60°C

+ CHCl3 + NaOH -
60°C
¥
rAr-oOH OCH3

CHO
Gualacol Vanillin

The reaction is carried out by refluxing an alkaline solution of phenol and chloroform at 60°C for
sometime (1/2 h). Excess chloroform is distilled off, the mixture acidified with sulphuric acid and steam
distilled. Unreacted phenol and the ortho-isomer distil over leaving behind the para-isomer. The two isomefS
are further purified by sodium bisulphite. The yield is low.

Mechanism
It is believed that chloroform and sodium hydroxide react to produce an electron-deficient electrophiJe.
dichlorocarbene (:CCl2) .
 REIMER-TIEMANN REACTION 165

e
HO
~Cl
+ H --[Link] --
fast e/./Cl
+ 'C-CI
eK-/ slow
•c-c1 e
1CCl2 + Cl
"Cl
" Cl
" Cl

Dichlorocarbene then attacks the aromatic ring to yield a dichloro anion (i) which takes up a proton from the
solvent. The product (ii) tautomerizes to crdichloromethyl phenol which after hydrolysis and acidification gives

6-
salicyl aldehyde.
e
c.:.o o o ~o 1

V. -0~ci ~ CHC I~
N._0e
J
H :cc1 2 "- H

V V' 2
H20•
V' 12
Tautomerisatlon
h
CHCl 2

(I) (II}
e e
.-!
u-- CHO ..JL
@
:t
lJ
~CHO OH

That the reacting species is dichlorocarbene is supported by the following:

(i) Dichlorocarbene is known to cause ring ~xpansion which is observed in the reaction of pyrrol e with
chloroform and alkali.

0 ~CHO+ ~Cl
NI N
I
i!.__.N :J
H H 3-Chloropyrldlne
Pyrrole (Ring expansion)

(ii) When p-cresol instead of phenol is used besides the normal aldehyde, a ketone (Ill) with
dichloromethyl group is obtained as a by-product.

~CHO
OH

¢ CH3
CHCl3

HO
e y
CH3

The compound {Ill) may be explained to be formed by the attack of some :CCl2 at the para position and
subsequent gain of a proton from the solvent. As this para position has no ring H that can be lost as proton to
re·aromatise the ring, the reaction does not proceed further.
Due to its insolubility in basic aquoeous medium and crowding around chlorine atoms. the dichloro
:ompound (Ill) is not hydrolysed.

:cc12 nXe
H3C
0

CCl2
H
from solvent
@

(II)

he presence of negative groups such as CN, COOH, N02 , S03 H, etc., decreases the yield.
he yield is nearly 50% and a large amount of phenol remains unreacted. This is probably due to the formation
f diphenylacetal derivative.
166 REACTIONS, REARRANGEMENTS AND REAGENTS

(vi) Abnom
1 . Pyrrole ur;
Norm<
Carbon tetrachloride in place of chloroform under RTA condition gives salicylic acid.
Applications
The reaction affords a good method for introducing aldehyde or carboxyl group in phenols.
(i) Preparation of vanillin

&OCH3 _1_
. c_2~-:-=~:-+_K_o_H ~OCH3
Guaiacol CHO
Vanillin

Abnc
(ii) Preparation of piperonal

O~HO
HO~ + HO~cHO CH2l2 + NaOH
H~~.M
1. CHCl3 NaOH

HO 2.H@ HO 0
Catechol fYiperonal
Tl'le
(iii) formylation of heterocyclic compounds
(vii) Cert
(a) (b)
0s CHCl3
KOH
11:)..-cHO
s
0 N
I
CHCl3
KOH
li:).-cHO
~
Thiophene-2-aldehyde H H
Pyrrol&-2-aldehyde

(c) ~ CHCl3 O::rCHO

~N)J KOH T'hi
I I
H H The proc
~lndole-aldehyde

The compound has been used to synthesize the amino acid, tryptophan.
(iv) Formylation of naphthol

CHCl3
KOH
roOH
2-Hydroxy-1-naphthaldehyde

(v) Preparation of acid

When carbon tetrachloride in place of chloroform is used, a carboxyl group is introduced. Alkyl h.
SOC1 2 ,
OH ha loge
isomer
CCl4
NaOH
6-COOH pOsitio
Sallcyllc acid
 SANDMEYER REACTION 167

(vi) Abnormal Reimer-Tiemann reaction

1. Pyrrole undergoes normal and abnormal RTR
Normal reaction-

0 N
CHCl3 + NaOH
( l CCl2)
-+ 'Et>-H~
c::N' ---CCl2
- - - . {)-cHCl2 -
~
I
H
@
H~ ~CHO
N.
I
H
Pyrrole-2-aldehyde

Abnormal reaction (Ring expansion)-

~ Cl
0 CHCl3 + ~-aOH f/\E/C'c1
~~.{"
----+ ~
N
N (I CClz.)
I
H SJ 3·Chloropyridlne

The reaction has been used to prepare pyridine and its derivatives.

(vii) Certain phenolic compounds also exhibit normal and abnormal RTR

~CHO CHCl2

()()
ar-2-Tetralol
OH
CHCl3
NaOH ~ OH
Normal product
+cti 0
Abnormal product

The abnormal product may be reduced and then oxidized to give a product with angular methyl group.
The process has been utilized in steroid chem istry .

1O-Methyldecal-2-one

SANDMEYER REACTION
Alkyl halides are more often prepared from the corresponding alcohols by reacting the alcohols with PC13 ,
SOCl 2 or concentrated HCl/ZnCl 2 . The aryl halides cannot be prepared from phenols by these methods. Direct
halogenation of aromatic compounds yields a mixture of isomers from which it is difficult to isolate the desired
isomer.
Sandmeyer reaction affords a useful method for introducing a halogen substituent at the desired
position of an aromatic ring.
 168 REACTIONS, REARRANGEMENTS AND REAGENTS

The method involves the conversion of an aromatic primary amine into an aryl diazonium salt by
treatment with nitrous acid in the presence of mineral acids (usually HCI or H2 S04 ) at low temperature
(0-5°C). Subsequent decomposition of the diazonium salt by heating with cuprous chloride or bromide in the
presence of an excess amount of the corresponding halogen acid gives aryl chloride or bromide. The overall
reaction is, thus, the replacement of the amino group of the aromatic amine by halogens.

CH3@ e
&NH2 NaN~+HCl

o-5°c
&N,CI CuCI, HCI
60°C
&Cl

¢ ~
~
CH3
NaN02+H~04 CuBr, HBr
100°c
1S-20°C
e Br
NH2 @N2HS04

Mechanis1n
It seems that cuprous copper has the power to reduce diazonium ion to aryl radical by oxidation-reduction
involving one-electron transfer. The copper first acts as reducing and then as oxidizing agent.

@ 9 I @ I 9
C5H5 -N ::NCI + CuCI - C5H5 -N ::N + CuCl2
@ I 9 . II
Ct)H5-N:N + CuCl2 .__. C 6 H 5 + N2 + CuCl2
• II I
CsHs + CuCl2 __....... C5H5CI + CuCI

The formation of aryl radical is substantiated by the decomposition of benzene diazonium chloride in the
presence of acrylonitrile when 2-chloro-3-phenylpropionitrile is obtained through free radical addition.
• cue~ 1
•-c 6 H 5 + CH2 :=CH-CN - C5H5-CH2-CH -CN -___;;;.• C5H5-CH2 -9H -CN + CuCI
Cl

The formation of the halide by the cupric copper may also involve a carbocation intermediate or an
organo-copper compound.

• II @ I
e
Cl I
CsHs + Cu ____.,. C5H5 + Cu -"-"-+ CsHsCI + Cu

or
11
·csHs + Cu + Cl ____.,.
e C5H5-Cu-CI ____.,. C6 HsCI + Cu
I

For the preparation of aryl iodide, the aryl diazonium salt is treated with potassium iodide solution. The
cuprous catalyst is unnecessary because iodide ion is sufficient to decompose the diazonium salt. However.
in this case also oxidation-reduction is probably involved since enough iodine is liberated in the reaction.
 SANOMEYER REACTION 169

Kl soln.
©r'
Aryl fluoride is prepared by treating the diazonium salt with fluoboric acid or fluoborate. Sparingly
soluble diazonium fluoborate which separates is washed and dried. The dry salt is then decomposed by
heating.

This reaction is known as Schiemann reaction.

Cattermann modification It has been found that copper powder or copper bronze in place of cuprous chloride
acts similarly to yield the aryl halides. This may be due to the formation of cuprous copper on the surface of
the copper metal.

Applications and extension

Sandmeyer reaction for the preparation of arylhalides from diazonium salt Is more important and useful than
direct halogenation for several reasons.
(i) Direct halogenation of aromatic compounds gives a mixture of isomers so that the yield of the
desired isomer is low and difficult to separate. On the other hand, the diazonium salts give only one
halogen derivative since the halogen enters at the position previously occupied by the diazonium.
group.
(ii) Aryl iodides and fluorides which are seldom prepared by direct halogenation can be prepared by
Sandmeyer reaction and Schiemann reaction respectively.
(iii) In some cases direct halogenation at a particular position is not possible for reasons of electronic
factors but this has been possible through Sandmeyer reaction, e.g ..
(a) Preparation of m-dichlorobenzene

N02 Cl

~
©-Cl
Fe+ HCI t NaN~ + HCI, o-si::;

~N~ 2. CuCl,HCI

(b) Preparation of 2-ch loronaphthalene

t H2 so,., 120°c
_2._N_a_O_H_fu_s_e_.,. ~o OH __
t_(N_H_.._h_So_3_·_NH_3_.H_2_0_._1ss__c_
0

3. H@ ~ 2. Aq NaOH, 100°c
~ - Naphthol

rArA'( NH2 t NaN02HCI, 0-S'C OOfo Cl

~ 2. CuCl,HCI
~ -Naphthylamine 2-Chloronaphlhalene

(c) Preparation of acids- Diazonium salts on treatment with cuprous cyanide and potassium
cyanide give nitrlles which on hydrolysis give acids.
 170 REACTIONS, REARRANGEMENTS AND REAGENTS

@
CeJ-i5CN Hf' • CeHsCOOH

(d) Removal of amino group from aromatic rings- Amino groups of aromatic amines after
conversion to the corresponding diazonium salt and treatment with hypophosphorous acid are
removed from the aromatic rings. The reaction has been successfully useq to prepare compounds
which cannot be prepared by direct substitution. Thus, m-nitrotoluene may be prepared form toluene.
Toluene on nitration gives~ and ~nitrotoluenes. The para-isomer after separation is processed as
below.

~ _1_.R_ed_n_~ HN03 HCI

¥N0i
[Link]:;P ¥
NHAc

SCHMIDT REACTION
Carboxylic acids and hydrazoic acid react in the presence of sulphuric acid to give amines. This reaction is
known as Schmidt reaction.

Free hydrazoic acid is highly toxic and hence sodium azide is slowly added to the solution of the carboxylic
acid in sulphuric acid when hydrazoic acid is liberated.
The reaction is closely related to Hofmann and Curtius reactions, all of which involve the formation of
isocyanate intermediate through the migration of a group from carbon to nitrogen.
Schmidt reaction also occurs between ketones or aldehydes and hydrazoic acid when ketones give
substituted amides and aldehydes give a mixture of nitriles and N-formyl derivatives.

RCONHR + N2

RCN and RNHCHO

Nitrile N-Formyl derivative
(Major) (Minor)

The rearrangements in these cases closely resemble the Beckmann rearrangement. Dialkyl and cyclic
ketones react more readily than alkyl aryl ketones. With alkyl aryl ketones, it is the aryl group which migrates.

Mechanism
(~) Acids (i) It was found that the transformation occurs most rapidly without heating with sterically hindered
acids (e.g., mesitoic acid) which readily form acyl cations in sulphuric acid. This clue led to suggest the
formation of protonated acyl azide (I), in the first step, which eliminates nitrogen to form the intermediate (II).
The intennediate (II) then undergoes rearrangement to form isocyanate which is hydrolysed under the
reaction conditions to amine and carbon dioxide.
 SCHMIO ~ ACTION 171

H
~ HS O
il(i ~ $"
H-t{-N!N 0ii H~
Is - N2 .. ~~<i>
R -C-OH _....;..;.._• R-C - - - - - A - C - N NcN
-HiO (Hydrozolo told) (I) (II)

Q:C:N-R
l1ocyn1tt

(ii) Acids which do not torm acyl c ton react through the protonated acid on heating as below.

0
H
R-y _.,.
II
R-Y\;p
$ OH
1 [Link] H-~-~ENI 9H~
_ _....g..__.....,R-y - N-N:N
<i> - H'/J ~?J~
R C=NtN:N
OH OH OH
(f J'\ I
.
- N2. - H""""
- - - - - - A-N :C :Q _....._..~ RNH:z + CO:z

Isocyanate ls not Isolated under the acid condition although It ha'l been Isolated under anhydrous condition.
The rearrangement Is intramolecular since the migrating group never becomes free. This has been concluded
from the crossover experiment and from the fact that the migrating group retains Its configuration.
(b) Carbonyl compounds The mechanism tor the reaction with ketones was suggested by Schmidt. The
reaction proceeds through the protonated carbonyl compound .

0 $ OH 9GJ OH ~ A' (.i)

11 I H
R-C-R ______. R-i-R
I I H-N-N:N
R-C-R 1 - H:zO c/~ ~ R'-c=N-R
I Ci> II Ci>
H-N-N:N N N:N
(Ill)
H:zQ H@ n.
R'-y=NR - R_i,y':NR --;:-- R'-~-NHR
®6H2 [Link] 0

Steps from (Ill) on'l(ards resemble Beckmann rearrangement.

In the case of aldehyde the Intermediate (Ill) will have the structure (IV) In which migration of H will give
nltrile and migration of R will give formyl derivative.

MlgraUon of H @('"'.>) - H®
R-C=N-H __... R-C:N
(a)
~9H ~
Mlgrallon of R
(b)
(i)
A-N =C-H 7
H

-H
A -N-CH -;;;::::;- R -NH-C-H

Sulphuric acid is the most common catalyst for Schmidt reaction but Lewis ac ds have also been used. ·

Applications
1. Preparation of amines Primary amines In good yield are obtained directly from the acids, provided the
acids do not contain groups sensitive to concentrated sulphuric acid. The reagent, however, Is dangerous to
handle due to Its poisonous and explosive nature.
 REACTIONS, REARRANGEMENTS AND REAGENTS

H2S04
(1) C5H11CH2COOH + N3H - - • C5H5CH2NH2 + N2 + C02
Phenylacetlc acid CHCl 3 Benzyl amine

p-Tolulc acid p-Toluldlne

2. Preparation of a-amino acids Ethyl acetoacetate and hydrazoic acid react in the presence of sulphuric acid
to give a-amino acid .

A·CH(NHz)'COOH

Note that the reaction with ketones is virtually the insertion of NH group between the carbonyl group and the
alkyl group of the ketone.
3. Preparation of lactams Cyclic ketones react to give lactams. Cyclohexanone gives e -caprolactam.

Cc=o
NH

With excess of N3 H substituted tetrazoles are obtained from ketones. Cardiazole, a heart stimulant has
been prepared from cyclohexanone and N3 H

~o +
l.,.._,)
2NJH __..rr7 .
~N'~·~N
N
N2

SOMMELET REACTION
Sommelet reaction involves the oxidation of chloromethyl group (-CH2CI) to an aldehyde group by the use of
hexamethylenetetramine (C6 H12N4) and subsequent hydrolysis in acidic medium (pH 3-6.5). The reaction is
successful with benzylic halide (ArCH 2 CI).

CHO

Quaternary salt
00
1-Naphthaldehyde

Mechanism
The mec~anism of the reaction is not clearly understood. According to Angyal and co-workers, the halide
reacts with hexameth~len~tetramine to form a quaternary salt (I) which is hydrolysed to amine (II).
Hexamethyle~e tetramine 1s . also hydrolysed to formaldehyde and ammonia which subsequently form
methylene amine (Ill). The amine (II) then transfers a hydride ion to methylene amine (Ill) to form an imine (IV),
 SOMMELET REACTION 173

which is finally hydrolysed to aldehyde.

~
H~ @
(ii) CsH1~4--••CH~ + NH3 __.,. CH2=NH2
(Ill)

@
__.,. C~s -CH =NH2 + CHj',jH2
(IV)

Reaction of benzylamine with excess of C6H 12 N4 to produce aldehyde is the actual Sommelet reaction
(the last three steps) . When benzylamine is refluxed with hexamethylenetetramine (hexamine) in acidic
medium benzaldehyde is obtained. This lends support to the above mechanism.
Strong deactivating groups as also o-substituents decrease the yield. When both the o-positions are
substituted , as in 2, 4-dinitrobenzylchloride, the reaction completely fails. The yield is also very poor with
phenolic compounds.
The reaction is generally useful for the preparation of aromatic aldehydes.

Applications
The reaction has proved useful for the preparation of aldehydes from amines and halides. Various types of
aromatic, heterocyclic, some aliphatic aldehydes and amines have been prepared.

CHO

(•)¢
CHzBr

1 : 1Ac0H
+ CeHt2"'4 - /1
rAo
¥
Br Br
p-Bromobenzaldehyde

1 1
(b) fJ--cH'/;1 + (CH2)6'114 : AcOH fJ--cHo
5 A 5
Thiophene·2·aldehyde

~HafllH2 1 : 1 AcOH ~CHO

(c) ll.,~
N
+ (CH2)eN4 A ~..N~
Pyridlne·3·aldehyde
174 REACTIONS, REARRANGEMENTS AND REAGENTS

HCI
(d) CHr(CH2)4 -CH2NH2 + (CH2)5N4~ CH3-(CH2)4 -CHO
n-Hexanal

Excess NH3
C5H5CH2NH2
A
Benzylamine

The reaction (e) has been utilized for the preparation of an aminoketone intermediate required in the
synthesis of chloromycet in.

1. (CH2)5N4. HCI
02"' -\Q>-cocHiSr 02"' -\Q>-cocHiNH2
2.NH3o A
,:rNltro-<i>-bromoacetophenone Intermediate for chloromycetin

Another way to ox1d1ze benz1hc halides to aldehydes 1s the Krohnke reaction . The reaction consists of
treatment with pyridine followed by p-nitrosodimethylaniline and subsequent hydrolysis.

STOBBE CONDENSATION
[Link] and ketones condense with the esters of succinic acid in the presence of bases such as
C2H50Na, Me3COK or NaH to give the salts of af3-unsaturated half esters but not the alcohol. This is known
as Stobbe condensation .

The reaction is specific for succinic ester although the carbonyl compound may be varied over a wide
range. The carbonyl compounds which may be used are:
(a) Aliphatic and ex, f3-unsaturated aldehydes
(b) Aliphatic, aromatic, alicyclic and cyanoketones as also ketoesters.
However, ketones are more often used than aldehydes. In practice, the reaction mixture-ketone,
diethyl succinate and ether solution of sodium ethoxide-is allowed to stand at room temperature for several
days and then the product is recovered by acidification. The yield is improved and the reaction time is reduced
on using potassium tertiary butoxide in tertiary butyl alcohol as base.

Mechanism
The mechanism of Stobbe condensation Is not very clear. According to the accepted mechanism, the base
accepts a proton from one of the methylene groups of succlnic ester. The succinic ester carbanlon then adds
to the carbonyl carbon of the substrate to give (I). The adduct (I) then undergoes cyclization (ester-lactone
interchange) generating alkoxide Ion from the more remote ester group. The cyclized product (II) is a lactone.
Subsequent base-catalysed elimination causes Irreversible ring opening to produce a salt of unsaturated half
>
[Link] CONDENSATION
175

ester (Ill).
Lactones have been isolated from the reaction mixture in some cases, which support the mechanism.

CH2-COOEt
eCH-COOEt
I I
CH2-COOEt CH2-COOEt

6 5 C5H5
C H '-c--CH-C00Et -EtO '-c--CH -COOEt
/I I /I I
CsHs 0 CH C5H5 0 CH2
1c./ 2 "c/
~c~
II r vc;;1
II
(I) 0 0 ( 11)

Irreversible

Applications
Stobbe condensation has been used to prepare a large number of varieties of unsaturated and saturated
acids. The condensation has also been useful for the synthesis of many types of polycyclic ring systems. It
has also been used during the synthesis of estrone. Some of its synthetic applications are given below.
1. Synthesis of acids

HBr ?
R2C -CH2 -CH2 -CO
r
Ac OH

1. NaOH
2. N3/Hg

2. Synthesis of polycyclic rings (a) Naphthol and indenone derivatives-Stobbe condensation product with
aryl ketones on cyclodehydration gives polycyclic rings. Since Stobbe condensation product is a substituted
olefin , the aryl group may be cis to CH2COOH group or to COOH group so that two products may be obtained
on cyclodehydration

KOCMe3
and
Me3COH
 ·176 REACTIONS, REARRANGEMENTS AND REAGENTS

~COOH CH3
and

Naphthol derivative lndenone derivative

(b) Tetralone derivative-

( i)
1. NaOH

~co
Stobbe HBr ,AcOH
2 . Na/Hg
condensation
. I
Me

HOOC
'CH 0 ( ii ) 0
I

(]x) 00·
2
~
1) t-C4H90K
/CH2
~CH 2) HJO(±}
I
Me Me
4-M ethyl tetralo ne

(c) Phenanthrene deri vative-

~yo 1. Stobbe cond .

~CH3 2. HBr, AcOH
2-Acetytnaphthalene

1 . Na/Hg + HCI

2 . Pd/C
1-M ethytphenanthrene

3. In the synthesis of estrone In the synthesis of estrone, the ·intermediate (iv) obtained by Friedel-Crafts
acylation between methylphenyl ether and glutaric anhydride was subjected to Stobbe condensation to obtain
the lactone (v) which was further processed (several steps) to get estrone.
 STORK ENAMINE REACTION

CH2COOEl
I
CH2COOEt
MOJCOK

(IV)

STORK ENAMINE REACTION

1nytammes which are a, ~nsaturated amines are called enamlnes.
Enamines on treatment with reactive alkylhalldes and subsequent hydrolysis give a·alkylated ketones.
1s 1s known as Stork enamine reaction.
~COCH

Since enamines are normally prepared from ketones, the reaction Involves a·alkylatlon ol the ketone
from which the enamine has been derived.
Enamines required for the reaction are prepared by treating ketones, having an a-hydrogen with
secondary amines.
-Crat!S
) Qbtai11

Htmlamlnal Enamnt

An a-hydrogen is required in the ketone for the ellmlnallon of water with the formation ot a
catbon~n double bond. The water is removed azeotropically to complete the reaction.
Primary amines give imines due to the hydrogen on the nitrogen (cf. vinyl alcohol).
I H I
" vN-H __.... 1 ~N
-c=c, ~ -c-c,
I I
Enamne Imine

and elimination predominates with tertiary amines. Hence the use of secondary amine In the prep ration ol
enammes.
The reaction is not successful with ordinary primary or secondary halides due to N-alkylat on. With
 178 REACTIONS, REAARANGEMEHTS ANO AEAGEm'S

tertiary halid~s elimination is significant. The reaction Is succesfuf with active alkyl halides e,g,, aJly1, ~,
propergyl half des etc. Alkyl group Is attached to the less substituted side ot the ketone.
Enamlnes prepared from aldehydes are in general less stable than those prepared from ketones,

Enamines derived from acyclic amines are not resistant to heat or acid. Enamines obtained from C)'dc
secondary amines e.g., pyrrolidlne, piperidine, morpholine etc. react faster and are more stable.

The cyclic enamine, N-1-cyclohexenyl-pyrrolidine (I) is prepared by boiling et;clohexanone and

pyrrotidine with a trace of p-toluene-sulphonic acid as catalyst.

The water is removed azeotropically.

It is seen that enamines are resonance hybrides (1) and the ~rbon is the nucleophilic centre. Hence,
enamines are useful intermediates for organic synthesis.

(\ I(). e I @/
-c=c-N(- -C-C=N,
I m I
from the resonance structure it is seen that the ~rbon is susepfible to electrophilic attack. [Link]
are easily hydrolysed to regenerate ketones. Hence substitution followed by hydrolysis gives varidly
substituted ketones.

Applications
The nucleophilic behaviour of enamines has been ~tilized in various important synthesis. Stork and coworkers
have widely investigated the properties of enamines.

On reacting with alkyl halides nucleophilic displacement in the alkyl halide results in the fonnulation of
imine salt (II) which after hydrolysis gives a-alkylated ketone (Ill).

Alkylation
Enamines undergo alkylation at the f3-carbon by reactive alkyl halides. With a-bromoacetic esters, the
P-carbon is substituted by carbmethoxy methyl group.
 179

__Rx_..,..Q <J ~o•Q=O•H2~Cl e @ xe

R R e
Qt1CJ~t! Q=o•H2~U
~COt-49 CH2 C0 2Me
2-Carbmethoxy-methyt
cydohexanone

rea occurs under mild con<frtions and gives only mono alkylated ketones since mono
~suru[eo.. enan(nes are difficult to alkylate further.

[Link]-.~~ are readily acytated with acid chlorides to give an intermediate which on hydrolysis gives

GN=O~GNH2Cl+O=O
COR COR
1, 3-Dlketone

Long chain carboxylic acids can be prepared from cyclic 1, 3-diketones.

e

Q= O
1

2)H
) o; RCO (CH 2 ) 5 COOH ZnlHg
+HCI
R(C~ )6 COOH
COR

The length of the carboxytic acid chain depends upon the size of the cyclic ketone used In the
preparation of enamine.
By using dicarboxytic acid chlorides. the carbon chain of the dicarboxylic acid may be extended still
further.

0 0
6CO(Cj~:;'6
N-Cydohexeno

6- CO(CH C0-6
morpholine
0 0
COOH COOH e
( - CO(CH 2)6 co
1 1
'1 1)0:
2)6
~ !Zn-Hg ~ 2)H
HCI

HOOC (CH 2 )5 CH 2 (CH 2 )6 CH 2(CH2 ) 5 COOH

or
HOOC (CH 2 ) 18 COOH

Since acytated enamines are weak bases, Et3N is used to absorb the acid produced in the reaction.
 180 REACTIONS, REARRANGEMENTS AND REAGENTS

Michael type condensation

Enamines react with activated aryl halides e.g., 2, 4-dinitrochloro benzene and with a, p-unsaturated ketones,
esters, cyanides etc. The reaction is a Michael type of reaction in which the enamine acts as addend.

ON!}{)_
~2-G:HCOOR
G'Q
~r-COOR
e

0
=0 ::;. 0"-0
c~ - CHi-COOR c~- Ctif-COOR

Two molecules of acetylene add together in the presence of cuprous chloride and ammonium chloride to give
vinyl acetylene.
NH4 CI
2HC = CH HC=C - CH=CH2
Cu Cl
In the same way terminal alkynes add to the double bond of enamines.
' CuCI I I
RC=CH + /C=C- NR2 NH4CI RC::C-C-CH-NR2

Enamines derived from aldehydes only add to Michael type olfins and also to ketenes to form stable four
membered rings.
Enamines derived from ketones add to isocyanates to give P-lactams.

ULLMANN REACTION
Ullmann reaction encompasses the synthesis of diphenyl amines. diphenyl ethers and diphenyls.

Cu
(ii) CsHsOH + CsHsBr + KOH - (CsH5)20 + KBr + H20
Reflux

CsH5N02
(ill) 2CsHsl + Cu CsHs-CsHs + Cul2
6
The preparation of diaryls (eq. iii), called Ullmann coupling reaction, is the most Important reaction and
is discussed below.
Ullmann coupling reaction involves the condensation of aryl halides In the presence of finely divided
copper or copper bronze at an elevated temperature (100- 350°C) to yield diaryl derivatives. Thus, iodo-
benzene in nitrobenzene when heated in the presence of copper powder gives diphenyl in 80% yield.
Alternatively, the reactants may be heated in a sealed tube.

2@-1 + 2Cu _c_s_~s_N_o2-@--© + 2Cu1

The reaction is successful with aryl iodides. However, aryl bromides and chlorides also react when
electronegative substituents, which activate the halogen, are present.
•
[Link] REACTION 8

N()i Oi Oi

2<(}c1 6 -
•2Cu _do-~
0
Dimethyl fonnamtde y--y + 2CuC

A better yield is obtained on using dimethytformamide as sotvent Nitro group strongly activates the
halides but only from the ortho position while alky1 (R) and alkoxy (OR) groups activa e from positions.
Electron-releasing groups inhibit the reaction. The reaction is important since it is simple. straightforward and
the structure of the product is known from its synthesis.

Mechanism
The mechanism of the reaction is uncertain. A radical mechanism has been suggested.

2 (g-1 + 2Cu - 2Cul 2 ©- -(Q)-©

There are evidence against the radical mechanism and hence a mechanism si ilar to that of Wurtz reaction
has been suggested.

CsHsl + Cu - c~ - (

CsHsCuJ + CsHsl - CsHs-csHs + [Link] (2)

The fact that iodides give good results suggests that iodides undergo step (J) more reacity.

Applications
The reaction provides methods for the preparation of compounds which cannot be read?ty prepared by othEM"
methods. The yields of the products are high in most cases.

(A) A large number of biaryls and polyaryls have been synthesized by the Ulbnium coupling
reaction.
1. Symmetrical biaryls

(i) 2HOOC-O-I ~u HOOC~

p-lodobenzoic acid 4 . 4 '-Oiphenc aod

Me e e

(i) 2 M e - f i - I ~u Me~ e

2. Unsymmetrical diaryls With a mixture of two cflfferent af)'t halides, tnree products are ob![Link] Yo'f'lllt"h

poor synthetic value for the yield of the desired product is lo

the unsymmetrical product is only formed, e.g.,
182 REACTIONS, REARRANGEMENTS ANO REAGENTS

0N*CI •-0+0,N~
NO;i
N~

2
NO;i
N02
Picryl chloride 2, 4, 6-Trinitro biphenyl

3. Polyaryl hydrocarbons

1
2.2 1-0 iiodo-5, 5 ·dimethoxy dibenzyl 2, 7-0imethoxy-9, 10-dihydrophenanthrene

(ii) (Q)--1 Cu (Q)--(Q)

2
(Q)-i A(1S0-220°C) (Q)--0
1, 8-Diiodonaphthalene Perylene

(iii)

_,,.
Cu
A

Ethyl-8-chloro: 1-naphlhoate

Anthanthrone

Anthanthrone and its halogen derivatives are used as dye.

(B) Ullmann reaction also provides methods for the preparations of diarylamines and diaryl ethers
1. Diarylamines An arylamine and an arylhalide are refluxed in the presence of anhydrous potassium
carbonate and copper powder.

rA'f COOH
©('')~tH3
~Cl N
o-Chlorobenzoic acid p-Anisidine I
H
p-Methoxyphenyl anthranilic acid

2. Diaryl ethers A phenolic compound and an aryl halide are refluxed in the presence of potassium hydroxide
or K2 C03 and copper. The reaction has been employed in the synthesis of thyroxine.

CH,C-0-0H *NO, +
K~03 1
Butanone
Cu
CH"'--(Q)--o*NO,
Several
• • •Thyroxine
steps
I
A diaryl ether I
 VILSMEIEA·HAACK REACTION 183

VILSMEIER-HAACK REACTION
Vilsmeir-Haack reaction involves a convenient method for the formylation of aromatic rings. The method is
however applicable to active aromatic substractes such as amines and phenols. Aromatic hydrocarbons and
haterocyclics more reactive than benzene can also be formylated. The reagent used for formylation is
N-phenyl-N·methyl tormanilide which is prepared from N-methyl aniline, formic acid and phosphorous
0
xychloride. Cobalt chloride may be substituted for phosphorous oxychlorlde.

Toluene
Rrflex

N-mettyl formanlllde

Me
I
r.... I e
Me
Poc1 3
Me
I
~-~
I ct
Ph-N-C~O-Ph-N=C-0 Ph-N=C~
· + /
·U I ® I ® H 'c1
H H Cl

Me Me Cl Me
In Cl e I. I I Cl e
Ph-N::fc( + OPOCl 2 - Ph- N- C-OPOCl 2- - Ph- N-C~® OPOCl
® H .. I .. " 2
H H
Active elecirophlle

Nuclear Magnetic Resonance and other evidence support the formation of the active electrophite.
The formylation of aromatic compounds with N-methyl formanilide probably proceeds as given below:

Ph-N-CH--
I
@<%PoCl2

I
OH
~
~e
CH-N-Ph-1
61 <%Poc12
6-:Q

#
CH-
I
c1e
~
~-Ph
Me Cl 0POCl
2
a
aq Na acetate
Steam dist.
6-CHO, ~P0 4 + HCI

Phenolic ethers and dialkyl anilines are smoothly formylated at ortho and para positions.
Amongst hydrocarbons only anthracene is formylated at position-9.

9-Anthraldehyde

Synthesis of aromatic aldehydes has considerable importance, for the aldehydes are used as
intermediates in the synthesis of other valuable compounds.
 REACTIONS, REARRANGEMENTS AND REAGENTS

WAGNER-MEERWEIN REARRANGEMENT
Reactions involving the change in the carbon skeleton through the rearrangement of the carbocation
intermediate are collectively known as Wagner-Meerwein rearrangement.
When neopentyl bromide is hydrolysed under SN 1 condition it Is found that instead of the expected
neopentyl alcohol (Me3CCH 20H), 2-methyl-butan-2-ol and 2-methyl but-2-ene are formed

Me Me Me
I I I
Me-C - CH2Br Me-C-CH2Me + Me-C=CHMe
I I ... (i)
Me OH 2-Methyl bui-2-ene
2-Methyl butan·2·ol

Similarty, neopentyl alcohol on dehydration gives 2-methyl-but-2-ene and 2-methyl-but-1-ene.

Me Me Me
I ~$~ I I
Me-C-CH20H - - • Me-C=CHMe + CH2=C-CH2Me
I
Me 2-Methyl but-2-ene 2-Methyl but-1-ene

In both cases, changes in the carbon skeleton are observed. Such rearrangement was first observed in
bicyclic terpenes.

lsobomeol Camphene

Mechanism of the dehydration of alcohol is discussed below.

Mechanism
Protonation of the hydroxyl group of the alcohol followed by the loss of water molecule affords a
1°carbocation. The 1° carbocation then rearranges to the relatively more stable 3° carbocation by 1, 2-methyl
shift before the product is formed. The greater stability of the 3° carbocation provides the necessary force for
the migration of the methyl group from the adjacent carbon. The rearranged carbocation 1hen stabilizes itself
by the loss of a ~-hydrogen to form olefin. Zaitsev's rule governs as to which of the two ~-hydrogens will be
eliminated.

1, 2-Methyl @
Me - C-CH2Me
I
shift
Me (2")
 WAGNE~RWEIN REARRANGEMENT 185

(Hydrolysis of neopentyl halide similarly gives first a rearranged 3° carbocation which can either accept a
nucleophile from the solvent to give alcohol or eliminate a proton to give olefin; see eq. 1.)
Rearrangement does not occur if the initially formed carbocation can stabilize by other factors. Thus. 3,
3-dimethyl-2-bromo butane (neopentyt type) undergoes~ 1 hydrolysis with rearrangement.

e le
Me~
I
Me
I
9OH Iw Me
-<[Link]
I
e-C-CH
I
Me-C-CHMe - Me-~-lHMe - Me~-CHM~ @ OH
Me Br 5 N1 ~ @ - H 'e-C=C I
I
OH

while its phenyl analogue gives product without rearrangement

Me 9 MeH .('.l/"(J MeH

Me-?-<;:HCsHs ~ Me-?-i-O- Me-?~-0
Me Br Nl Mew - •eOH
BeniJOc cation
(stable)

The ben2ilic cation is stabilised by the phenyl group through dek>cali:zation and so does not rearrange.
Rearrangement in the alicycllc system may in\IONe migration of ring methytene group resulting in the ring
expansion and contraction.

~OH '(, @ ~ ~ $ ~~ CH2

v =~-:~~_.w~w=«
lsobomeol ~

Other examples are the conversions of camphene hydrochloride to isobomyt chloride. bomyi chloride to
camphene, pinene hydrochloride to bomy1 chloride, etc.
Some simpler examples are:

()'' ~ ~
(a)
AQNOi
+

lodocyclohexane NitrocydOhelcan C)

(b) [::>-cH;!NH2 HNC>.! ..

[::>-c~ +[JOH
Cyciopropyleart>inylamine Cy~lbirlOl C\1

The migrating group besides being alkyl and ring methylene groups may be hydride ioo or aryt 9~
ti
.
e~
 186 REACTIONS, REARRANGEMENTS AND REAGENTS

The aryl group migrates faster than alkyl group. Electron-releasing group in the aryl group increases the rate
of migration while electron-withdrawing group decreases the rate of migration. Thus, elimination is many times
faster in neophyl bromide than in neopentyl bromide. This is because the rearranged phenonium ion 1s
relatively more stable due to delocalization than the rearranged carbocation from neopentyl bromide. Hence
the former has lower energy and more easily formed than the latter.

@
@ -H
[Link]
I
- C&Hs-C=CHCeHs
I
C&Hs C&Hs

Phenonlum ion

Pinacol and benzilic acid rearrangements are also examples of this carbon to carbon migration of H, R
and aryl groups with consequent change in the carbon skeleton. This rearrangement has important
applications especially in steroid chemistry.

WITTIG REACTION
Wittig reacton affords an important and useful metho·d for the synthesis of alkenes by the treatment of
aldehydes or ketones with alkylidenetriphenylphosphorane (Ph3 P=CA 2) or simply known as phosphorane.

1, 1-Diphenyl Triphenyl
ethylene phosphonium
oxide

The Wittig reagent, alkylidenetriphenylphosphorane, is prepared by treating trialkyl or triarylphosphine

usually the latter with an alkyl halide in ether solution. The resulting phosphonium salt is treated with a strong
base (such as C6H 5Li, Buli, NaNH2 , NaH, C2H5 0Na, etc.) which removes a halacid to give the reagent,
methylenetriphenyl phosphorane (II).
@ 9 CsHsLJ @e
PhJP + CH3Br - PhJP -CHj3r PhJP -CH2 - Ph3f' =CH2 + CsHs + UBr
(I) (II)

tn the alkyl halide a hydrogen is necessary on the halogen-bearing carbon. Alkylidenetriphenylphosphoranes

are also called ylids due to the presence of opposite formal charges on adjacent atoms as in one of the
resonance structures (I). The methylene structure (II) has a dn-pn bond between phosphorus and carbon. The
ylid may be considered as a carbanion stabilized by the adjacent phosphonium cation.
The carbonyl compound is directly treated with the ethereal solution of the reagent.

Mechanism
The reaction probably proceeds by the nucleophilic attack of the ylid on the carbonyl carbqn. The dipolar
complex (betain) so formed decomposes to olefine and triphenylphosphine oxide via a four-centred transition
state.

®e @
Phj> -CR2 PhJP -CR2 Ph3f' --CR2 Ph3P CR2
.,;~~(el
1 1 11
- I ~~1
1 0
---+ II + II I II
O=CR R" O-CR R 0 - - CA R" 0 CR R
Betain

d
 WITIIG REACTION 187

The mechanism is supported by the fact that an optically active phosphonium salt reacts to produce a
phosphine oxide with retention of configuration.

Since desired alkyl groups can be introduced in the alkyl halide and the carbonyl compound, it is
extremely useful for the synthesis of desired substituted alkenes. Double or triple bonds even when
conjugated with the carbonyl group (P=O)does not interfere. The reaction with the carbonyl group of esters is
very slow and does not interfere.
Phosphorous ylids react in the same manner with the C=O
groups of ketenes and isocyanates as also
with the N=O and C=N groups of nitroso and imine compounds respectively.

1
R2 c =c=o 1
R2 C =C=CR2
Ketene
1
R N=C=O 1
@ e lsocynate
R N=C=CR2
Ph3P -CR2 1
R N=O 1
R N=CR2
Nitroso compound
1
R2 C =NA 1
R 2C =CR2
Imine

Applications
The reaction has many useful synthetic applications. Many natural products which are otherwise difficult to
prepare can be synthesized by Wittig reaction.
1. Formation of exocyclic methylene group

/\,_
~O + Ph3P-CH2
<±> e /\,_
_ . . ~CH2 + PhJP=O
Cyclohexanone Methylene cyclohexane

This method of introducing exocyclic methylene group is extremely valuable and has been widely used
in the preparation of methylene steroids.
2. Preparation of f3, y-unsaturated acids

<±> e e e
R;zC =O PhJP-CH -C H;zCOO R;zC =CHCH;zCOO + Ph3P.:O

In all other methods isomerization to ex, (3-unsaturated acids results.

3. Preparation of natural products
(i) ~-carotene (pro vitamin A)
188 REACTIONS. REARRANGEMENTS AND AEAGE:NTS

l}-Carotene

(ii) Vitamin A

CHO [ @ 9H3 ~ 9 ~~Na

+ Phj>-CH2-C :CHCOOR B r - - - -
-Ptl:)P =O

Cttpi

vitamin A

4. Formation of large rin~ containing 5 to 16 carbons

5. Synthesis of vinyl halides Chloromethylenetriphenylphosphorane (P~P=CHCI) required for trus synthesis

is prepared by reacting chlorocarbene with triphenylphosphine.

@ €>
:cHCI + Ph3P - Ph:JP-CHCI or (Ph:JP=CHCI)

@e
(i) CsHsCHO + Ph3P-CHCI - CsHsCH=CHCI + Ph:JP=O

(ii)
O= @e
0 + Ph3P -CHCI - O= CHCI + PhJP =O

6. Synthesis of ethers Methqxymethylenetriphenylphosphorane reacts with carbonyt compounds to give

diphenyl substituted vinyl methyl ethers.

Hydrolysis of the product gives aldehyde.

[Link] -CHO
Diphenyt acetaJdehyde
 WOLFF-KISHNER REDUCTION 189

WOLFF-KISHNER REDUCTION
Wolff-Kishner reduction involves the conversion of carbonyl groups of aldehydes and ketones to methylene
groups by heating their hydrozones, semicarbazones or azines in the presence of strong base such as
ctisONa or NaOH.

Thus, ketones and aldehydes can be conveniently reduced to hydrocarbons by this method. Earlier method of
heating the hydrozones of carbonyl compounds with C 2H50Na at 180°C in an autoclave has since been
modified. In the modified procedure, hydrazine hydrate and the carbonyl compound are heated with KOH or
NaOH in ethylene glycol for several hours. The water fonned escapes and the temperature rises to 200°C
When the hydrazone decomposes with the formation of hydrocarbon with evolution of nitrogen .

C:zHsONa, Glycol
/!;.

In a further modification, the reduction can be carried out at room temperature by using dimethyl
sulphoxide as solvent and potassium tertiary butoxide as base. The yield is excellent. Thus, benzophenone
gives diphenyl methane in high yield.

iesis Mea(:OK,
- - - - - CeHs ·CH2-CeHs + N2
~. 30•c
Oiphenyl methane

Unlike Clemmensen reduction, the reaction does not fail with acid-sensitive or high molecular weight
substrates.

Mechanism
First step Involves the formation of the anion of the hydrazone (I) which is protonated at the carbonyl carbon
to form a substituted dilmlne (II). This is followed by simultaneous loss of nitrogen and formation of
hydrocarbon. (Compounds of the type (II) are unstable and decompose to hydrocarbon and nitrogen probably
through carbanion or free radical mechanism.)

give

During the course of reduction, semlcarbazones and azlnes are first converted to hydrazones before
reduction.
R2C =N·NH·co·NH2 + H ; P - R:iC =N·NH2
Semlcart>azone
190 REACTIONS, REARRANGEMENTS AND REAGENTS

R~ =N-N:CR2 + 2NH2 NH2 ____,. 2R:iC :N°NH2

Aline

The method is specific for the reduction of carbonyl groups only, for other functlonal groups ln the
substrate remain unaffected. The method is. however, not sultable for a, r3-unsaturated ketones.

Applications
Wolff-Kishner reduction has been frequently used for the reduction of carbonyl groups to methylene groups
in various types of syntheses.
The ·method unlike Clemmensen reduction is applicable for the reduction of high molecular weight and
acid-sensitive compounds .
• Reduction of high molecular weight compounds High molecular weight compound, e.g., 24-keto-
Cholesterol, has been successfully reduced.

Wolll-Klshner
reduction "

HO HO
Cholesterol
24 ·Ketocholesterol

2. Reduction of camphor to camphane

Lo Wollf-Klshner ~
W
Camphor
reduction l!J
Camphane

3. Introduction of long straight-chain alkyl groups In aromatic rings In the Friedel-Crafts alkylatlon a
straight-chain alkyl group longer than ethyl group cannot be Introduced to an aromatic ring because of
rearrangement of the alkyl group. However, this has been achieved by acylatlon followed by reduction.

"l)r-cOC~9 Wolff-Klahner rtJr-cH~.Ha

~ reduction ~
n-Butyl phenyl ketone n·Pentyl benzene

4. In the structure determination of oestrone The formation of 7-methoxy-1 : 2-cyclopenteno-phenanthrene,

a compound of known structure, by the reduction of oestrone methyl ether followed by dehydrogenation with
selenium indicates the carbon skeleton of oestrone as also the position of the methoxy group.
0

Wolff-Klshner
reduction
Meo MeO Meo
Oestrone methyl ether 7-Methoxy· 1: 2~clopenteno
phenanthrene
 WOLFF REARRANGEMENT 191

I fhe

WOLFF REARRANGEMENT
a-Oiazoketones on treatment with solid silver oxide split off nitrogen and rearrange to ketene. This is known
as Wolff rearrangement.

to-
a-Diazokelone

The rearrangement may also occur on irradiation or on heating. When the reaction Is carried out In the
piesence of water, alcohol, ammonia or amine, the highly reactive ketene readily reacts with the nucleophiles
present, e.g., H20 .. AOH,'etc., to give respectively acids, esters, amides or substituted amides of the next
higher homologue of the acid from which the a-cliazoketone is prepared .

R-CH=C=O-
R'OH
RCH2COOR' [Link] R=allphallc,aromatlc,
helerocyclic and allcycllc

Mechanism
13
It has been shown (Huggett et a/.) with isotopically labelled carbon ( C) in a series of transformations•
that the carbonyl carbon of a-diazoketone is present in the resulting acid as the carboxyl carbon when the
reaction is carried out in the presence of water. Obviously, migration must have occurred during the
rearrangement. On the basis of this, the following mechanism has been suggested:

1
13ce>i + PhMgBr -Ph13cOOH · SOCl 2
2 . CH2N2

CuO · Cr203
13C02 + PhCOOH
Quino llne
192 REACTIONS, REARRANGEMENTS AND REAGENTS

~o oG ~
R~gr~-~-N: ..... R2:fc-c+~=N: Ag
20 ~#.D·
~CH
I I -N2
Carbene
H H
a-01azoketone
l Rearrangement

13 13
R-CH2-COOH R-CH=C-=O
[Link]

Splitting of nitrogen and migration of R group may be concerted. In some cases ketenes have been isolated.
The group R migrates with retention of configuration. This has been confirmed by the following observation.
A higher homologue of an optically active acid (I) obtained by Arndt-Eistert-Wolff rearrangement on
degradation by Barbier-Weiland method gave the original acid with the same configuration (Lane and Wallis).

Ph Ph 1· CH 2N2 Ph Ph
I Amdt-i:istert I 2 . PhMgBr I I
nC4H9-C-COOH - - - - - nC4H9-C-CH2COOH - - - - - nC4H9-C-CH2-C-OH
I react ion I 3 . H20 I I
Me (I )
(+) a.-Meth~Hx-phenytcaproic acid
Me Me Ph
l Boiling Ac20

1 •
Cr03 , AcOH
-Ph2CO
Ph
I
nC4H9-C-CH==CPh2
I
Me

Application
Arndt-Eistert homologization utilizes Wolff rearrangement in which an acid is converted to its next higher
homologue.
SOCl2 CH2N2 Ag 20
RCOOH .. RCOCI RCOCl:iN2
-N2

Various classes of diazoketones may be prepared to give varied types of acid derivatives for further synthetic
applications.
pa

Chapter 3

Important Reagents

Introduction
Organic reactions involve reagents and substrates. A group of organic compounds serves as substrates for a
particular type of reaction when treated with a specific reagent.
Chemical reagents bring about various types of changes In organic molecules to yield products of
immense value. Reagents have been found that can degrade complex molecules to simple known molecules
which enabled us to elucidate the structures of complex compounds. A suitable choice of reagent and reaction
conditions are essential for the success of a reaction for the desired product.
A few of the most important and widely used reagents along with a few novel catalysts for the synthesis
of a large varieties of natural products, commercially useful chemicals of medicinal and industrial importance
have been included in this section. Their preparations, mode of applications and mechanistic aspects along
with their uses have been briefly described. The reagents have been described In alphabetic order for
convenience.

193
 REACTIONS. [Link] AND REAGENTS

ANHYDROUS ALUMINIUM CHLORIDE

nt atatyst is prepared by either of the two methods.
l. Reducti~ chlorination of bauxite ore Bauxite ore is mixed with coke asphalt and heated strongly to
'" ter, The mi ture is placed into a kiln and rapidly heated to a high temperature and then a stream of
s · passed. Aluminium trichloride is formed and sublimes out of the kiln . It is cooled and the white
re collected in well-stoppered bottles.
A~°-1 + 3C ~ 2AI + 3CO ; 2AI + 3 C l 2 - 2AICl3

2~ Direct chlorination Small pieces of clean aluminium metal or its scrap are placed in a hard glass tube
· heated strongly while passing a stream of chlorine through the tube. Aluminium trichloride sublimes
the tube and is collected.
6
2Al + 3Cii - 2AICl3

The second method is suited for laboratory purpose.

Uses
· 'um trichloride has an electron-<ieftcient atom and functions as Lewis acid. It initiates the reaction by
accepting an electron pair and furnishing a real or potential carbocation.

S+ &- @ 9
RX + AIC'3- R---X---AIC'3 ___.. R + XAJCl3

It is .a versatile catatyst and has been used in a large number of reactions. A few of them are mentioned below.

1. Friedel-Crafts alkylation and acylation

Atum'nium trichloride is found to be the best catalyst for these reactions.

AIC'3
(I) CsHs + RX CsHsR + HX

AICl3
(ii) CsHs + RCOCI - - - CsHsCOR + HCI

CsHsCOCsHs + 2HCI

The reactions may be employed to prepare hydrocarbons, polynuclear hydrocarbons, cyclic ketones, etc.
Thus.
I ) CsHs + RCOO AICI} .. CsHsCOR Na-Hg C5H5CH2R
HCI

M JCsHg + CHC'3 AICl 3 .. (CsHs)JCH

Triphenytmethane
 ANHYDROUS ALUMINIUM ~LORIDE 195

\Zn-Hg,HCI

2. SOCl2
©() "IGl:i

COCI 0
-r-Phenylbutanoyl a -Tetralone
[Link]
t Zn -Hg , HCI
2 Pd/C
Naphthalene

0 IC!;:} rAY COOH rA1

·©(/o-~ M
\Cone. H2S04
[Link], dist
co co
[Link] nhydride o-Se02oylberuoic add

O ty\ chlonde

2. Fries reaction
Phenyt esters on treatment with anhydrous aluminium trichloride are converted to o- or ~ydroxy ketones.
The reaction involves rearrangement through migration of a group from oxygen to carbon.

l. Gattermann-Koch aldehyde synthesis

A mixture of dry carbon monoxide and hydrochloric acid gas is passed through a solution of benzene in ether
or nitrobenzene containing anhydrous aluminium trictlloride and a little cuprous chloride. The mixture of
carbon monoxide and hydrochloric acid behaves as formyl chloride . Cuprous chloride is necessary to perform
the reaction at atmospheric pressure otherwise 100-250 atmospheric pressure is required for the reaction.

ArH + CO+ HCI AfCHO

C1.t2°'2

Fonnylation has also ~n effected by dichloromethyl methyl ether in the presence of anhydrous aluminium
trictlloride.
196 REACTIONS, REARRANGEMENTS AND REAGENTS

4. Amidation
(i) Gattermann amide synthesis Carbamyl chloride In the presence of anhydrous AIC1 3 substitutes amide
group in aromatic ring.
AJCl3
CaHe + CICONH2 .. CaHsCONH2
Carbamyl Benzamlde
chloride

(ii) Substituted amide lsocyanates in the presence of anhydrous AICl 3 react with aromatic compounds to give
substituted amide.

AICl3
C5Ha + RNCO .. CaHsCONHR

5. Carboxylation
Phosgene reacts with benzene in the presence of anhydrous AICl 3 to give benzoyl chloride which can be
hydrolysed to acid.

AICl3 H:J(>$
C5He + COCl2 .. CeHsCOCI - - - - · CeH5COOH

Excess of benzene may give benzophenone.

6. Wagner-Meerwein rearrangement
Long-chain halides undergo rearrangement In the presence of anhydrous AICl 3.

7. lsomerization
Reforming of gasoline fraction to Increase branching occurs In the presence of AICl 3 , e.g.,

CH~H~H~H3
(20%)
-
AICl3o 150°C
(CHJ)~H
(80%)

Traces of alkyl halide or alcohol are necessary to Initiate the reaction.

Another example is Interconversion of methylcyclopentane and cyclohexane.

(25%)
0(75%)

8. Dealkylation
Tertiary alkyl groups are lost more easlly.

rAroMe COPh AJCl 3

¥ CeHe•A

CMe3
 ALUMINIUM ISOPAOPOXIDE. CMeaCHOhAI 11J7

Addition to olefines
; ·ICY, halides add to olefins in the presence of anhydrous AICl 3 .

/" c= c"-
/
+ RX
AJCl3 "
/
~ /
c-~°"'

certain Diels-Alder reactions are accelerated by AICl 3 under milder conditions.

ALUMINIUM ISOPROPOXIDE, (Me 2CH0) 3Al

Aluminium isopropoxide is a good reducing agent. It reduces by transfer of hydride ions.

Preparation
The reagent is prepared by refluxing anhydrous isopropyl alcohol with aluminium amalgam in the presence of
a small amount of carbon tetrachloride as catalyst. After the evolution of hydrogen ceases, the mixture is
distilled under reduced pressure when aluminium isopropoxide distils over at 140-150°C (12 mm) as a
colourless liquid.

Uses
11 is a specific reducing agent for the reduction of carbonyl compounds to alcohols without affecting other
sensitive reducible groups. With excess of the reagent at elevated temperature, diary! ketones may be
reduced to hydrocarbons.
The reduction is carried out by heating the carbonyl compound with the reagent in isopropyl alcohol and
distilling off the acetone as it is formed.

Since the reaction is reversible, the reagent can also be employed for the oxidation of alcohols. The reverse
reaction is known as Oppenauer oxidation. The position of equilibrium can be controlled by the amount of
acetone present. The equilibrium shifts forward on distilling out the acetone as it is formed. An excess of
acetone favours oxidation (reverse reaction).
The reagent is better than other metallic alkoxides because it is relatively less polar. The
aluminium-oxygen bond is almost covalent and does not give alkoxide ions which generally cause much
condensation of carbonyl compounds.

Mechanism
The reaction proceeds by complexing the carbonyl oxygen of the substrate with ~uminium and then transfer
of hydride ion to the carbonyl carbon of the substrate in the cyclic transition state (t}, resulting in the formation
)fa mixed alkoxide (II).
 REACTION$. REARRANGEMENTS AND REAGENTS

R Me
,~c-Me
RCHO + ~OCHM92}3 ---+ / C Q tp M92CO + RCH20-Al(OCHM92)2
H 0 .. .• Al(OCHM92)2 (U)
(I)

M92CHOH
RCH O-Al(OCHM92)2 RCH20H + Al(OCHM92)3
(Ill) (R = Saturated
or unsaturated)

Metal alkoxides undergo rapid acid-base exchange with their corresponding a~ohols. Hence,
excess of isopropyt alcohol is used so that it exchanges with the mixed alkoxide (II) to liberate the redu
aldehyde (Ill), i.e.. the desired alcohol. Hence, the hydrogens tor .the reduction are supplied one each by
catalyst and the solvent. That a hydride ion is transferred from the reagent to the carbonyl compound is pro
by the fact that with (Me2CDO)sAJ. the carbonyl compound gave RCHD(OH). This indicates that the rea
proceeds via the cyclic transition state.

Appliations
Some of its important applications are given below.

1. Meerwein-Ponndorf reduction

(i) CH3-CH::CH-CHO
~yde
+ M92CHOH
(M92CHO)JAI
A CH3-CH=CH-CH 20H + M92CO
Crotyl alcohol
f

(i) CH3-CO-CH2-CH2-CH3 + M92CHOH

2-Penlanone
(M92CHO)JAI
CH3-CH(OH)-CH2-CH2-CH3 + Me:zCO
2-Pentanol
t
CHO CH20H

(i) ©r-NO, (M92CHO)JAI

+ Me;zCHOH &-NO, + Me,CO

2-Nitrobenzyt alcohol

(rv) Ct;H5-CO-CH3 + Me;zCHOH (Me;zCHO}JAI

A C5H5-CHOH -CH3 + M 92CO
Acetopheoone a-Methyl benzyt alcohol

0
(v)
6 + Me,CHOH

2-Cydohexene-1-ooe
(M92CHO)JAI
A
X
v
0
H

2-Cyclohexene-1-<>I
+ Me:zCO

(vi) CfJC-CO-CH3 + Me;zCHOH --A---

{Me;zCHO}JAI
Cl3C-CHOH-CH3 + Me;zCO
Trichloracetone 1, 1, 1-Trichloropropanol-2
p

BORON TRIFLUORIDE, BF3 199

(Me2CHO)JAI, ti.
i {CH3 3C-CO-CQiC2H5 + M &iCHOH (CH 3)J C -CHOH -C02C2H5
Eth l tnmethyipyruvate - M ezCO Ethyl lrlmethyllactate

2.• Reduction of diaryl ketones to hydrocarbons

~ excess reagent and at higher temperature complete reduction has been achieved.

~
~
(Me:zCHOhAI
2so·c
0
Anthraquinone Anthracene

3. In Oppenauer oxidation
though aluminium-tertiary butoxide is the generally used catalyst for this reaction, aluminium isopropoxide
has also been used for the oxidation. An excess of acetone or better hydrogen acceptors like qui nones or aryl
e ones are used along with the reagent.

(ii)

HO~
~
~o
... 6 (M&iCHO)JAI
Toluene, boll
~HOH

o~·O
Cholesterol Cydohexanone Cholestenone Cyclohexanol

The reagent has also been used to reduce camphor to borneol and isoborneol, carvone to carveol,
oestrone to oestradiol and in the synthesis of chloromycetin.

BORON TRIFLUORIDE, Bf 3
Preparation
Boron trifluoride is prepared by the following methods.
1. Ignition of boron in a current of fluorine gives boron trifluoride.

Ignition
26 + 3F2 2BF3

2. By heating calcium fluoride and boron trioxide with concentrated sulphuric acid.

3. By heating borax, fluorspar and cone. H2S0 4 (large-scale preparation).

b
 - -~

200 REACTIONS, REARRANGEMENTS ANO REAGENTS

It Is a colourfess fuming gas.

Uses
Boron trifluoride is used as a Lewis acid catalyst in organic reactions. Boron in BF3 has a vacant orbital. Hence
it has a strong tendency to coordinate with an unshared electron pair of donor elements. e.g., oxygen and
nitrogen to form a relatively stable coordination complex which catalyses the reaction.

~e e
A-N:..,. BF3'
I
H

Some of the important reactions catalysed by BF3 are given below.

(a) Friedel-Crafts reaction Although AICl 3 is the most commonly used Lewis catalyst for this reaction, other
Lewis acids including BF3 may also be used. Boron trifluoride is less reactive than AICl 3 but it has certain
advantages over AICl 3 such as (i) less by-products are formed, (ii) it forms a relatively stable coordination
complex and (iii) a suitable catalyst for those electrophilic regents (e.g., alcohols, acids, ethers, etc.) which
produce water, alcohol or acid as by-products.
(i) Alkylation

Boron trifluoride brings about alkylation with alkyl fluorides but not with other alkyl halides. This gives a method
for introducing halo alkyl groups in aromatic rings.

lsopropytbenzene 3-Phenyl-n-propyl chloride

(cumene)

Alkylation may be effected with olefins in the presence of BF3.

o-~ CH2CH3
0 + CH2=CH2 ~
BF3
h

Ethylbenzene

Boron trifluoride and AICl 3 catalyse alkylation in certain substrates to yield different isomers.

ROH ROH
~
~
AIC'3 BF3

R
2. 6-Dialkylnaphthalene 1 , 4-Dialkylnaphthalene
 BORON TRIFLUORIDE, BF3 201

(ii) Acylatlon-Ketones react with acid anhydride in the presence of BF3 to give 1, 3-diketones.

BF3
CHJ(::OCH3 + (CH3CO):P - CHJ(::OCH~OCH3 + CHaCOOH
Acetyl acetone
BF3
C5H5COCH3 + (CHJ(::O)):P CsHsCOCH~OCH3 + CHsCOOH
Acetophenone Benzoyl acetone

Alcohols and phenols are acetylated with CH 3CONH2BF3 which is a good acetylating agent.

@e
CHJ(::ONH2 + BF3 - CHJ(::ONH~F3

@ e 'i? @ e
ROH + CHJ(::ONH~Fs- RO-C-CH3 + NH3f!F3
Ester

(b) Formation of esters Boron trifluoride catalyses the formation of esters from alcohols, acids, olefins, ethers,
etc.

1 BF3 I
ROR + R COCI _.... RCOOR + RCI

12s-1ao•c
ROR + CO + BF3 RCOOR
500atm.

Alkynyl ethers react with carbonyl compounds in the presence of BF3 to form ex, 13-unsaturated esters.

1
0 R R 0
11 BF3 I I II n
R-C-R + R'c:c-0R R-C=C-C-OR
(c) Formation of acids

125- 1ao·c RCOOH

ROH + CO + BF3 500 atm.

(d) Nitration and sulphonation Boron trifluoride Is an effective catalyst for nitration. Yields are better and the
products are pure. It is specially useful for nitrating aromatic rings with negative groups. " .
'._,

o-Dlnitrobenzene

Nitronium tetrafluoride is a useful nitrating agent.

202 REACTIONS. REARRANGEMENTS ANO REAG NTS

Boron trifluoride effectively catalyses sulphonation as well.

BF3
~H6 + H2SO, ~$503H + ~8F3

(e) Reduction of esters Boron trifluoride etherate catalyses the reduction of esters to ethers by UAIH~ .

1
UAJH.t 1
RCOOR ----- RCH2()R
EtiQ _,. BF3

Rearrangement Boron trifluoride brings about the Beckmann transformation, Benzidine rearrangerne
(f)
and Fries rearrangement.

Ph /OH BF
3
M
'c=N••
/ Beci<mann rearrangement
PhCONHMt
e N-~nwhde

6" Fnu::~nl r5--00R + ¢ [Link]

(0rth0) (Para)
Hydroxy ketonM

(g) Formation of amides Nitriles are hydrolysed to acids through the formation of amides. The reaction can be
stopped at the amide stage by using BF3 .

Hi<> H20 t+lO

RCOOH +--- RCON12 ....__ R-C :.N RCONH-z
BF3

(h) Methylation of alcohols Methytation of alcohols with diazomethane is catalysed by boron trifluoride wh
increases the acidity of alcohol for the reaction to occur.

@a c~
R -OH + 8F3 - A -<j>-BF3 ROCH3 + ttz + 8F3
H

HF-BF3
C':H3 -(CH2)6 -CHiQH + CH2N2 Oi:)-(Cti2>e -CH;z -O-c::ti3 + ~
n-Octyt alcohol Methyl·n«tyt tther

(i) Polymerization lsobutylene on treatment with BF 3 at -100°C gives a high molecular weight polymer (atx>Ut
400-SOOO C,H 8 units) which is sold under the trade name Vistanex.
 N-BROMOSUCCINIMIOE (NBS) 203

0) Analysis of potassium Sodium tetraphenylboride is used for the detection and estimation of potassium in
the presence of sodium. The sodium salt is soluble in water but its potassium salt is insoluble in water and is
quantitatively precipitated.
The reagent is prepared by reacting phenylmagnesium chloride with boron trifluoride and subsequent
treatment with sodium chloride.
e@
4C 6 H 5 MgCI + BF3- (CsHs}4BMgCI + 3MgCIF

e@ C02 e@
(CsHs)48MgCI {C5H5)48Na + MgCO~
NaCl
Sodium tetraphenyl
boride (water soluble}

Boron trifluoride has been used in the Fischer indole synthesis, polymerization of oils, gasoline, etc.

N-BROMOSUCCINIMIDE (NBS) ¢Ner

0
Preparation
The reagent is prepared by gradually adding bromine to an ice-cold solution of succinimide in alkali.
N-Bromosuccinimide precipitates out immediately.

_..........co _..........co
CH 2 "' NaOH CH 2 "'-
bH2 NH + Br2 ooc 1 NBr + HBr
CH 2 /
"-'co/ """co
Succinimide NBS

Bromination with NBS is generally carried out in carbon tetrachloride as solvent In which the liberated
succinimide is insoluble and easily separated.
N-Bromosuccinimide is a valuable reagent for brominating specifically allylic and benzylic positions.
Such reactions are called Wohl-Ziegler bromination. The reagent is also used for brominating positions a- to
the carbonyl group and triple bond. When both double and triple bonds are present in a compound, the
preferred position for bromination is a- to the triple bond. The reagent can be used to oxidize primary
alcohols, secondary alcohols and primary amines.

Specificity of allylic and benzylic position

Allylic and benzylic hydrogens have low bond dissociation energy, it is only 77 kcal, while for vinylic and
methane hydrogens it is 104-122 kcal and 102 kcal respectively. Also the allylic or benzylic radical (or ion)
formed on dissociation is stabilized by delocalization.

I
H-cr-CH=CH 2 - H
• (\ (Y)
+-C- CH=CH2-
c1 = CH - c· H 2
1
 REACTIONS, REARRANGEMENTS ANO REAGENTS

Hence, the allylic and benzilic hydrogens are easily substituted by bromine from NBS.

Mechanism
The reaction proceeds only in the presence of free radical initiators, i.e., peroxide or UV light Hence the
reaction is a free radical reaction. It is suggested that the reaction is initiated by a smaJI amount of brooine
atom, Br. Thus,

+ Br2

•
-CH-CH=CH2 + Br2 - -CHBr-CH=Ctii + Bl
•
Function of NBS is to provide a slow constant supply of a low concentration of bromine by reacting with
HBr fonned in the first step. This is substantiated by the observation that on passing bromine vapours slowty
into a solution of cyclohexene in carbon tetrachloride, 3-bromocyciohexene has been obtained.

Uses
1. As brominating agent (allylic bromination) (a) Preparation of bromoesters

cc~ CHCO
2
CH3 -CH =cH-COOC2H 5 + tes - BrCH 2 -cH =CH-C~Hs + ' >NH
CH2CO
E~~

This compound is used in the synthesis of vitamin A by Aeformatsky reaction

{b) Conversion of monoenes to dienes and trienes

0 ~~
~
Alc:OH 0 [Link]
2..AJcKOH. A
0
I fl

Such allylic bromination followed by dehydrohalogenation has been used in the commerical production of
cortisone.
{c) Degradation of olefinic compounds-The reagent can be employed to split off carbons from suitable
olefinic compounds, which may be obtained from alcohols.

~..t:>3
CH,JCH~H~H~H~
360°C
n-Pentanol
AJc KOH
1.0:J
CH~HO
- HBr
2Hi().Zn
 N-SROMOSUCCINIMIOE (NBS) 205

Such degradations help in determining the structure of compounds. It may be noted that when an olefine has
tw0 different a-positions the pref erred position of attack is the secondary carbon for reasons of stability of 2°
radical.

(d) Conversk>n of vitamin A 1 to vitamin Ai

Bromo retinal
Br

1. N·Phenylmorphofine, - HBr
2. LiAJH4
Vrtamin~

(e) Addition reaction-NBS also exhibits addition reaction but the yield is very poor. [Link], the
ad<fltlon reaction may be catalysed by tetraalkytammonium salts.
Br

6 -NBS_ 0-NBS-
(90•/o)
(Substitution) @0
R4NX
r-YBBrr
~
1, 2-Dtormocydohexane
(75%)

2. As oxidizing agent NBS oxidizes primary alcohols and primary amines to aldehydes and secondary
alcohols tO ketones. The reaction proceeds readily in the absence of light. Hence the reaction is· not radical
type. It probably involves attack by positive bromine. The mechanism is not known.

RCH20H -NBS
- - RCHO + HBr + ¢ 0

0
NH ;

NBS- R2CO + HBr +

R2CHOH - ¢
0

0
NH

3. Degradation of amino acids a-Amino acids, peptides and proteins are decarboxylated with NBS in
aqueous medium.
NBS
CH:JCH(NH2)COOH - - CH:JCHO + NH3 + CO:!
a · Alanine

NBS has also been employed for allylic bromination in the synthesis of some important natural products.
 206 REACTIONS, REARRANGEMENTS AND REAGENTS
It is mair
thods (Amd1
~without a
~()111pletio~ of t
and explosive r
+ The reacl
DIAZOMETHANE, CH 2=N=N or CH 2 N2 !tie subtrate in
Various N-nitroso-N-alkyl amides undergo elimination on treatment with a base to give diazomethane. The iS generated 'in
most useful and convenient general method for the preparation of diazomethane is the treatment of 01 ;ts important
N-nitroso-N-methyl amides with alkali In ether.
uses
~ Ether 1. Methylation
R-C-N-NO
I
+ NaoH- CH2N2 + H:P + RCOONa
also methylate!
CH3
only in the pres
The elimination occurs probably through the tautomer, diazoester of the N-nitrosamide (a) Acidic

~O)
CHrN-~-CH3
0
--
---- CH3-N=N-O-~-CH3
0
N-Methyl·Mnitrosoacetamide Methanediazoacetate

r-..... ~ ct
NaOH + ~CH2"\..N:NfOCOCH3 -
@ e
CH2=N=N: + H:P + CH3C00Na Ethyl acetoace
V Diazomethane

Preparation
Several N-nitroso-N-methyl compounds have been used to prepare diazomethane.
It is very usefu
1. Alkaline hydrolysis of bis-( N-nitroso-N-methyl) terephthalimide.
NO
1 -1)\--
CH3-N-~~~-N-CH3 - - •
NO
1 2NaOH
2CH~ 2 + Naooc--Q-cooNa
0 0

2. Distillation of N-nitroso-N-methyl-p-toluenesulphonamide with base.

H3C
-0- SOr~ -CH3
Ethanolic
H3C
-O- SQ:PK + CH~2
NO KOH
The reagent h
3. Warming N-nitroso-N-methyl-N'-nitroguanidine with potassium hydroxide. in various nat1
(b) Alec
NH KOH acidity.
II '
CH3 -~ -C-N HN02 Warm
NO

Diazomethane is a yellow gas (b.p. -23°C). It is highly toxic and explosive. It sometimes explodes even
in gaseous state. It decomposes readily. Its ethereal solution may be stored at 0°C for about 24 h without
appreciable decomposition. Diazomethane is a resonance hybrid of the following canonical structures:

@e e @ G.> e
CH2=N=N - CH2-N:N - CH2-N=N
 . -
DIAZOMETHANE, CH 2=N=N or CH 2N2 207

It is mainly used as a methylating agent for reasonably acidic compounds. The reagent provides
methods (Amdt-Estert reaction) for the conversion of acids into their higher homologues. It reacts rapidly
even without a catalyst and the yield is high. The reaction is clean since the other product is nitrogen.
Completion of the reaction is indicated by the stoppage of the evolution of nitrogen. Hence, lnspite of its toxic
and explosive nature it is one of the most useful and versatile reagents for preparative purposes.
The reaction is carried out, at about 0°C by adding ethereal solution of diazomethane to the solution of
the subtrate in ether till evolution of nitrogen ceases and a yellow colour persists. Sometimes diazomethane
is generated 'in situ' by adding potassium carbonate to the alcoholic solution of N-nitrosomethyl urea. Some
of its important uses are given.

Uses
1. Methylation It is used as methylating agent for acidic compounds such as carboxylic and mineral acids. It
also methylates reasonably acidic substance like phenols, enols, etc. Alcohols and amines are methylated
only in the presence of catalysts.
(a) Acidic substances

CH2N2 CH2N2
RC OOH RCOOCH3; RS03H RS03CH3;
-N2 - N2

CH2N2 CH2N2
C5Hs(>H C5H50CH3; HCI _ ____. CH3CI
-N2 - N2

Ethyl acetoacetate is 0-alkylated.

It is very useful for the preparation of methyl esters of rare and acid-sensitive carboxyllc acids.

CH2N2
C5H5 -CH =CH-COCH CsHs -CH =CH -COOCH3

"'-._ CH~2 "'-._

V-CH2-COOH - - - V-CH2COOCH3

Cyclopropylacetic acid Methylcyclopropyl acetate

The reagent has been employed for the qualitative and quantitative estimations of carboxyl and enolic groups
in various natural products.
(b) Alcohols-Alcohols have weak acidic hydrogens and hence catalyst is required to increase the
acidity.

HBF4
CHJ(CH2)5CH2')H + CH2N2 - + CH3(CH2)eCH2')CH3 + N2
n-Octyl alcohol Methyl-n-octy\ ether
 208 REACTIONS, REARRANGEMENTS AND REAGENTS

The same mechanism operates for the reaction of diazomethane with acids and amines.
(c) Carbonyl compounds-Aldehydes and ketones react with diazomethane to yield higher ketones and
epoxides as side reaction.
0
/\
R -C-CH3 + R -CH -CH2
II
0

e e
-
?
R-C-CH2
fff:•
N2 -
?
@
R-C-CH2 + N2
I I
R R (1)

o e e
I \ Attack of 0
R2C-CH2 - - - - R-C-CH2
Epoxlde
I
?@
R (I)
Rearran !J9fT'1ent
(migration of R)
0
II
R-C-CH2R
Ketone
J
Some cyclic ketones undergo ring expansion.

/\_r-. CH~2 ~
\__F'"' - v---0
Cyclohexanone Cycloheptanone Epoxide
(63%) (15%)

(d) Amines-Amines are methylated in the presence of Lewis acid since amines are not acidic enough
to react. Hence BF3 is used as catalyst.

Primary amines give a mixture of secondary and tertiary amines.

2. Amdt-Eistert reaction Acid chlorides prepared from acids are converted tp diazoketone with excess of
diazomethane.
SOCl2
RCOOH " RCOCI

RCOCI + CH2"'J2- RCOCHN2 + HCI

Diazoketone
 OIAZOMETHANE, CHrN=N Of' C~N:z 209

CHiNi + HC1 - CHsCI + Ni

If excess of diazomethane is not present to react with HCI then chloromethyl ketone is formed.

RCOCHNi + Ha - RCC>CH2CI + Ni

Diazoketone undergoes Wolff rearrangement in different mediums in the presence of catalyst. Ag 2 0 (or Ag,
Pt, Cu} to yield acids, esters, amides, etc. , all with one carbon more (homologization) than the starting acid.

1
RC OCH Ni R 0H
.,..._.._ _ RCHiCOQR1
1
R Nt-ti
t----.:- RCH2CQNHR1
NH:3 ~ RCHiCONHi

It forms ·hydroxymethyl ketone with water and formic acid.

RCOCHN2 + H:z() HCOOH RCOCH:z()H + ~

Amdt-Eistert reaction has several important synthetic applications.

3. Synthesis of heterocyclic compounds Diazomethane condenses with ethylenic and acetylenic bonds to
give heterocyclic compounds.

- ·11132 .
0
CH
(II) 111 + Cti2N2 -
s".1,t.i . CH
N N
I I
H H
Pyrazollne Pyrazole

9~
(Ill) CHi =C -C02CHs
4c!t:GH3COiCH3
- 1
- 3 2,NH
N
S·Methyl-5-carbmethoxy pyrazoline

Pyrazollnes are Important intermediates for the preparation of cyclopiropane rings. On heating with KOH
on platinized ~sbestos, pyrazolines are decomposed to cyclopropane and nitrogen.
4. formation of carbene (methylene) Photolysis of diazomethane yields carbene which is extremely reactive
species with a very short life period.
 REACTIONS, REARRANGEMENTS AND REAGENTS
210
reaction Is nonselective and
drocarbons by Insertion Into carbon-hy d rogen bon d · The
Carbene reacts wIth hy
hence useless for synthesis.

I~ I
-C+H +I CH2- -C-CH2-H
I~ I
(IJ
CH3 eJ
CH2N2 cH 3 -cH 2 -cH 2 -CH2-CH2-CH3 + CH3-CH-CH2-CH2-CH3
cH 3 -CH2-CH2-CH2-CH3 UV
n-Pentane n-Hexane 2-Melhylpentane

+ cH 3 -CH2-CH-CH2-CH3
I
CH3
J-Methylpentane

Carbene also adds to aliphatic and aromatic double bonds.

/c~
(I) CH3 -CH =CH-CH3 + CH2N2 ~ CH3 -CH - CH-CH3
1, 2·0imethyl cyclopropane

(II) 0 + CH2N2 ~ [~cHJ - 0

Tropllidene

DICYCLOH EXYLCARBODI IMI DE

Preparation
Olcyclohexylcarbodiimide may be prepared by any of the methods given below:
(i) By the oxidation of N, N'-dicyclohexylthiourea with mercuric oxide

II
s HgzO
C6H11-NH-C-NH-C6H11·-~- C6H11-N=C=N-C5H11 + Hg2S + H20
N, N'·Olcyclohexylthlourea Olcyclohexylcarbodllmlde

(ii) By the dehydration of dicyclohexylurea with p-toluenesulphonyl chloride In hot pyridine

The reagent will be represented by the abbreviation, occ.

Uses
Dicyclohexylcarbodllmlde finds application as a dehydrating agent usually under mild conditions. Thus, the
 OICVCLOHEXVLCAABODllMIOE 211

reagent has been employed as dehydrating agent In the synthesis of various compounds such as, esters,
elhers, enhydrldes, amides, lactones, lactams, peptides, etc.
1. Esters Esterltlcatlon of acids with primary or secondary alcohols is promoted by the reagent.

RCOOH + R'OH + CoH11-N=C=N-CeH11_. RCOOR' ... CaH11-NH-CO-NH-CaH11

DCC OCC, H20

Mechanism-The reaction Is catalysed by acid. The acid reacts with the reagent to form the compound
(I) with a good leaving group. Subsequent reaction of the compound (I) with alcohol gives the ester with the
expulsion of dlcyclohexylurea. The sequential steps of the reaction are given.

0 r+WH-C9H11 0 NH-CaH11 m o,, NH-CsH11

-
0 N-CeH11
II II 11 ~ ii' II
I ., I
(a) R-C-OH + C R-C-0 + C - R-C-0-C ~ R-C-0-C
II II II II
N-CeH11 N-CaH11 N-CaH11 ®NH-C6Htt
m
e
~ 0 ) NH-C9H11 H o'J NH-C5H11 ~ 0
;, ~II I I I~ I w II
(b) R' -OH + C-0-C - R'·Q-Cl-O~C -:tL_ R' -0-C
H I II @ I (II I
R @NH-C5H11 R @NH-CaH11 R

The driving force of the reaction is the formation of a very stable compound, dicyclohexylurea.
2. Amides Amides are not directly obtainable by the treatment of acids with amines. In the presence of this
dehydrating reagent however, amides in good yield are obtained at about the room temperature.

Mechanism-It is suggested that the reagent first converts the acid to its anhydride which with amine
gives the amide.
The acid first reacts with the reagent, as in the case of esterification to form (I) which reacts with another
molecule of the acid to form the anhydride. The anhydride then reacts with the amine to form amide.

ft
~
(t)
0 ~ NHCoHn R-C-O NHCaH11
II \::J ~~II I I
R-C-O + R-C-0-C ______. R-C + o=c
II I II I
0 NH-CaH11 0 NHC5H11

(RCO)iO + R'NH2 - RCONHR' + RCOOH

The reaction has been employed to prepare lactams (cyclic amides).

3. Ethen A mixture of phenol, alcohol and the reagent on prolonged heating under pressure gives aryt alkyl
ether.
212 REACTIONS, REARRANGEMENTS AND REAGENTS

4. Acid anhydrides The reagent gives an excellent yield of acid anhydrides from carboxylic acids.

The reaction has been employed to produce symmetrical anhydrides from N-substituted amino acids.

CsH5-CH2-CH-COOH

CsHsCH20CONH
I DCC
- - + (C5H5-CH2-CH-C0)20 + CsH11-NH-CO-NH-C5H11
I
N-Carbobenzoxy-p- C5H5CH20CONH
phenylalanine Anhydride

The amino group of the amino acid is substituted by carbobenzoxy group to prevent the amino group from
reacting with the carboxyl group. The carbobenzoxy group may be easily removed by hydragenolysis after the
reaction.
5. Diacyl peroxide Diacyl peroxide can be prepared by the treatment of carboxylic acids with hydrogen
peroxide under mild conditions in the presence of this reagent.

2RCOOH + H202 + DCC--+ R-C0-0-0-CO-R + DCC,H20

6. lactones Dicyclohexylcarbodiimide in pyridine has been found to be a better reagent than acetic anhydride
in pyridine for the lactonisation of y-hydroxy acids. The method has been used during the synthesis of
reserpine.

7. ~Lactams Lactams are cyclic amides. ~-Lactams are highly strained rings, sensitive to acids while most
reagents for amide linkage involve strongly acid reagents. This caused serious problems in the synthesis of
penicillin. However, the difficulty was overcome by using dicyclohexylcarbodiimide for the amide ring.

PhO-CH2CONHCH-CH ~' C(CH3}2 -o~ PhOCH2CONH-CH-CH ~'C(CH3)2

I I I I I I
HOOC HN-CH-COOH Q::C-N--CHCOOH
Penicilloic acid Penicillin V

Diisopropylcarbodiimide has been found to be a better reagent for amide ring formation as it is a very
mild reagent.

8. Peptides Amino acids in which the amino function has been protected by phthalyl (c 6 H4<co- ) or
co-
carbobenzoxy (C6 H5 CH2 0-CO-) group condense with amino acid esters in the presence of
N, N' -dicyclohexylcarbodiimide at room temperature to give peptides.

After hydrolysis of the product, the protecting group is removed by treating with hydrazine. (See Gabriel
synthesis.)
jP

FENTON'S REAGENT (H 20 2 + Fe2•) 213

Phthalyl and carbobenzoxy groups are used as protecting groups since they can be easily substituted
and easily removed. Carbobenzoxy group may be removecf by hydragenolysis (H 2 + Pt).
9. Barbituric acid Barbituric acid derivatives may be prepared by the treatment of malonic acid with the
reagent.

Inorganic ions which can change their valence state by losing or gaining one electron (oxidation-reduction)
2
have been used to produce radicals. Thus, ferrous ions (Fe •) generate from hydrogen peroxide, hydroxyl
radicals which can oxidize organic compounds.
A mixture of ferrous sulphate or acetate and hydrogen peroxide known as Fenton's reagent has been
used to oxidize organic compounds. The mixture consists of ferric Ions, hydroxyl Ions and hydroxyl radicals.

2®
Fe
3®
+ H-0-0-H _ , . Fe + HO + HO
• e
In Fenton's reagent the ferrous ion catalyses the oxidation of hydrogen peroxide generating hydroxyl radicals
which oxidize organic substances. The oxidation is carried out by adding slowly a solution of hydrogen
peroxide into an ice-cold aqueous or alcoholic solution of the organic substance and ferrous acetate or
sulphate.

Uses
1. Oxidation of hydrocarbons (a) Hydroxylation-Aromatic hydrocarbons are hydroxylated with Fenton's
reagent. The generated hydroxyl radical abstracts a hydrogen from the site of attack and oxidizes the
substrate. The yield is, however, poor.

H
HOH HOH

Ho+ 6 -0·=
v 9. ~
HOdH

I h
•~3@
+Fe -
6
I
OH

h
2@
+Fe
@
+ H

(b) Coupling-The hydroxyl radical may abstract a hydrogen from the susceptible position of the
substrate producing radicals which couple. The susceptible reactive positions are supposed to be the
a-positions to the phenyl, ether, cyano, carboxyl, ester groups, etc.
Thus,

2C5H5-0-CH3
Anisole
 214 REACTIONS, REARRANGEMENTS AND REAGENTS

The reaction is, however, not a general one.

2. Oxidation of a-hydroxy acids a-Hydroxy acids are oxidized with Fenton's reagent to a-keto acids.

2@
H20i + Fe
CH3 -CH(OH)-COOH CH3 COCOOH
Lactic acid Pyruvic acid

3. Oxidation of glycol
2@
CH20H H20i + Fe CH20H
I I
CH20H CHO
Glycol Gfycolaldehyde

4. Oxidation of sugars Aldoses may be degraded to the next lower member with Fenton's reagent (Ruffs
method). Aldoses are oxidized to aldonic acid, the calcium salt of which on treatment with Fenton's reagent
gives the next lower member.

CHO COOH
I I
CHOH Br2 CHOH Ca(OH)i
I I
(yHOH)3 H20 (CHOH)3
I
CH20H CH20H
Glucose

s. Oxidation of tartaric acid Tartaric acid Is oxidized to dlhydroxyfumaric acid.

9ooH H20i + Fe2@ HOOC-C(OH)

(CHOH)2 II
COOH (HO)C -COOH
Tartaric acid Dihydroxyfumaric acid

Dihydroxyfumaric acid forms a complex with the ferric ions. The complex has a violet colour in alkaline
medium. This is used as a test for tartaric acid.

HYDROGEN PEROXIDE, H2 0 2
Hydrogen peroxide is an oxidizing agent useful for synthetic purposes. It may be prepared by the following
methods.
11. From barium peroxide Ice cold dilute sulphuric acid is added to a paste of barium peroxide in water until
just acid.

The solution is filtered and the filtrate is concentrated by slow evaporation at 7ff'C.
2. Electrolytic process Electrolysis of 50% sulphuric acid gives 30% hydrogen peroxide solution.

e
20S03H - - - . H2S20 8 + 2e H2S2Ca + H20 - H2S05 + H2S04
Perdisulphuric Caro's acid
acid
p

HYDROGEN PEROXIDE. HP1 2 15

1. Nonclcctrolytlc process 2-Ethylanthraqulnone is reduced with nickel and hydrogen to 2-ethyt-9-anthrol

which oxldl ,od w th oxygen of air to the starting material, 2-ethytanthraquinone and hydrogen peroxide. The
roacllon I performed In organic solvent and hydrogen peroxide is extracted with water. The method is not
ullable tor the production of a high concentration of hydrogen peroxide which undergoes explosive
d composition with organic impurities.

0 OH

$El 2H2 ©©©-E

l + 2!!_..
0
2·EthylanlhraQu1none 2-Elhyl-9-anthrol

Its structure le suggested to be

H-0-0-H
~
.....,.. H-~-0
e
Uses
II ls a good oxidizing agent and also catalyses many reactions.
In alkaline medium hydrogen peroxide supplies oxygen nucleophiles as the attacking species for the
oxidation.

e
H-0-0-H + HO--+ H-0-0 + H20;
e e ee
H-0-0-H + 20H ----+ 0-0 + 2H20

$
In acidic medium It probably forms the conjugate acid of H20 2 which can transfer OH moiety of protonated
H20 2 to the unshared pair of electrons of the element of the substrate, e.g., alkyl sulphides, amines, etc.

@
@H @
H-0-0-H ~ H-0-0-H - HO + H20
I
H

Applications and uses

11 is a good oxidizing reagent and catalyses many reactions.
1. Preparation of alkyl hydroperoxides and alkyl peroxides (a) Alkyl hydroperoxides are prepared by reacting
alkyl halides or sulphates with alkaline hydrogen peroxide.

They may also be prepared from alkenes by sulphuric acid-induced addition of H202.
 218
REACTIONS, REARRANGEMENTS ANO REAGENTS

Secondary and tertiary hydroperoxldes undergo acid-catalysed rearrangement and cleavage to ketones and
alcohols or phenols.

~ H@ ~ @ ~ H10 ~ r-- ~
R-C-0-0-H
I
R - H20
R-v-
R
-R-&-OR -H
@ ~ R-C\"OR
., I -R-CII +ROH
LOH 0

Aryl group migrates In preference to alkyl group. The method has been employed for the industrial
production of ketones and alcohols or phenols. Thus,

@
CH3
I H
CsHs-C-0-0-H
'
CH3
Cumene hydroperoxlde

(b) Alkyl peroxides are prepared by reacting alkyl halides with Naa02.

2RX + Ni20:? - R-0-0-R + 2NaX

2. Preparation of acyl hydroperoxidn and acyl perorldn (a) Acyf hydroperoxldes are prepared by treating
carboxyllc acids with 90% H20 2 In the presence of acid.

0
H2SO" II
CH3COOH + H2~ - - - CH3-C-O-O-H + H20
Acyf hydroperoxide
(peracetic acid)

Peracids are important oxidants.

(b) Acyf peroxides are prepared by treating excess of acetic anhydride or acid chloride with alkaline
H202.

0II 0II
2{CH3C0}20 + Na20:? - CH3-C-O-O-C-CH3 + 2CH3COONa
Acetyf peroxide

2CsHsCOCI + N~O:? - CaH5-CO-O-O-CO-CeH5 + 2NaCI

Benzoyt peroxide

Peracids may be prepared from acyfperoxides also.

0 0 0
11 " CiHsONa "
CtJH5-C-O-O-C-C5H5 - - - · CsHs-C-0-0Na + CsHsCOOC2Hs

Peroxides often react through tree radical mechanisms.

3. Hydroxylation of aJkenes With hydrogen peroxide and formic acid, alkenes undergo trans hydroxylation. In
contrast, alkaline KMno. or Os04 gives cis product. Formic acid is first converted by H2 0 2 to performic acid
which epoxklates the aJkene. Protonation of the oxygen, ~2 attack by formate anion, and subsequent
hydrolysis yields trans diol.
 HYDROGEN PEROXIDE, Hi02 217

0
II
H202 + HCOOH - H -C -0-0H + H20

-6l-6-
f+ I I I 1f'e I 9-ocH H2 o I ~
o~ --c-c-+ HCOOH ~-c-c- + OOCH --c-c- ------c-c-
Gc-H y \9/).
0
I
OH I OH I
H

4. Hydroxylation of aromatic hydrocarbons Hydrogen per-Oxide and ferrous sulphate (Fenton's ragent) react
wtih aromatic hydrocarbons to yield phenols.

2@ 3@ e .
Fe + HO-OH - Fe + HO + HO

H H 3+H~.f\ OH

0 •
+OH- NOH
v ~aOH~~~
2+ ~ - H 0 .6-
- Fe 2

5. Substitution of aldehyde group by hydroxyl group (Dakin reaction) Aldehydic group ortho or para to NHi
or OH group is converted to hydroxyl group.

6. Oxidation of trialkyl boranes Trialkyl boranes are oxidized by alkaline hydrogen peroxide to alkyl borates
which may be hydrolysed to alcohols.

H202 H20
RJB e ., (RO)JB - 3ROH + B(OH)J
OH

[
R
,
R-~
R
e
+ 0-0H -
R
le
R-J-:~(oH ._
CV
,
R-~
R
H20z, OH
.
OR (Twice)
6
<(R H20
OR-~ - - • 3ROH + B(OH)3
OR
J
The reaction has been utilized in the preparation of alcohol by hydroboration of alkenes.

7. Oxidation of nitrites Nitriles are oxidized to unsubstituted amides.

 218 REACTIONS, REARRANGEMENTS AND REAGENTS

2o,, ~H &:H,
(I) 6--CH3H
2-Methylbenzonitrile 2-Melhylbenzamide

8. Oxidation of ami~es Tertiary amines are oxidized by H20 2 to N-oxide.

Primary and secondary amines are oxidized to N-alkyl-substituted hydroxyl amines.

[ C2Hsr!JH~ -~]-- C2HsNHOH

N-Ethyl hydroxylamlne

Hydroxyl amines are easily oxidizable and in case of 1° amines the oxidation may proceed to form nitro
compounds.

Aromatic amines are oxidized to nitro compounds through the intermediate formation of N-phenyl
hydroxyl amine and nitroso compounds.

9. Oxidation of sulphur compouds Thiols on vigorous oxidation with 30% H20 2 gives sulphonic acids through
the intermediate disulphides.

Sulphides are oxidized to sulphoxides and sulphones depending on the concentration of the oxidant.

Alkyl sulphide Dialkyl sulphoxide Dialkyl sulphone

 HYDROGEN PEROXJDE. ~2

30%H202 (1.5 mol)

~H2 CH3COOH
(ti) CH 3 S-CH2CH2 -CH -COOH
30%H202 (3.5 mol)
CH3COOH
Methionine

1o. Cleavage of ardiketones a-Diketones undergo oxidative cieavage by alkaline HP2 SO two ~ of
acids.
oo
II II H2~.
eOH
R-C-C-R 2RCOOH

Similarly, a-hydroxy and a.-keto acids are cleaved (cf. lead tetraacetate).

R' e R'
H2~.0H I
(I) R-C-COOH R-C=O
I
OH

0 e
Hz~. OH
(ii) R -C-COOH RC OOH

11. Degradation of sugars Aldoses are first oxidized to aldonic acids. Subsequent oxidation d the ca1cUn
2•
salt with Fenton's reagent (H 20 2 + Fe ) converts the aldose to the next lower member.

CHO COOH
CHOH Br2, H20 CHOH Ca-salt CHO
I
<9HOH)3
---1
(9HOH)3 H202, FeS04
- - - - - I(9HOH}J + COz + HzO
CH20H CH20H CH20H
Aldohexose Aldopenloee

12. Epoxidation of a, ~unsaturated ketones

e e
HO-OH + OH - H0-0 + HzO

I I I (l I I 1(0 I I I
-c=c-c=o - -c-c=c-o ---c-c-c=o
l' v HO\.b-.) v
~O-OH 0

In the presence of osmium tetroxide, the dihydroxy compound is obaained.

Hz~
RzC =CHCOR - R2C(OH)-CH(OH)-coR
Os04
HO
R ACTIONS, A ARRANG M ·NTS ANO REAGENTS

LEAD TETRAACETATE, (CH 3C00) 4 Pb or Pb(OAc) 4

Besides being an excellent oxidizing agent, It Is also a good methylatlng and acetoxylatlng agent.

Preparation
The reagent Is prepared by gradually adding red lead with stirring to a mixture of acetic acid and acetic
anhydride. The temperature Is maintained at 55° to 80°C.

On cooling, lead tetraacetate which separates Is filtered and recrystallized from acetic acid.

Uses
The reagent Is generally employed as an oxidizing, methylatlng and pcetoxylatlng agent.
1. As oxidizing agent The reagent oxidizes alcohols to aldehydes or ketones, 1, 2-glycols to aldehydes,
ketones or both, hydroxy quinones to quinones, etc.
The oxidizing property of lead tetraacetate Is due to Its ability to dehydrogenate the substrate while
undergoing reduction to lead acetate and two molecules of acetic acid.
The mechanism of the oxidative cleavage of 1, 2-dlols Is given for Illustration. The mechanism was
suggested by Criegee.

0
I
-C-OH Pb(OA)4 -c< ~b(OA)2 I
-c=o
I
-C-OH
' -AcOH' -Cµ 1:-'°".
o_, - +
-c=o
+ Pb(OA) + MeCOOH
2
I '9J ~C-Me
~:1
(a) Oxidation of alcohols-Lead tetraacetate with pyridine oxidizes alcohols to aldehydes or ketones at
room temperature in good yield. The reagent in pyridine is mild enough not to oxidize aldehyde further.

Alcohols having hydrogen at a-carbon may be cyclised. Tetrahydrofuran is formed in high yield from
n-butanol.
 2'21

CH -CH2-CH2-CH20H
3
Pb(OAc)
4
Q + Pb(0Ao)2 + 2AcOH

Tetrahydro furan
(THF)

(b) Oxidation of 1. 2-glycols-Vlc dlols are oxidized by lead tetraacetate at room temperature With
cleavage of bond to aldehydes, ketones or both depending upon the structure of the glycols,

R R
I
I I
R-C-OH Pb(OAc)4 R'-c=o
(I) I , + + Pb(OAc)2 + 2AcOH
R'-C-OH AcOH R-C:O
I I (where R' • H Of alkyt)
R R

9H 9H Pb(OAc)4
(ii) CH3 -(CH2)7-CH-CH-(CH2)7-COOH A.c:OH CH3-(CH2)7-CHO + OHC-(CH2}7-coc>H
9, 10-Dlhydroxyatearlc acid n-Nonaldehyde Helf aldehyde of azelaic acid

The reaction is useful for the determination of the positions of the hydroxyl groups and for that matter the
position of the double bond In the oleflne from which the glycols are prepared.
Similar oxidative cleavage is observed In compounds having oxygen and nitrogen on adjacent carbons.

I
-C=NH
•
-C=NH
I

I
(Iv) -7- N~
-C-OH
Pb(OAc)4
Ac0H
-C=NH

-C=O
'
+

I
'
(c) Oxidation of hydroqulnones--lt Is an excellent reagent for oxidizing hydroquinones to quinones. The
oxidation is useful for elucidating structures of organic compounds.

(1)¢ Q
OH 0

+ Pb(OAc)4 + Pb(OAc), + Ac:OH

OH 0
p·Benzoqulnone

OH
(II)~ Pb((OAc)4 + H20
OJXJO
HO~ (P~)
2 , 6-Dlhydroxy naphthalene amphi-Naphthaqulnone
(2 . 6-NaphlhaQuinone)

Lead oxide, Pb02 ls actually the oxidant which is obtained by decomposing lead tetraacetate with water.
(d) Oxidative decart>oxytation-(i) ex-Hydroxy acids and cx-keto acids undergo cleavage with loss of
carboxyl groups (cf. hydrogen peroxide).
 222 AEACT/ONS, AEAAAANGEMENTS ANO REAGENTS

R' R'
R-C-COOH Pb(OAc)4 '
R-C=O I RC OOH
I
OH
(ii) Compounds having carboxyl groups on adjacent carbons (succlnic acid derivatives) undergo
bisdecarboxylation.

I I
-C-COOH Pb(OAc)4 -C
1 11 + Pb(OAc)2 + 2AcOH + 2C02
-C-COOH -C
I I

Similarly, malonlc acid derivatives undergo blsdecarboxylation with lead tetraacetate.

R COOH R OAc H O R
' / Pb(OAc)4 ' / 2 '
/c, /c,,_ - /c=o
R COOH R OAc R

Monobasic carboxylic acids give esters which may be hydrolysed to alcohol but there are many side products.
Pb(OAc)4 HiO
R-COOH R-0-Ac R-OH

(e) Oxidation of amines-Oxidation of aromatic primary amines gives azo compounds.

Pb(OAc)4
2 ArNH2 ArN :NAr
Azo compound

Ortho-dlamlnes are oxidized with ring opening. This is an important industrial method for cleavage of
aromatic rings.
Pb(OAc)4 CN
(
CN
c/s-c/s-Dinilri/e

2. As acetoxylating and methylating agent When bolled with glacial acetic acid, lead tetraacetate breaks up
inlO lead acetate and two acetoxyl radicals.

The acetoxyl group may directly abstract hydrogen causing dehydrogenation or may decompose to carbon
dioxide and methyl-free radical.

R-H + CH3Coo•-----+ R. + CH3COOH

or CH3COO -
• COi + •CH3

The methyl radical may combine with the alkyl radical to give methyl derivative,
or it may dehydrogenate the substrate to produce a radical which combines with the acetoxyl radical to give
acetoxyl derivative.
 223

(a) Acetoxylat\on-(l) Carbonyl compounds-The reagent acetoxylates the reactive methyl groups and
the active methylene groups.

(ii) Hydrocarbons-In aromatic hydrocarbons the susceptible positions of attack are benzilic and
9 or 10-positions of anthracene.

Benzyt acetate
~ OAc
9-Acetojy anthre~ne

In cyclo alkenes both the double bond and the allylic position are attacked.

0 P~OAc)4 6
OAc

+ er:: ;
Cls and trans
rYOAc

V-OAc
Cis and trans
er:
Oiol
1, 2-Diecetates 1, 2-Diaoetates

It is in fact a process of hydroxylation.

(b) Methylation-Direct methylation can be carried out by boiling the compound with lead tetraacetate
and glacial acetic acid.

CH3

Pb(OAc>. A OiN~NQi Pb{OAc)4

© AcOH,Boil g AcOH, Boil

N~
TNB
A substitute of vitamin K (antihemorrhagic factor) is 2, 3-dimethyl-a-naphthaquinone which can be prepared
by direct methylation.

AcOH •
Pb(OAc)4 _ __..., 2 Pb(OAc)2 + 2CH3COO
Boil
 REACTIONS, REARRANGEMENTS AND REAGENTS

Other reactions
Hunsdleckler reaction (decarboxylative brominatlon) may be conveniently effected by treating the acid witti
tead tetraacetate In the presence of halide Ion.
0 Pb(OAc}4
RCOOH + Br RBr

A reaction similar to Hofmann rearrangement may be performed by treating the amide with lead tetraacetate.
The Initially formed Isocyanate and the amine may react to form substituted ureas or the amine may react with
the liberated acetic acid from the reagent to yield amide.

RCONH 2
Pb(0Ac) 4
R -N :c :Q
H 20
--. RNH 2
-<R-N=C=O
:
RNHCONHR
CH COOH Substituted urea
3
' - - - - - RNHCOCH3
Substlluted amide

LITHIUM ALUMINIUM HYDRIDE

Lithium alumlnlum hydride (LAH) Is one of the most important and useful reagents for the reduction of carbonyl
compounds along with many other compounds.

Preparation
The reagent Is prepared by slowly adding a calculated amount of anhydrous aluminium chloride to a paste of
lithium hydride In dry ether or THF.
Dryelher @E>
4LIH + AICl3 or THF LIAIH4 + 3UCI

Precipitated lithium chloride and the unreacted lithium hydride are removed by filtration. The filtrate is
evaporated in the absence of air and carbon dioxide when lithium aluminium hydride is obtained as a grey
solid. It is spontaneously Inflammable and react!:i violently with water and alcohol with the evolution of
hydrogen. It is soluble in ether, tetrahydrofuran (THF) and dloxan.

Reduction procedure
Powdered LiAIH 4 is added to dry ether or THF and ~[Link] in a flask which is fitted with a condenser and
a dropping funnel. Solution of the substance In ether is then gradually run Into the flask so as to maintain a

tee
gentle bolling of the mixture. The reduction product is decomposed with water and acid.

4R -C =O + LIAIH 4 Ether
'•
R
I ~
R -C -
1,
R
4
AILI
H
I
4R-C-OH
1,
R I
+ Al2(S04)3 + ~S04

(where R ;: alkyl, OH, Cl. etc. )

Excess of UAIH 4 is also decomposed by water and acid.

Mechanism
The reagent can supply hydride Ions to a large variety of compounds having groups with polarized multiple
bonds such as, C--0, Cw=N, C=N, N=O, etc. It is suggested that as the nucleophilic hydride ion attacks the
 ...

LITHIUM ALUMINIUM HYDRIDE

positively charged carbonyl carbon, aluminium complexes with the oxygen, i.e., the reaction is concentrated.
The intermediate (I) formed in the first step has three more hydrogens which are similarly transferred to three
other molecules of the substrate to yield the complex (II). The latter on hydrolysis with water and acid gives
the reduced product.
R
-@
e @ 3 'c=o
R
'~fo
,/
R
,......-....0
+ AIH 3 u -...
H
@ R

R
,'c(
/
(I)
H
OAIH 3 U R'/
- - -.....
R

R'
) c(
(II)
0

H
fIU HCI R
---.4 1 )
H20 R

The first step ls fast but the subsequent steps are slow because the electron-withdrawing effect of the alkoxyf
c(
(I)
OH

H
+ AICl:J + UCI

group inhibits the hydride Ion transfer. It is seen that in reducing the cabonyl compound, half the hydrogen is
supplied by the reagent and the other half is supplied by the solvent, Le., water.
It reacts readily with acidic hydrogens. One fourth of the valuable reagent is lost in the formation of
hydrogen on reacting with the hydrogens of acids.

e@
R-COOH + UAIH4 - R-COOAIH3U + H2

Hence acids are better converted to their esters before reductlon with lithium aluminium hydride.

Uses
The reagent may be used to reduce aldehydes, ketones, acids and their derivatives, epoxides, etc., to
alcohols. The reagent can also reduce nitriles, aliphatic nitro compounds, anilides, azides and isocyanates to
amines. The substrates and their reduction products with liAlH 4 are listed below.

Substrates Reduction producta Reduction products

Substrate$
RCHO RCH20H
R-C:N RCHOorRNH2
ReOR RCHOHR
R-NQi RNH2
RCOOH RCH20H
Ar-NQi ArNH=NHAr
1 1
RCOOR RCH20H + R 0H
ArNHCOCH 3 ArNHCH2CH3
RCOCI RCH20H
R-N=C=O RNHCH3
/°'. RN3 RNH2
R-CH - CH2 RCHOHCH3 + RCH2CH20H
(RC0)20 2RCH20H

The list is by no means exhaustive.

1. Reduction of carbonyl compounds The carbonyl compounds are smoothly reduced without affecting
double or triple bonds.
1. UAIH_., ethel
(a) CH3(CH2),.CHO @ CH3 -(CH2)4 -CH20H
Hexanal 2.H30 Hexanol

(b) CH3 -CH =CH-CHO CH3-CH=CH-CH20H

Crotonaldehyde
Crotyl alcohol

Sometimes the double bond Is also reduced when a phenyl group is attached to the ~rbon.
 REACTIONS, REARRANGEMENTS AND REAGENTS

t LIAIH4 1 ether
CsHs-CH =CH-CHO C5H5-CH2·CH2 -CH20H
@
Clnnemaldehyde 2. H30 3-Phenylpropanol-1

UIAIH4 , ether
(c) CH3CH2COCH3 CH3CH2CH(OH)CH3
(£)
MEK 2.H30 Butan-2-ol

tUA IH4 , ether

(d) CH3COCH2COOEt CH3 -CH(OH)-CH2 -CH20H
@
Ethyl acetoacetate 2.H30 Butan-1,3-dlol

(e) The reagent is of considerable utility for the reduction of sensitive and expensive carbonyl
compounds.
H

cf'oH
Cydobutanone Cyclobutanol Nitrober

2. Reduction of acids and their derivatives Acids are resistant to reduction by all other reagents.

Acids
[Link], ether
CH3 -(CH2)14 -COOH CH3 -(CH2)14 -CH20H
(£)
Palmltlc 2.H30 Hexadecanol-1 (cetyl alcohol)

CH3-CH =CH-COOH CH3 -CH :CH-CH20H

Crotonlc acid Crotyl alcohol

1. LAH, ether
CH2(NH2)CH2COOH CH2(NH2)CH2CH20H
(£)
fl-Alanine 2. H30 3-Aminopropanol-1

[Link], ether
Acid chlorides CH 3COCI
(£)
2.H30

[Link], ether Nitrile

@ the reactior
2. H30
at I (a) Al
ow tern~
[Link], ether
CH3 -CH =CH -CH20H
@
2.H30 But-2-ena-1-ol

Amides-Unsubstituted amides give 1° amines while substituted amides give 2° or 3° amines.

in eth (b) /.
er or
p

227
UTHIUM ALUMINIUM HYDAIOG

(I) RCONH2 ,
(11) RCONHR
1
(Ill) RCONR 2
I [Link], ether

2.H30
@
(I) RCHa NH a
(II) RCH 2 NHR
1
(Ill) RCH2 NR 2
1

Anilides are similarly reduced to 2° or 3° amines.

(I) CsH5-NH-CO-CH3 ) ro CoH&-NH-CH2-CH 3

[Link], ether N·Elhyhmlllno (2°omlno)
Acetanillde
0 (II) C0H s-N(CH3)-CH2 -CH 3
(Ii) CsHs-N(CH3)-CO-CH3 2.H30 0
N-Methylacetanmde N-Methyl-N·elhyl onlllno (3 nmlno)

3. Reduction of nitro compounds, azides, oximes, nitrites, etc., to primary amines

Nitro compoyods

Nitrobenzene, however, gives azobenzene via azoxybenzene.

0
LAH
2C5H5N02 _ ___,~ CsHs-N=N-C5H5 -
+ C5H5-N=N - C5H5
Ether Azobenzene

~ LAH
RN3 RNH2
Azlde Ether 1•amloe

LAH
CH2 =cH-CH2CH2N3 Ether CH2=CH-CH2-CH2-NH2
Allyl carblnyl azlde Allylcarblnyl amine

~ LAH
(CsHs)2C =N -OH (CsHs)2CH -NH2
Ether
Benzophenone oxime Olphenymethyl amine

Nitriles-Reduction of nitriles with liAIH 4 may give amine or aldehyde depending on the conditions of
the reaction.
(a) Aldehydes are given when a solution of LiAIH4 ls added to the solution of a nltrlle in dry ether or THF
at low temperature.
@
~ LAH, Ether HJO
R - CH =NH ~ R - CHO
R-C:N - so·c
Imine

(b) Amines are obtained when a solution of nltrlle Is added to the solution of lithium aluminium hydride
in ether or THF.

b
 228 REACTIONS, REARRANGEMENTS ANO REAGENTS

LAH [Link], elher

R- C: N R- CH=NU
lhnr lmlne 1011 @
2. H30

4. Reduction of halides
Elher

S. Reduction of epoxldes to alcohols

LAH
4 CH3 -c\i iCH-CH3 Ether
0

6. Reaction with compounds containing active hydrogens The reagent reacts with alcohols and amines to
evolve hydrogen. The method can be used to estimate active hydrogen.

7. Introduction of deuterium In organic molecules Lithium aluminium deuteride has been used for
introducing deuterium In organic compounds.

(ii)
0 - 0 0

Cyclohexanone
L_IA_10_,._ 0H

0
Cyclohexanol-1-d

OSMIUM TETROXIDE, Os04

Osmium tetroxide is a reagent for els-hydroxylation of carbon-carbon double bond.

Preparation
It is prepared by the oxidation of osmium metal or its compounds by strong heat in the presence of air. More
commonly it is prepared by heating osmium metal to red heat in air.

Red heat
Os + 202 (air) Os04

Osmium tetroxide is toxic and volatile. Its vapours are specially dangerous for eyes. Since it is an expensive
and toxic substance it is used only for the synthesis of fine chemicals \pharmaceuticals) and for degradative
purposes in the elucidation of structures.
For the oxidation purpose, a solution of Os04 ,in ether or t-butyl alcohol is added to the solution of the
 OSMIUM TETROXIDE, Os04 229

·n the presence of a base, e.g., pyridine which catalyses the reaction by coordinating with the resulting
ester. The osmic ester is then hydrolysed by refluxing with an aqueous-alcoholic solution of a reducing
~t. e.g., sodium sulphite which prevents further oxidation of the product.
Osmium tetroxide, like permanganate, undergoes initial cis-cycloaddition with the olefine from the less
red side to yieki cis-1, 2-diol as the final product.

"'-/
c
"'-/
\\c +
0
~of/
~ ~
0
~
C-0
\ 'of
/ ~
0
Aq.-alc.Na2SO:l
Reflux
I
C-OH
+ Os0)
e

l
0 0 C-Q 0 C-OH
/"'- /"'. /"'.
0
Os~
Osmic ester (
+ H20 - H20s04
Osmic acid

The addition of eso. is slow but almost quantitative. The cyclic osmic ester is insoluble. The reaction
generally occurs at room temperature.

Uses
1. Preparation of c&1, 2-diols

H
I
R-C-0 0
.,
,.,"' R-CH +
OsO• - I 'art [Link];. Ni2$0)
R-CH / ~ Reftux
R-C-o 0
I
H

{ii)
0 tOsOc,2~Nai~ "Y
2. [Link] .
~HC
Cydopentene OH
Cis-Cydopentan· 1, 2-diol

2. Bucidation of the structures of polynuclear hydrocarbons Anthracene is oxidized by Os04 to tetrol (I)
which on further oxidation with potassium ferricyanide gives naphthalene-2, 3-dicarboxylic acid (II). The
carboxyt groups at positions-2 and -3 indicate ortho fusion of the third ring in anthracene and also linear fusion
of the three rings.

OH

[Link] ~OH ~COOH

~COOH
2 . NazS<>:,
~OH
(I) OH (II)

Similar treatment indicates ortho fusion of the two rings in naphthalene.

3. As~ [Link] Since it is an expensive and toxic reagent, it is sometimes used in small catalytic amounts
with other oxidizing agents. e.g .• H20 2 which reoxidize osmium in its lower valence states to Oso.. to continue
the oxidation of the substrate.
 230 REACTIONS, REARRANGEMENTS AND REAGENTS

(Q CH2=CH-CHO - - CH2(0H)-CH(OH)-CHO
Acraldehyde Os04 Glyceraldehyde

CH3 CH3
1 H20i + t-butanol 1
(IQ CH3-C=CH2 - - - - - - - CH3-C(OH~-CH20H
Os04, O'C , 24 h
2-Methyl propane 2-Methylpropan-1 , 2-diol

H202 + Os04 in t-C4H70H CH(OH)-COOH

(llQ c6H6 I
CH(OH)-COOH
Several hours
mesotartaric acid

(iv) Conjugated double bonds are also hydroxylated with Os04 and H2 0 2 .

H20i + 0904
(IV) (a) R2C=CH-COR R2C(OH)-CH(OH)-COR
a. !}-Unsaturated ketone a. P-Olhydroxy ketone

(b) C5H5-CH:CH-COOH C5H5-CH(OH)-CH(OH)-COOH

Cinnamic acid Phenylglyceric acid

M CH-COOH NaCJ():J +. OS04 CH(OH)-COOH

II I
CH-COOH SO'C,24h CH(OH)-COOH
Maleicacid mesotartaric acid

4. Elucidation of the structures of unsaturated compounds Hydroxylation of carbon-carbon double bonds by

osmium tetroxide and their cleavage with specific reagents, e.g., lead tetraacetate or peracids offer a good
method for the degradation of unsaturated compounds. Identification of the degraded products gives the
presumptive structure of the unsaturated compound.
The reagent has also been employed in the synthesis of cortisone.

PERBENZOIC ACID (Peroxybenzoic acid), C6H5 C03 H

Several percarboxylic acids have been prepared of which perbenzoic acid is the most commonly used in the
laboratory. The percarboxylic acids are unstable reagents and hence they are freshly prepared before use.
Perbenzoic acid may be prepared by several methods.

Preparation
1. A cold solution of benzoyl peroxide in chloroform is added to a cold (0°-5°C) solution of sodium
methoxide in methanol. The product, sodium perbenzoate is extracted with ice-cold water which is
acidified with cold normal sulphuric acid and extracted with chloroform. Chloroform is removed by
distillation under reduced pressure when perbenzoic acid is obtained as a solid, m.p. 41 °C. The yield
is about 82%.
p

231
PERBENZOIC ACID (Peroxybenzolc acid), C8H6C03H

0 0
0 0 II
II
11 II
c 0 H5 -c-o-o-c-csHs + CH30Na ---+ CaHs-C-0-0Na + CeHs-C-OCH3

H2S04
- - - CsH5COOOH
CHCl3

2. To a solution of benzoic acid in methane sulphonic acid, 70% hydrogen peroxide is added dropwise
with constant stirring. The temperature is maintained at 25°-30°C. The stirring is continued for two
hours. The mixture is extracted with benzene, washed with ammonium sulphate solution and filtered
when perbenzoic acid is obtained. The yield is 80-90%.
0
II
C5H5COOH + H2~----+ C5H5-C-O-OH + H20

3. A mixture of methylated spirit and magnesium sulphate is added with stirring to an aqueous solution
of sodium peroxide (or better hydrogen peroxide and sodium carbonate) at about 20°C. Benzoyl
chloride Is then added slowly with stirring to the resulting mixture. The solution is then filtered,
acidified with sulphuric acid and extracted with benzene. Perbenzolc acid Is obtained on distilling off
benzene.

CsHsCOCI + N11202 - - - . CaH!;C03Na + NaCl

2CaHsC03Na + H2S04 - 2CaHsC"3H + Na2S04

Procedure
Ethereal or chloroform solution of perbenzoic acid is added to the substrate. The mixture is kept from one to
several days (according to the substrate) at room temperature. The mixture is washed with dilute alkali, dried
and the solvent distilled off.

Use
Perbenzoic acid is a good oxidant and reacts with oletinic bonds to yield epoxides (oxiranes). Some of its
important uses are-
(a) Epoxidation Perbenzoic acid reacts quantitatively with non--coniugated double bonds to form epoxides.

0
/\
R-CH=CH-R + CsHsC03H - R-CH-CH-R + CeHsCOOH

Except amino group, other groups such as hydroxyl, ester, aryl, etc., do not lntertere. The reaction conditions
are mild and the yield is high. Electron-donating groups increase the reaction rate . Thus, 1, 2-dimethyl
1, 4-cyclohexadiene forms epoxide with the alkyl substituted double bond.

Unsaturated groups adiacent to the olefinic bond decrease the reaction rate by electron withdrawal, e.g., the
reaction is very poor with a., r>-unsaturated acids or esters. With a., r>-unsaturated a\dehydes or ketones,
Baeyer- Vi\liger oxidation may compete with epoxidation.

-
 """'
REACTIONS, REARRANGEMENTS AND REAGENTS

Mechanism of epoxidation-A widely accepted mechanism involves the formation of a cyclic

- enneciate state which transforms into products.

Evidence · favour af this mechanism are--

ff' the reaction is second order (II) reaction occurs readily in nonpolar solvents, i.e., without ion formation and
(111) the addition of oxygen is stereospecific, e.g., cis-olefin gives cis-epoxide.
Epoxides may be transformed into alcohols, diols, carbonyl compounds, etc. Thus,
Ak:otloJ-Epoxides on reduction with LiAJH4 gives alcohols. Cleavage occurs so that a 3° alcohol is
formed and if 1hat is not possible then a 2° aJc:ohol is formed.

l..iAIH4
R-CH -CHz R -CH(OH)-CH3
\/
0

Ve ciots--Epoxides are hydrolysed to trans 1, 2-diots. the reaction is acid- or base-catalysed.

@, OH
-H ' I
-/9-c-
OH
trans 1, 2-Diol

Depencing upon reaction concfitions the cfiols may undergo pinacol-pinacolone rearrangement to aldehydes
orketones.
(b) Oxidation af ketones to estttS (Baeyer-Villiger rearrangement) Ketones are converted to esters and
cycic ketones to lactones on treatment with perbenzoic acid (or better with CF 3C03 H). Lactones are formed
with mg expansion.

()=o c,H,CO.-.H ()=

Caprolactone

Cc) Oxitiation of~ and 1, 2-quinones to add anhydrides The anhydrides obtained by oxidation
may be hydrolysed to acids.
 233

a 0
OOH
COOH
((
~
o-Cerboxyallocinnamic acid

l\t~ ~\\~na\\c ~ 0 and 2° am\nes are ox\d\zed to a'kyl and dia,kyl hydroxylamines

_ __..., R-NH-OH
N-Alky\ hydroxylamine

CsH~03H
R2-NH _ _ _....,. R-N-0 t ~@e~ _
R
__.,. R2N-OH
N, N-Dia\kyl hydroxylamine

,\nes ate eas\\'I ox\d\zed and ~ 0 am\ne may be oxidized to n\tro compound.

~0 am\nes ate o~\d\2ed to am\ne ox\des and aromatic amines are oxidized to nitro compounds.

0..N
C6HsC03H,CH3C(hH
Reftux G.J•e
N
0
Pyridine-N-oxide

:e) Ox\dat\on of azobenzene Perbenzoic add oxidizes azobenzene to azoxybenzene.

CsHsC03H @
l>.r-N=N-Ar Ar-N=N-Ar
be
[Link] benzene

~f) 01<.\da\\on of th\oethers Th\oethers are 1irs\ oxidized to sulphoxides and on further oxidation to sulphones.

C2Hs, CsHsC03H C2Hs, ho

/s=o---- s"
C2Hs C2H( "o
Oielhyl s~lphoxide Diethyl sulphone

~v,') Ox.\da\\on of benza\dehyde Senza\dehyde is oxidized to benzoic acid.

 234 REACTIONS, REARRANGEMENTS ANO REAGENTS

benzaldehyde to benzoic acid.

(h) Detection and estimation of double bonds The presence of double bond is detected by the formation of
epoxide which may be separated.
For the estimation of double bonds, a known quantity of the olefinic compound is allowed to react with
an excess of perbenzoic acid in chloroform for several hours. The unconsumed peracid is determined by
iodometry. The number of double bonds in the compound is then calculated from the amount of peracid
consumed and the weight of the olefinic compound.

This valuable reagent is prepared by the following methods.

1. On passing chlorine into a boiling solution of sodium hydroxide and iodine, a precipitate of disodium
orthoperiodate is obtained. The latter on treatment with aqueous silver nitrate solution gives silver
orthoperiodate which on treatment with chlorine in the presence of water gives orthoperiodic acid. It is then
filtered.

6NaOH + 3'2 ~ Nal03 + 5Nal + 3H20

HiO
Ag5I06 + Cl2 - Hsl05

The filtrate on evaporation over concentrated sulphuric acid gives orthoperiodic acid crystals , H 5106 or Hl04•
2H 2 0 which on heating to 100°C in vacuum gives metaperiodic acid, HI04 .
2. Perchloric acid solution in water on treatment with iodine gives periodic acid.

3. By the anodic oxidation of iodic acid, HI03 .

The characteristic property of periodic acid is the oxidative cleavage of bonds with adjacent oxidizable
groups such as, 1, 2-diols, a-hydroxy carbonyl compounds, 1, 2-diketones, o:-amino alcohols, etc. The
reagent does not react with 1, 3- or 1, 4-diols or carbonyl compounds. Also, the reagent has no effect on the
oxide ring of carbohydrates. For two adjacent oxidizable groups (e.g., -CHOH-CHOH-, -CHOH-CO-, etc.)
one molecule of the reagent is consumed which oxidizes a CHO group to formic acid, CH 20H group to
formaldehyde, CHOH group to aldehyde group or formic acid according to the positions of the groups. This is
illustrated below.

-HI03
R-CHOHtCH20H + HI04 R-CHO + HCHO
'
-HI03
R-CHOHfcHOH-R' + HI04 R-CHO + R'CHO
'
p
235

1
R2C(OH)4-CHOH-R + HI04
I

- 2H103 1
R-CHOH tCHOH tcHOH -R' + 2H104 RCHO + HCOOH + R CHO
I I

-HI03 1
1
R -co+cHOH-R + HI04 - - - R -COOH + R-CHO
I

I I 1
R-CO+CO-R R-COOH + R -COOH
I

-H~
RCHNH2 ... CHOH -R' + HI04 RCHO + R'CHO + NH3
I

No reaction

Each dotted line represents one mole of periodic acid and the position of the cleavage of bond. The reactions
are practically quantitative. The oxidation is carried out at room temperature with the aqueous solution of the
oxidant.

Mechanism
The reaction probably proceeds via a cyclic intermediate (II) or (Ill) resulting from the reaction between the
substrate and the ion (I) of the reagent.

OH OH 0
R-CHOH H0....._1,....oH R-CH-0 . . . . I / OH R -CH-0 II 0 RCHO
1
R CHOH
+ I 0 - I
1 I 0 ~1-0
1.J - +
R CH1:)~
1
,Ho,....11.' o R CH-O_....ll'O 1
R CHO
0 0
(I) Hydrated ion (II) Dehydrated ion (Ill)

Uses
Periodic acid has important synthetic and analytical applications. The reagent is very useful in the
determination of the structures of carbohydrates and in general of 1, 2-glycols. Different substrates consume
different amounts of the oxidant to give different amounts of formaldehyde and formic acid. This is indicative
of the structures of the substrates.
Periodic acid can be estimated iodometrically. Similarly, formaldehyde and formic acid produced in the
reaction can be estimated. Since the oxidation reactions -are practically quantitative, the knowledge of the
number of moles of periodic acid consumed and the number of moles of formic acid and formaldehyde
liberated can afford valuable informations about the structure and size of the ring of carbohydrates.
Identification of the fragments of periodic acid oxidation of glycols provides evidence for the structures of
glycols. Qualitatively, the oxidation with H 5106 is indicated by the formation of a white precipitate of Agl0 3 with
 REACTIONS, REARRANGEMENTS AND REAGENTS

AgN03 solution.
1. Identification of aldoses Predictable amount of periodic acid consumption per mole of different aldoses is
four moles for aldopentose, five moles tor aldohexose, six moles tor aldoheptose, etc. Thus, the number oli
carbons in the aldose can be known from the amount of the oxidant consumed.
I I I I

CH20HtCHOH~[Link]~CHO
• • I ,
+ 4HI04 ___. 4HCOOH + HCHO + 4Hl03
Aldopentose

. : . . .
CH20HtCHOHt-CHOH·kHOH.f-CHOH+CHO + SHI03 - - + SHCOOH + HCHO + SHI03
. .
Aldohexose
: : '

2. Distinction of aldohexose and ketohexose Glucose and fructose consume different amounts of periodic
acid and give different amounts of formic acid.

' · • SHI04
f
CH20H tcHOH tCHOH cHOH tcHOH CHO f SHCOOH + HCHO + SHI03
Aldohexose (glucose) ·

I : : I 4HI04
CH20HtCHOHtCHOHtCHOHtco-cH20H HCHO + 3HCOOH + HOOC-CH20H + 4Hl03
Ketohexose (fructole)

From the amount of periodic acid consumed and the amount of formic acid liberated, the two
monosaccharides can be identified.
3. Determination of the size of the oxide rings of sugars When glucose is treated with methyl alcohol and
hydrochloric acid it giveli two isomers of methyl glucosides. The one (l) prepared under hot condition
consumes two molecules uf periodic acid and gives one molecule of formic acid and no formaldehyde. This
fits in with the 1 : 5-oxide ring structure (pyranoside).

Methyl glucoside (1) Acetaldialdehyde

The other isomer (II) prepared under cold condition consumes two molecules of periodic acid and gives one
molecule of formaldehyde but no fonnic acid. This observation fits in with the 1 : 4-oxide ring structure
(furanoside).

MeO-C~H Meo-~
CHOH
I
CHO 0
CHOH 0
-~HOH I 9Ho I
HC~ H-C.:.=.._j
I
I CHO + HCHO
,_
__CHOH
CH20H
Methyl glucoside (II)
4, Structure of sucrose Each molecule ~f su~rose consumes t~ree. molecules of periodic acid and gives a
tetraaldehyde and one molecule of formic acid. Subsequent ox1dat1on of the product followed by hydrolysis
gave glyoxallc acid, glycerlc acid and hydroxy pyruvic acid. From the degradation products and the number of
molecules of periodic acid consumed the C-C linkage of the two moieties In sucrose was established.

yHO + C020H
I

COOH co
I
Glyoxalic acid COOH
3HI04 + Hydroxy pyruvic acid
-HCOOH COOH +
I
H-C-OH COOH
I
I
CH20H
H-C-OH
I

D·Glyceric acid CH20H

D·Glyceric acid

5. R1ng size of the sugar residue of nucleosides The sugar residue of nucleosides Is a five-membered
turanose ring, since it consumes one molecule of periodic acid producing only a dialdehyde.

I
H-C----.
I
9HOH O
I
9HOH
H-c-J
I
CH20H
Sugar residue of
nucleos1des

6. Oxidation of alkenes Periodic acid has no reaction on oleflns. However, oleflns can be hydroxylated to 1,
2·glycols and then oxidized with periodate to carbonyl compounds. Exocyclic olefinic bonds can be oxidized
by this method.

Cold di\, KMn04

<>= CH2

A mixture of dilute aqueous solution of permanganate or hydrogen peroxide and sodium periodate (Lemieux
reagent) may be used to oxidize olefins In one step.
KMn04
CH3-(CH2)7-CH =CH-(CH2)7-COOH Na\0
Olelcacid
4
n-Nonaldehyde Half aldehyde of azelalc acid

7. Estimation of amino acids Amino acids having hydroxyl group adjacent to the amino group consume one
molecule of periodic acid and liberate one molecule of ammonia on oxidation with periodic acid. Evolved
ammonia and the oxidant consumed may be estimated and from this the percentage purity of the amino acid
can be determined.

CH3-CH-CH-COOH
I I
OH NH2
Threonine

The reagent has been employed in the determination o1 the chain length of polysaccharides. in the
elucidat\on of the structure of chloromycetin, and in the synthesis of some natural products such as,
cholesterol, reserpine , etc.
 REACTIONS, REARRANGEMENTS AND REAGENTS
238

RANEY NICKEL
Nickel has found extensive use as a catalyst for hydrogenation. Haney nickel is an extremely active form Of
nickel.

Preparation
Raney nickel is prepared by adding nickel-aluminium alloy (1 : 1) over a period of 2"""'3 hours to an ice-cold
solution of sodium hydroxide (25%). The mixture is heated to 115°C-.120°C with occasional stirring for about
four hours. A further quantity of sodium hydroxide solution is added and the temperature maintained at
11 s 0 c-120°c till the evolution of hydrogen ceases. The alkali layer is decanted off and the residue (nickel
catalyst) is washed several times with water and then with alcohol. It Is stored under absolute alcohol, ether
or dioxan in a stoppered bottle.

NI-Al + NaOH + H20 - - + NaAIOi + Ni-H + H2

Raney nickel

Raney nickel is a black spongy metal powder with a weak nickel-hydrogen bond. Hydrogen is bound to the
surface of the catalyst (50-100 ml/g). The degree of catalytic activity depends upon the reaction conditions of
preparation. Based on different degrees of activity they have been designated as W-1 to W-7 (W =
Wisconsin).

Uses
Raney nickel is a widely used powerful reducing agent. Most olefins ate reduced at room temperature at about
atmospheric pressure while resistant compounds require higher temperature (about 100°C) and pressure
(about 100 atmosphere). Double bonds common to two rings are generally difficult to hydrogenate. Aromatic
hydrocarbons and aromatic amines require a higher temperature and pressure.
1. Reduction of carbon-carbon multiple b_onds Raney nickel reduces multiple bonds present in aliphatic,
alicyclic and aromatic compounds.

Nf-H
(~ ~C~CH CH3-CH3
Room temp.

OH

6 120-~';;;~c. 6
OH

(iii) 01
~
Nl-H
1oo·c. Press.
0 (W)
Press.
Cyc1ohexane Cyclohexanol

Nl-H, 150°C Ni-H , 200'C

(v) ( ( )
30atm 200:-300 atm
Tetralln Decalln

2. Reduction of aromatic ethers Aromatic ethers are reductively cleaved on heating with Raney nickel.
Hydrogen comes from that normally contained In Raney nickel and from the solvent.
 RANEY NICKEL 239

Ni-H
ArOR t. ArH + RH

When R is aromatic it may be reduced to cyclohexane unless degassed Raney nickel is used.

Mechanism- Ni-H 0
ArOR Ar + ROH

Ar takes up proton from the solvent and ROH is reduced by hydrogenotysis.

3. Reduction of nitro group to amino group

Ni-H
(CH3)2~ -CH2-CH2-COOCH3 so·c (CH3)iC-CH2 -CH2 -COOCH3
I
NQi NH2
Methyt-4-methyt-4-nitropentanoate Methyl-4-methyt-4-aminopentanoate

The product on heating is cyclised to pyrrolidone derivative.

4. Reduction of nitrites Depending upon the conditions of reaction, nitrites are reduced to aldehydes or
primary amines.
(a) Nitrites in aqueous acetic acid-pyridine medium are reduced to aldehydes with Raney nickel and
sodium hypophosphite.

Ni-H, NaH2PCh
0 yr-AcOH

(b) When nitriles are treated with Raney nickel under pressure, primary amines are formed.

Nl-H
R-CN
Press.

The primary amine may react with the aldinlme to form secondary amine. This may be prevented by
carrying out the reaction in the presence of acetic anhydride which converts the primary amine to its acetyl
derivative.
S. Reduction of halides Dehalogenation is accomplished by several reagents. The advantage of using Raney
nickel is that it removes all the halogens including fluorine. Similarly, phenyl tosylates can be reduced.

ArX
Ni-H
ArH(whereX=Cl,Br,landF);
~ Ni-H
~OTs---~
IQ\
Na OH

6. Desulphonation Sulphonic groups may be easily replaced by hydrogen.

7. Desulphurization Thioalcohols, thioethers, disulphides, thioamides, sulphoxides and sulphones are

desulphurized by *hydrogenolysis with Raney nickel. Hydrogen is not required externally as Raney nickel
contains sufficient adsorbed hydrogen for the reaction.

Ni -H 1 1
Nl -H
R-S-R'--- RH + R H ; RCSNHR - - -

Thioether Thioamlde

Thlophene derivatives which may be considered as cyclic thioethers are desulphurized with accompanying

• Hydrogenolysls means the cleavage of carbon·hetero atom bond by catalytic hydrogenation.

 240 REACTIONS, REARRANGEMEHTS AND REAGENTS

reduction of the double bonds.

R~R' Ni-H
s
2' 5- 0iaJkylthiophene

The reaction is very important for the elucidation of the structure of thiophene derivatives e.g., biotin. seienium dioxide is an i
[Link].
0 0

A
HN NH HN
A NH
Preparation
is prepared by the di1

Q-(CH2)4 -COOH
Ni-H
H
CH3 (CH2)s -COOH
selenium dioxide. The c
s Delhlobootin
Biotin
is a white crystallim
Desulphurization may also be employed to prepare higher acids and compounds which are otherVlise liffiaj reagent, in general,
to synthesize. respectively.

(i) 0 S
+ yHr~o _1._A_IC..;l3_ _ _ _
CH2-CO [Link]-Hg + HCI
IC>-
S
(CH2)3-COOH
RCOCI

SnCl4
Double bonds, 1
1. Wolff- Klshner reductlon
usually carried out in
- - - - - - - R-(CH2)s-COOH
[Link]-H oowi may also be u

Uses
Besides oxidation of
hydroxylation . allylic
1. Oxidation of read

Desulphurization has been utilized for the conversion of a ketonic group to methylene group. When the
carbonyl compound to be reduced is sensitive and cannot be reduced by Clemmensen or Wolff-Kishner
methods, they are converted to cyclic thioketals with 1, 3;>ropanedithiol and then desulphurized with Raney
nickel.

Raney nickel is not poisoned by sulphur compounds.

8. Hardening of oils Raney nickel is employed in the industrial production of hydrogenated oils (vegetable~~
Oils are glycerides of unsaturated fatty acids. The unsaturated hydrocarbon part of the fatty acid is
partially hydrogenated with Raney nickel at 150-200°C under pressure to yield the hydrogenated oil.

CH2-0-CO-Cn H2n -1 CHrO-CO-Cn H2n -1

I H 2 +Ni I
CH-0-CO-Cn H2n -1 CH-0-CO-Cn H2n +1
1 1S0-2oo•c I
CHi-0-CO-Cil H2n -1 CH2-0-CO-Cn H2n +1
Glyceride of unsaturated Partially hydrogenated oil
fatty acids (oils) (vegetable ghee)
--
SELENIUM DIOXIDE, Se02

SELEN\UM D\OX\DE, Se0 2

Selenium dioxide is an important oxidizing agent, specific for the oxidation of reactive methylene and methyl
groups.

Preparation
It is prepared by the direct oxidation of metallic selenium. Selenium bums with a blue flame in air producing
selenium dioxide. The oxidation is catalysed by nitrogen peroxide.
Se + ()i(air ) - s902
It is a white crystalline solid, dissotves in water forming selenlous acid (HiSe03) and is highly toxic. The
reagent, in general, oxidizes active methylene and methy1 groups to ketonic and aldehydic groups
respectively.
0 0 0 0 0
II $eOi 11 II II ~ 11
-CH2-C- - - • - C - C - ; -C-CH3 - - • -C-CHO

Double bonds, triple bonds and aromatic rings may also activate the methylene group. The reaction is
usually carried out in acetic acid or acetic anhydride at a temperature between 1OO°C-140°C. Alcohol or
dioxan may also be used as diluents.

Uses
Besides oxidation of the active methylene and methyl groups, the reagent has been employed for aJlyllc
hydroxylation, allylic oxidation, dehydrogenation and as a catalyst in some reactions.
1. Oxidation of reactive methyl and methylene groups

SeOi
(a) CH3CHO CHC'CHO
Glyoxal

SeOi
(b} CH3COCH3 CH3COCHO
Melhytglyoxal

SeOi
(c) CsH!;COCH3 C5H~OCHO
Acetophenone Phenytgtyoxal

SeOi
{d) H2C(C00C2Hsn .. O=C(C~Hsn
Oiethyt malonate Diethyl mesooxalale

(e) CH3CH2COCH3 CH3CH2COCHO + CH3COCOCH3

Butanone Ethytglyoxal Oiace~
(major) (minor)
242 REACTIONS, REARRANGEMENTS AND REAGENTS

he cycloalk
.•111en t
;d ol the double
()_CHO
N
a-Picollne a-Picollnic aldehyde

(g) C&HsCH2CsHs C5H5COC&Hs

Diphenylmelhane Benzophenone
(v) Termina
(h) Activated ring methylene groups are also oxidized to carbonyl groups.
dOUble bond.

Cyclohexanone Cyclohexan-1 , 2-dione

3, Dehydrogenatic
Mechanism
The oxidation is carried out in aqueous acetic acid medium and hence the actual reagent is selenious acid,
H2 Se03 . The mechanism is still not clearly known. It is suggested that the reaction proceeds by the attack of
selenious acid on the enol form of the substrate to yield selenate ester which eliminates water and seleniu(fl
to give the product.

-c:O + Se
I
-CH2

2. Allylic hydroxylation and oxidation The methylene or methyl group a to the most highly substituted end of
the double bond is hydroxylated according to the order of preference of oxidation CH 2 > CH 3 > CH groups.

9H3
(i) CH3 -CH =C-CH3
2-Methyl-2-bulene
- SeC>i 9H3
CH3 -CH =C-CH20H
2-Methyl-2-butenol-1

9H 3 Se02 9H3
(iijCH3-CH=C-CH2CH3 - CH3-CH =C-CH(OH)-CH3
3-Methyl-2-pentene 3-Methyl-3-pentenol-2

9H3 SeC>i 9H 20H

(fii) CH3 -C =CH-CH2 -CH3 - CH3 -C =CH -CH 2 -CH3
2-Melhyl-2-pentene 2-Melhyl-2-pentenol· 1
O>lie_
II c
(iv) In cycloalkenes, the ring methylene group at a-position to the double bond is oxidized to ketonic group. Hc - c

0 ~6
Cyclohexene 2-Cyciohexent-1-one
.....

SELENIUM DIOXIDE, Se0 2

243

When the cycloalkene is substituted on the double bond, the methylene group at o.-position to the substituted
end of the double bond is oxidized.

0-R
Alkylcyctohexene
6R
a -Hydroxy alkylcyclohexene

(v) Terminal double bonds are oxidized to primary alcoholic groups along with allylic migration of the
double bond.

CH3 - CH2 -CH7-CI I :CH2 CH3-CH2-CH=CH-CH20H

Pentene-1 2-Pentenct-1

3. Dehydrogenation Selenium dioxide has been used for dehydrogenation at elevated temperature .

(ii) 2CH3COOH CH2-COOH

I
CH2-COOH
Succinic acid

(iii) CH3 -CO-CH2 -CH2 -CO-CH3 CH3-CO-CH=CH-CO-C~3

Hexan-2. 5-dione 3-Hexene-2. 5 dione

(iv) H2C -COOEt EtOOC-CH

I II
H2C-C00Et HC-COOEl
Ethyl succinate Ethyl fum;:irato

4. As a catalyst It catalyses the trans·hydroxylation of some unsaturated compounds by hydrogen peroxide.

OH
I
H-C-COOH
I
H-C-COOH
I
OH
Meleic acid OL-Tartaric acid

(ii) CH3 -(CH2)7-9H =CH -(CH2)7-COOH CHJ -(CH2)1-CH(OH)-CH(OH)-(CH2)1-COOH

9. f ll-Dihydroxy&learjc acid
Olelc acid
 REACTIONS, REARRANGEMENTS AND REAGENTS

SODIUM AMIDE (SODAMIDE), NaNH 2

Preparation
This useful reagent is prepared by reacting metallic sodium with liquid ammonia In the presence of ferric
nitrate.

Uses Acylation
ft finds use in various reactions in which the reacting species is the amide anion. Some of its important
(bl r'
reactions are given below.
1. Dehydrohalogenation of alkyl halides Sodamide is the most commonly used base for the formation of
triple bonds from suitable alkyl halides, e.g.,

~r 2NaNH2
R-CHrC-R' or RCHBr=CHBrR' R-C:C-R' + 2NaBr + 2NH3
9r vlc-Dlhallde
gem-Dlhallde
NeNHz
R-CH:CBrR' - - - R-C:C-R' + NaBr + NH3

(c) Formatio1
Thus,

1120
(I) C5H5-CH :CH Br C5H5-C:CNa - C5H~:CH
P·Bromostyrene Phenyl acetylene
(d) Fonnatic

l. Reaction with t{!rmln;1I acetylenic compounds Terminal §Ctttylenlc compounds having acidic hydrogens
sodami~~ t9 form sgdium acetylenes which may be convEuted to acids and higher acetylenes.
rf:!FtCt with 4. Cleavage of no1
give amides, R 3 C
n~rous acid give t

Cl13 -C =~ -Ct1rCH3
The starting com
2-Pentyne
(reaction 3a(ii) at
Internal acetylenes on heating with sodamide In an Inert solvent yield terminal acetylenes. 5. Cleavage of ed
 SO~IUM AMIDE (SOOAMIOE), NaNH1 245

CH3-CH2-c:cH
1-Butyne

3. Formation of nucleophiles Sodamide reacts with compounds having reactive methyl or active methylene
groups (activated by even a single electron-withdrawing group) to yield anions which act as nucleophiles in
various reactions.
(a) Alkylation of acids and ketones

0 CeHsCH2CI
CH3-CO-CH2 CH3-CO-CH2-CH2-CeH5
4-Phenyl butanone-2

(b) Acylatlon of ketones and nitrites with esters

NaNHz 0 CH3COOR
CH3-CO-CH2 CH3-CO-CH2-CO-CH3
Acety1 acetone

(II) R -CH2 -CN

e
R-CH-CN
CH3COOR
1

CH3-CO-CH-CN
I
R
l}-Ketonltrlle

(c) Formation of ~-ketoester

NaNH2 0 CH3COOC2Hs
CH3COOC2Hs CH2COOC2Hs CH3COCH2COOC2Hs
Elhylacetoacetate

(d) Formation of a-cyanoester

R-CH2-CN + CO(OC2Hs)2 - - - R-CH(CN)-COOC2Hs

Ethyl carbonate a-Cyanoester

4. Cleavage of nonenolisable ketones (Haller-Bauer reaction} Ketones of the type ArCOCR 3 are cleaved to
give amides, R 3C·CONH 2 which are not easily obtainable by other methods. The amides on treatment with
nitrous acid give tertiary carboxylic acids.

HNQi

The starting compound may be prepared by the repeated treatment of acetophenone with NaNH 2 and RI
(reaction 3a(ii) above).
S. Cleavage of ethers Ethers on treatment with sodamlde undergo cleavage with the formation of olefins.
 246 REACTIONS, REARRANGEMENTS ANO REAGENTS

NaN Hz e
CsHfCH-?-' - CsHs·CHz-ONa + CH2=CH2

H_t'""\/CH2
CH2

Suitable haloethers undergo dehydrohalogenation accompanied by cleavage so that acetylene denvatlves

are formed.

(ii) CICH2 -CH(OC2Hs)2 HC:c-O-C2Hs

Dielhylchloroacelal NH3 Elhoxy acetylene

Ethoxyacetylene is an useful synthetic intermediate. SC

r--\ NaNH2 H20 l>OIOhydride is a red
(in) , _ .>-CHzCI NaO-(CHz)J -c :c Na - HO-(CHz)J-C :CH
0
Telrahydrofurfuryl chloride 4-Pentynol-1
~aiuminium hydride.
6. Rearrangement of quaternary salts (Stevens rearrangement) Quaternary salts containing an electron- ~ti on
withdrawing group (e.g., -COR, -COOR, -C6 H5 ,etc.) on the carbon attached to the nitrogen atom undergo
rearrangement to tertiary amines on treatment with a strong base such as sodamlde. 6 ~ by heating so<

e<ff. "
Ph - C H - N - R
1
- Ph-CH-N-R
R"
I I

"'I~
R P. - re reagent is insoluble in c
e.g., water or alcohol. The r
7. Amines from nonactivated aryl halides The halogens of aryl halides are substituted by amino groups on nis a milder reducing

o-
.
treatment with sodamide.
go~ of aldehydes, ketor
!&el,carboxyl, epoxide, ni1

0- Br NaNH2 1 liq.NH3
_ 33· c .........
I NH2
~ted are not affecte
remably rapid can be carri
9.IJ3IS can be reduced in a
ThE: reaction is believed to proceed through benzyne intermediate.
Mechanism
0
r 7 i 1 N H 3 - - • 0 - NH2 The mechanism of reductio
1
Ve dlle cart>onyt group with
Benzyne bi hydrogens of the reag
r;ies alcohol.
8. Amination of nitrogen heterocyclics (Chichibabin reaction) Pyridine in toluene on treatment with
sodamide at 100°C-200°c gives 2-aminopyridine. This is a nucleophilic substitution reaction. The attack of
the amide ion takes place at the electron-deficient sites, i.e., at 2·, 4- and 6· positions.
-C:Q + Nal
I
~,_H, ~0 ~0
0 t:J.
NaNH2

100-200°C ll~~
N NH2
.. 0
ll ..
N
J-NHNa ll N.. J-NH2
.. ..
Na

9. In the synthesis of indigotin Phenylglycine-o-carboxylic acid, prepared fkom anthranilic acid and
chloroacetic acid. on heating with KOH and NaNH2 gives indoxyl which on oxidat'lon gives indigotin.
 SODIUM BOROHYDRIOE, NaBH 4 247

COOH

NH2
+
(JcJO N
Oi (air)
lndigotln

I
H
Anlhranilic acid Phenylglycine- o-carboxylic acid lndoxyl

10. Preparation of organo sodium compound Triphenylmethane rea~ts with sodamide in liquid ammonia
solution to yield triphenylmethyl sodium which is an effective condensing agent.

e@
(C5H5)JCH + NaNH2 (C5H5)JCNa + NH3

SODIUM BOROHYDRIDE, NaBH 4

Sodium borohydride is a reducing agent. It reduces by transfer of hydride ions to substrates as in the case of
lithium aluminium hydride.

Preparation
It Is prepared by heating sodium hydride with trlmethoxyborane to 250°C.

2so·c
4NaH + B(OCH3)3 NaBH4 + 3CH30Na

The reagent is insoluble in ether but soluble in water or alcohol. Hence, It can be used in hydrolytic solvents,
e.g., water or alcohol. The reaction is carried out In ethanol or isopropanol.
It is a milder reducing agent than UAIH 4 . Reduction with NaBH 4 is more selective. It reduces carbonyl
groups of aldehydes, ketones and acid chlorides in the presence of many reducible groups such as nitro,
ester, carboxyl, epoxide, nitrile, double bond, etc., which remain unaffected. Double bonds either isolated or
conjugated are not affected. The reagent is slowly hydrolysed with water. Hence, reductions which are
resonably rapid can be carried out in water without considerable hydrolysis of the reagent. Thus, water soluble
sugars can be reduced in aqueous medium.

Mechanism
The mechanism of reduction is similar to that of LiAlH,.. The reaction proceeds by complexing the oxygen atom
of the carbonyl group with boron and simultaneous transfer of the hydride ion to the carbonyl carbon. All the
four hydrogens of the reagent are transferred to the four molecules of the substrate. Subsequent hydrolysis
gives alcohol.

-C=O + NaBH.t
@ e
--~-O-BH3~a --t-o~H3~a
@ @ "' c--o
3/ ( I
- - - • -cH, -o
ie~ <t>
N:
I I~ H ..
H20 I
- 4 -C-OH + NaOH + B(OH)J
I
H

NaOH + B(OH)J - NaH2B~ + HzO

 248 REACTIONS, REARRANGEMENTS AND REAGENTS

Applications
Some of Its Important applications are:
1. Reduction of carbonyl compounds and acid chlorides to alcohol

CH3COCH2CH2COOC2Hs CH3 ' CH(OH)' CH2 ·cH2 ·COOC2Hs

Ethyl-y-ketopentanoate Ethyl-4-hydroxypentanoate

NaBH4
C5H5·co·CH2'CH2·COOH - - - C5H5'CH(OH) ' CH2 ' CH2 ' COOH
P-Benzoyl propanolc acid y-Hydroxy -4-phenylbutanoic acid

Na8H4
CH3 ·co·CH2'CH2 ·co ·CH3 - - - CH3' CH(OH )•CH2 ' CH2 ' CH (OH)'CH3
Hexan-2, 5-dione Hexan-2. 5-diol

CH20H•(CHOH)4'CHO - - - CH20H ·(CHOH)4 ·CH20H

Glucose Sorbltol

C5H5·CH:CH-CH0---. C5H5'CH=CH'CH20H
Clnnamaldehyde Clnnamyt alcohol

NC ·CH2·CH2 ·CHO NC'CH2 ' CH2 ·CH20H

3-Cyanopropionaldehyde 4-Hydroxybutyronitrile

NaBH,.
R·co ·c1 - - - R·CH20H
Acid chlori de Alcohol

-o-~
02N1
-0-I/_~
Na8H4
CHO - - - 0 2N

p-Nitrobenzaldehyde
_ CH20H

p-Nitrobenzyl alcohol

In the above compounds it will be seen that only the carbonyl group is reduced and the other functional groups
remain unaffected. This high selectivity of NaBH 4 makes it the preferred reagent for the reduction of carbonyl
groups in sensitive polyfunctional molecules.
2. Reduction of carbonyl group to methylene group p-Toluenesulphonyl hydrazine condenses with carbonyl
compounds to give tosylhydrazones which on reduction with NaBH 4 give hydrocarbons.

R2C=O + H2N-NHTs ____. R2C=N-NHTs

Tosylhydrazone

The method is useful in the synthesis, e.g., ketosteriods.

3. Reduction of ozonides Sodium borohydride reduces ozonides to two molecules of alcohol and ozonides of
cycloolefins to diols.
 SODIUM BOROHYDAIDE, NaBH• 249

4. Reductive alkylation of amines When aldehyde or ketone is treated with amines (1° or 2°) in the presence
of NaBH 4 reductive alkylation occurs.
1
NHR' Hydrogenolysis NHR
I I
1 _ _ _.., R-C-R R-C-R
R -C -R + R NH2 I
II I reaction
0 OH H

5. Reduction of carbon-nitrogen double bond Although sodium borohydride does not reduce nitriles, it
reduces carbon-nitrogen double bond.

I I NaBH4 I I
-C=N ---•-CH-NH

6. Reduction of ester groups Ordinarily ester groups are unaffected by NaBH 4 but in the presence of LiCI or
AICl 3 in diglyme (diethylene glycol dimethyl ether) they are reduced to alcohols.

RCOOR'
UCI in diglyme

7. Hydration of olefins Olefins are hydrated under mild condition without rearrangement in high yield on
treatment with mercuric acetate followed by NaBH 4 'in situ'.

7H 3 tHg(OAc)2 CH3
I
CH3 -CH2-C =CH2 CH3 -CH2 -C -CH3
I
2-Methyl-1-bu!ene 2.NaBH4 OH
2-Methyt-2-butanol (90o/o)

8. Preparation of diborane Diborane which is used for the hydroboratlon of alkenes is prepared by reacting
boron trifluoride with sodium borohydride.

Boron trifluoride Diborane Sodium borofluorlde

Hydroboratlon Is done 'in situ' either In THF or in diglyme.

THF
4BF 3 + 3NaBH4 + 12R-CH=CH 2 Di I 4(RCH2CH2)JB + 3NaBF4
gyme

9. Reduction of diazonium borofluoride Diazonium borofluoride can be reduced with NaBH 4 in

dimethylformamide or alcohol.

1o. Reduction of azides Azides containing sulphur are not reduced to amines by the usual methods.
However, sodium borohydride reduces azides to amines.
 250 REACTIONS, REARRANGEMENTS AND REAGENTS

WILKINSON'S CATALYST
Wilkinson's catalyst is widely used for homogeneous hydrogenation. The catalyst Is a complex of the transition
metal rhodium. The name of the complex is tris(triphenylphosphine)chlororhodlum {I) and Its molecular
formula is AhCl(PPh 3)J. The three triphenylphosphine (PPh 3) ligands are bound to rhodium through the
unshared pair of electrons on phosphorus.

L" /C l
/Ah'-. where L"' P{C5H5}3 or PPh3
L L
Wilkinson's catalyst
Tris (triphenylphosphine) chlororttodium {I)

The ligands do not directly participate in the reaction but their presence is absolutely essential-they
influence the course of the reaction. The function of the metal Is to form bonds with the substrate and the
reagent and thus bringing them near each other for the reaction to follow.

Mechanism
The catalytic activity is due to the vacant coordination sites in the metal. The active hydrogenation catalyst is
formed by the addition of a hydrogen molecule to the complex and loss of one ligand (PPh 3).
It is believed that the reaction proceeds in the following steps:
The complex first exchanges one ligand with a solvent molecule to form RhCl(PPh 3h{solvent) which then
reacts with one molecule of hydrogen to form the dlhydrido complex.

L Cl H

L/
"'I '
Rh /
solvent
H
Dihydrido complex

For this the metal uses one of its electron pairs and is itself oxidized from +1 to +3 oxidation state (oxidative
addition). The energy liberated in the formation of two metal-hydrogen bonds more than compensate the
energy required to break the H-H sigma bond.
The active hydrogenation catalyst is now formed. The alkene then forms a tt-complex with the metal
probably by replacing the solvent molecule.

L Cl H L Cl H
'-.I ,. ' / ,1 / I
Rh + c=c, _ . 1 Ah.... c-
L / I 'solvent / I "- ''
H
Dihydrido complex
Lr
H
n-Complex
/1
{Active hydrogenation catalyst)

Now that both the reactants are bonded to the metal, the two hydrogens are consecutively transferred
to the alkene carbons. One hydrogen migrates from the metal to one of the alkene carbons and the other
carbon is bonded to the metal by a cr-bond.
The second hydrogen then migrates to the metal-bonded carbon. The addition being complete, the
 ? I

tu ted product leaves the sphere ot reaction. The c talyst Is reg n r t d nd rhodium r
in and the reaction continues.

L Cl H 1-t H
,1 / I
i R h ' C-____,.
L ........ I
-6 -A-
H ..,...C
~
01v nl I 1
I C I ly$1 S turnted product

The mechanism is supported by the detection and Isolation (In some cases) of lntermedl tes, kin tics studl s,
NMR spectroscopy, etc.

Stereochemical aspect
It was observed that malelc acid on hydrogenation with Wilkinson's catalyst, using deuterium (0 2) In place of
hydrogen gave meso-(2, 3-D 2)butanedlolc acid while fumaric acid under the conditions gave racemlc
butanedioic acid. From this It is concluded that addition of deuterium occurs from the same face of the double
bond, Le .. syn-addition occurs. The reaction is, therefore, both stereoselectlve and stereospeciflc.
This is explained in the following way: Due to the close proximity of the metal (Rh) and hydrogen In the
complex. the unsaturated carbons are held from one (or the other) face of the double bond by the metal and
hydrogen in the transition state (I) . After the migration of hydrogen to one of the doubly bonded carbons, the
other carbon is still held from the same face of the double bond by the metal. The second hydrogen is now
near the front side of this carbon (II) to which it migrates through the transition state (Ill) to give the
syf}-addition product and regenerated catalyst (IV).

H CL
L"IRh / ·~
L/ I ......H __•. " _..,.
Cl
(I)

Uses
Geometric isomers on hydrogenation with Wilkinson's catalyst having optically Inactive ligands give either
mesa or a mixture of enantiomers. However, by the use of Wilkinson's catalyst with proper choice of optically
active ligands, one or the other enantiomer may be preferentially formed (enantioselectivity) .
This method has been employed to prepare L-amlno acids which are required for the synthesis of
proteins. L-Dopa, an amino acid for the treatment of Parkinson's disease, is being prepared on an industrial
scale by this method.

CH:)Coo@--cH2-Ct-coo 9
CHs(> @NH3
3·Methoxy-4-acetoxyphenylalanlne
(L·Dopa)

A number of optically active ligands have been developed to prepare rhodium complexes ( Wilkinson's
catalyst) to catalyse many types of reactions and useful results are forthcoming. Thus, Wilkinson's catalyst
has vast potential. The complex RhH(CO)(PPhs)s, a Wilkinson's type of catalyst, has been found to be more
efficient than the cobalt complex, Co2(C0)8 for oxo process.
 REACTIONS, REARRANGEMENTS AND REAGENTS

ZIEGLER-NATIA CATALYSTS
Kur1 Ziegler (of Germany) and Giulio Natta (of Italy) developed catalysts which permit 'Stereoregular
polymerization of alkenes of the type RCH=CH 2 (where A= H, alkyl or aryl).
Ziegler catalysts are a combination of organometallics which consists of a complex of tftethylaluminium,
Eta-Al and a transition metal chloride, TiCl 4 . When these are mixed in a hydrocarbon solvent a heterogeneous
precipitate develops which catalyses polymerization of alkenes at low temperature and pressure.
The methOd consists in passing the monomer, say propylene under 1O atmospheric pressure into an
inert hydrocarbon solvent containing the catalysts at about 100°C.

Ziegler cat. 9H3 9H3

2n(CH3 -CH =CH2) -(CH - CH2 -CH-CH2)n -
1oo•c, 10 atm Polypropylene

Ethylene is polymerized to polyethylene in good yield at atmospheric pressure and room temperature
by the use of Ziegler process. lsoprene was polymerized by Ziegler catalysts to a substance identical with
natural rubber.

Me Me
I Ziegler cat. I
n CH2=C-CH:CH2 - - - - -(CH2-C=CH-CH2)-
lsoprene 100°c, 10 atm . Pol • n
c1s- 1,4• y150Prene
(Rubber)

The impact of Ziegler catalysts on polymer chemistry has been so enormous that Ziegler and Natta were
jointly awarded the Nobel prize in 1963. Before the development of Ziegler catalysts, nearly all addition
polymerization involved free radical process with no regard to the stereochemistry of the polymer chain.
Ziegler catalysts have revolutionized polymer chemistry since 1955. Developments since then has resulted in
recognizing and gaining control to the stereospecific polymerization.
Polymer chains with branches or irregularly oriented bulky side groups are unable to lie alongside each
other for steric reasons. Consequently, they have low crystallinity, are amorphous, low melting and
mechanically weak.
Polymerization by radical process under high temperature and pressure gives highly branched
polyethylene and irregularly oriented side groups (atactic) in polypropylene or polystyrene. In contrast,
polymerization by the use of Ziegler catalysts under mild conditions produces unbranched polyethylene and
stereoregular (isotactic) polystyrene or polypropylene.
Here in lies the usefulness of Zieglar catalysts which help the stereoregularity in the growing chain of
the polymer. These stereore~ular polymers are crystalline, high melting and mechanically strong.

Stereochemical aspect
In polymers prepared from unsymmetrical ethylenes, e.g., propylene or styrene, every
alternate carbon in the chain is asymmetric.
p

ZIEGLER-HATTA CA'T'ALY9T

For stereochemical purposes the carbon chain may be represented 3§ - d - d - l - • - ,

The stereochemlcal sequence of the asymmetric carboM in a ~ [Link] ,
by the term 'tactlcity' which means the placement of the asymmettfc carbon atom ·
chain.
If the stereo arrangement of the asymmetrfc carbons is (i) aJways the same. , ,,
- d - d - d - d - or - I - I - I - I - it is called lsotactic, (' a~ i.e.•
- d - I - d - I - d - I - it ls called syndlotactlc and (iii) random, Le,, - d - I - d - d - t - I - t -
it is called atactlc.
The placement of the asymmetric carbons in the chain, i.e ., 'tactidty' has an ~
bearing on the physical properties of the polymers, Thus, atactic pofyme<a hatle
crystalllnity, low melting points and are mechanically weak. In contrast, isotactlc ~
are crystalline, high melting and mechanically strong. The require~nt for ·y
be satisfied by the stereochemical regularity ( isotactic or 8 yndiotacti<:J rn the cnam.

Mechanism
Not much is known about the mechanism of polymerization by this catalyst.. Several mecha , hi!t1e
suggested but none are so well substantiated. Polymerization by Ziegler catalysts is neither free [Link]~
ionic types. It is probably a coordination potymerization. As to how each nnooomer unit adds to
chain is not clearly understood.
Ziegler catalysts are a combination of aluminium alkyts (e.g., B~ and a transition metal tlalde e,g...
TiCI,). Probably, triethylalumlnlum reduces the transition me1aJ to a lower valence state proOOcirig •
trichloride, diethyl aluminium chloride and an ethyt-free radical which combine to form the comptex. 1tle ad~
catalysts. The active catalysts (hetereogeneous precipitate) is suggested to be an OdahedrcD comptex of
titanium with a vacant coordination site and an ethyt group bonded to Ti.

In the generally accepted mechanism, it is suggested that the monomer coordinates at the vacant 5ile
of the metal with its pi-clouds to form a pi·bond. Now that both the monomer and the etny1 groop are
close to each other by Tl, the monomer inserts itself between the metaJ and the ethyf group to form a
four-carbon chain. The coordination site is now vacant for the coordination of another monomer · and 1he
process is repeated.
 1:1 -ACrtONS, REARRANO MENTS ANO REAGENTS

with the growing chain probably Influences the Incoming monomer molecules to fall

pplicntion ·
o~nn r ' l>tal11 d l>y tht} u e of Ziegler catalysts are superior to those obtained by the free radical process.
( 1) It produoos fin ar polyme;s without branching and gives stereoreguta~ (isotactlc and syndiotactlc)
polymers which are more dense, crystalllne, high melting and mechanically strong. Polypropylene C\-
obtained by the use of Ziegler catalysts Is extensively used for the preparation of sheets, pipes,
synthetic fll>res. domestic articles for everyday use, etc. "dine and otner
( ) TI1e copolymer of ethylene and propylene prepared by the use of Ziegler catalysts is an excellent ,j,3ti00 of PY". h'babin) react
elastomer. ~'.·· biO(TschtlSC I
(S) TI1e catalysts pennit stereochemlcal control about the carbon-<:arbon double bond. tsoprene has
been polymerized to all cis-1 , 4-potylsoprene, a substance practlcally identical to natural rubber.
~
0 +
10
NaNH2-
(4) Metal atkyts, obtained In the process, on heating In the presence of ethylene and nickel catalyst give
straight chain 1-alkenes of even number of carbons.
..
N

CH2=CH2, NI
M-(CH 2 -CH2)n-CH~H3 CH2=CH-(CH2-CH2) -CH~H3 The amino group is substitt
Heat n -1
~is substituted at positlon-4.
These atkenes are used for the manufacture of detergents on a commercial scale. In practice, pyridine disso
(5) The metal alkyls on heating In the presence of air give oxides which on hydrolysis give primary - and the sodium salt a
alcohols of straight and tong chain. 2-amnopyridine. Excess of soda

Mechanism
~to heavier nuclear charge c
mg are polarized towards the
~ency is more marked at p<
This will be evident from
The alcohol may be transformed Into various products. .
With Ziegler catalysts, polymers with carbon chain of six to twenty carbons are obtained.

Hence, pyridine underg

The reaction occurs by
combines with a proton 1ro1
2·aminopyridine on hydrolys·

Formation of the inte'

lhe .The nitrogen in the .
nttro group in nitrob n
An em
analogous rea1
 Appendix A

Some More Reactions and Rearrangements

CHICHIBABIN REACTION
Amination of pyridine and other nitrogen heterocycllcs by alkali-metal amides e.g., sodamide is called
chichibabin (Tschltschibabln) reaction.

0ti + NaNH
2
100-2oo·c ~I
~ .(JOI
\l..~NH ~
~
2 ' /.
NaNH2
100-2oo•c
~
~ ...N~NH2
N N
2-Amlnopyrldine 2-Amlnoqunollne

The amino group is substituted at posltion-2 (and -6) and when these positoins are occupied the amino
group is substituted at positlon-4.
In practice, pyridine dissolved In toluene is heated (100-200°C) with sodamide when hydrogen is
evolved and the sodium salt of 2-aminopyridine Is obtained. The latter on hydrolysis with water gives
2-aminopyridine. Excess of sodamlde produces 2, 6-diaminopyrldlne.

Mechanism
Due to heavier nuclear charge on the nitrogen atom compared to carbon atoms, the loose n -electrons of the
ring are polarized towards the nitrogen atom. Hence the ring carbons are electron deficient. The electron
deficiency is more marked at positions-2, -4 and -6.
This will be evident from its resonance structures.

e
Hence, pyridine undergoes nucleophillc attack by powerful nucleophiles e.g., NH 2 at these positions.
The reaction occurs by an addition-elimination mechanism. The leaving group is the hydride ion which
combines with a proton from the initially formed aminopyrldine to evolve hydrogen. The sodium salt of
2-aminopyridine on hydrolysis with water gives 2-aminopyridine and NaOH.

A
ll~
~
+ NaNH2-
~
tl~~ -
~'4 NH2
H1
l~
..~NH2 +
.~
-H2
NaH---- ..N~NHNa--=- 0
l~ H20
'l..~NH2
N
+ NaOH

• @ U 2-Aminopyridine
Na(ij
Formation of the intermediate ion such as (i) for quinoline has been substantiated by NMR spectra
The nitrogen In the ring of pyridine serves the same general purpose In substitution as do the oxygen of
the nitro group in nitrobenzene.
An analogous reaction is Ziegler alkylation which involves alkylation of nitrogen heterocyclic
255
 REACTIONS, REARRANGEMENTS AND REAGENTS
256

compounds with alkyl lithium.

~ ~--H''6 ~,'.;::::;
ll__ d + Buli - l~K" ~ ll..~Bu
N Nj Bu N
I
LI

Amlnoheterocyclic nitrogen compounds are important synthetic intermediates e.g., 2-aminopyridine is

used In the preparation of the drug, sulfapyridine,

O-NHSo,-Q-NH2
Quinollne is aminated at position-2 and isoquinoline is aminated at position-1.

BOUVEAULT-BLANC REDUCTION
Aldehydes, ketones or esters are reduced to alcohols on treatment with excess of sodium and alcohol. This is
khown as Bouveault- Blanc reduction.

EtOH EtOH EtOH

2
2
R 1 CH~OH
1
RCHO - ACH20H ; R CQiR -- + R 0H: R2CO
Na Na Na

Mechanism
It was thought earlier that this reduction occured through nascent hydrogen produced from sodium and
alcohol. It is now believed that the reaction occurs in several steps involving the transfer of electrons from the
metal to the substrate one at a time.
In protonic solvents e.g., alcohol, atoms of strongly electropositive metals (Na, K, etc.} produce solvated
electrons.
·~@ e
Na .._..---Na + e (ale.)

These electrons act as nucleophiles and add to the carbonyl carbon of the ester to produce radical
anion (I). The latter reacts further with sodium to yield the divalent anion (11). Protonation of (II) by alcohol and
subsequent expulsion of etho.1Cide ion produces an aldehyde.
Repetition of the above sequence of reactions give alcohol.

R Na + Ale. 9Na Na 9
e C2H50H
(oe
, r-:_
R-C - OEt (+) 8 R-C-OEt - R-C-OEt R-y\:JOEt
(Na+e) •
8 G 0 H -EIO
9H
®
H3o
0
1 EtOH
o• 2Na
o11
R-9-H R-9-H R-ceH - R-y
H H H
The solvent 1s very important since aprotic solvents such as ether, benzene, toluene favour acyloin
formation. It has been found that sodium hydride in place of sodium, gives better yield.
In the commercial reduction of esters, methyl-isobutyle alcohol is used.
p

Applications
The method has useful applicat om> In eynth01 • It ha8 been appl 9d to reduce ~ters to altohols and dul1ng
tl'le synthesis of many natural products e.g., cadalene, etJdalene, ab etlnol MC. The double bonds In the
substrate remain unaffected.
Bouveault·Blanc method haB now been largely reducOO by UAIH4 but th s meihod ls still in uoo wtlere
selectivity is required.

NEBER REARRANGEMENT
Preparation of a·amlnoketones by the treatment of ketoxime tosy1ate9 with a base auch as alkoxide ion or
pyridine and subsequent hydrolysis is known as Neber rearrangement
e
R'-CHrr,-A [Link] A'yH-Y,-A
'4-0T1 2..HiO t4Hz 0
The group A' is generaJly aryt but tt may be aJky1 or hydrogen and group A may be alkyl or aryl only.

Mehan ism

ISOiation of azirine substantiates the mechanism. NucieophiJic elimination of tosy1 group and formation of
azirine may be concerted or stepwise i.e., formation of azjrfne via the formation of nitrine.
ert
'rt
h-CH-C~3-h-CH=c-CH.3- h-CH-C-CHa
N I :/iI N#

When there are acidic hydrogen atoms on both the a-carbons as in unsymmetrical ke1ones, the amino
group is substituted to the carbon bearlng the more acicfic hydrogen.
Unlike Beckmann rearrangement, both syn and anti ketoximes undergo this rearrangemet i.e., the
reaction is non-stereospecific. AnaJogous rearrangement is observed in N, N-dichloroamines of the type
A'CHiCH(NC'2)R to WCH<NHVCOA. On treatment with base the compound first forms chloroimine with the
loss of HCI.
e e
00 BO H~
R'CHz-CH-R __..
. R'CHz-C-A - . . R'CH-CR - R-CH-C-R
1 -HCI Ti ' // 1 11
NClz ~Cl t4 NH2 0
~

a-Amin<> ketoneS have important synthetic applications.

 258 REACTIONS, REARRANGEMENTS AND REAGENTS

HOFMANN-MARTIUS REARRANGEMENT
Mono and dialkyl aniline hydrochlorides or bromides as also quatemery salts of aniline on strong heating
(200-300°C) undergo rearrangement which involves the migration of the alkyl groups from the nitrogen to the
para position and if the para position is occupied, then to the ortho position of the aromatic ring. This is known
as Hofmann-Martius rearrangement.

<±>e

6 200-~
Me2NHCI

Dimethylanlllne
hydrochloride
<±> e
NMe3CI

o-~
Trimelhylanilinium
chloride

Mechanism
The mechanism of the reaction has been advanced by Huges and Ingold based on the suggestion of
Hickinbottom. During the rearrangement the formation of alkyl halide and olefin were detected. Hence, the
reaction probably proceeds through the initial formation of alkyl halide intermediate. The carbocation from the
initially formed alkyl halide then can undergo elimination to give olefin or may attack the ring to give alkyl
substituted arylamine. Thus the reaction Is intermolecular.

C5H5NH2 + C2Hs8r
____..:::., ® e
C2H5Br ~ C2Hs + Br
@ @
+ C2Hs CaHsNH3 + C2H4
@ @
+ C2Hs p-C2H5C5H4NH2 + CaNsNH3

The mechanism is supported by the observation that if the alkyl group is primary it undergoes
isomerisation before attacking the ring.
~

©
HN-CH2CHMe2HBr

-~ Q + ...,CHCH2Br
lsobutyl bromide
N·lsobutyl anlllnlum (I)
bromide <t> e
Me2CHCH2Br~ Me2CHCH2 + Br
 COPE REARRANGEMENT 250

~ CMe3
p-t-butytanillne
(IV)

Thus formation of (II), (Ill) and (IV) can only be explained due to the formation of the intermediate (I)
derived from N-lsobutyl anilinium bromide.
Rearrangements of this kind - groups from the N-atom migrating to the ring - have been observed in
aniline derivatives. Thus, Orton rearrangement involves migration Qf chlorine to the ring carbon, e.g.,
N-chloroacetanilide to p-chloroacetanilide. Fischer -Hepp rearrangemeht involves migration of NO (nitroso)
group.

Quaternary salts of pyrtdine also undergo analogoos rearrangement. Pyridine methoiodide on strong
heating gives 2- and 4-methylpyndine hydrochloride

1:3
• ~~) e
~ I
H

COPE REARRANGEMENT
Cope rearrangement involves the thermal isomerization of 1 , 5-dienes with shift of double bonds and breaking
of 3,4-o-bond. Any 1, 5-diene undergoes this rearrangement.

:c ~
3, 4-Dlmethyt-1, 5-hexadiene
:=0
2, 6-0ctadlene
(I) (II)

The reaction is reversible and produces an equ1ll1bnum mixture of the dienes. That isomer, however,
predominates which is thermodynamically more stable. The reaction is facile (occuring at lower temperature)
when there is a phenyl or carbethoxy group at 3· or 4-positions. This is due to conjugation of the groups with
the double bonds in the product with consequent stablizatoin. When catalysed by transition metal compounds,
Cope rearrangement of simp1,.1, 5-dienes can occur at room temperature.
 260 REACTIONS, REARRANGEMENTS ANO REAGENTS

Mechanism
The rearrangement Is intramolecular since no cross over products were obtained on heating two different
1, 5-dienes. Stereochemical studies (Doering and Roth) indicate that the reaction proceeds via a cyclic
six-carbon transition state in the chair form. This was concluded from the stereospecific nature of the
rearrantgement. For example, the meso isomer of (I) on heating gave 99. 7% cis-trans olefin. This is only
possible if the transition state of the meso isomer is in the chair form in which one methyl group is on the axial
and the other methyl group is on the equatorial bond. Thus,

Me

~H ~H
rf-"
Me so
H
180~

..
:~
:-----~ ~/Me

T.S
H
-~Me
H
cis-trans-2, 6-0ctadiene (99.7%)

If the cyclic T.S. had been in the boat form, the product would be either cis-cis or trans-trans, since there
are two boat forms for the meso-isomer.
For the DL pair (racemic) there are three possible conformations of the T.S.:
(i) one boat form which would give cis-trans olefin,
(ii) one chair form with diaxlal methyl groups which would give cis-cis product (less stable due to diaxial
interaction) and
(iii) another chair form with diequatorial methyls which could give trans-trans product
In practice the product from DL-lsomer (Ill) is mainly trans-trans olefin (iv).

~~
H
A
____.. ..~/Me
~fMe -
22s 0 c :~
~·7 I
H H (IV)
Racemic (Ill) T.S trans-trans-2. 6-0ctadiene (90%)
(Dor L)

It is therefore suggested that the isomerization proceeds via a cyclic six-carbon T.S in the energetically
preferred chair conformation. The mechanism of Cope rearrangement is similar to Claisen rearrangement
which involves six-centered rearrangement of five carbons and one oxygen.
When there is steric restrain to the formation of six membered cyclic T.S. the reaction may proceed
through radical pathway (Hammond and De Boer). Thus, cis-1, 2-divinylcyclobutane (V) rearranges through a
boat-like six-carbon cyclic T.S. to yield 1, 5-cyclooctadiene (VI).

(V)
120°c

T.S
- 0 (VI)
cis

However, the trans4>omer (VII) unable to attain the cyclic T.S. due to strain, rearranges via a radical
pathway to give a mixture of (VI) and 4-vinylcyclohexene (VIII}, the latter beif')_p the major product.

iiiii c
 COPFREARRANGEMENT
26\

,z:1 ~
{VII) Trans
200°c
cc=-C ~
~~"o') •.j -
(VI)

Oivinylcyclopropane similarly undergoes the rearrangement with ring expansion by tour carbons. (Vogel
et...a{.)

<(-0
Thus, Cope rearrangement may involve either concerted or biradlcal mechanism the latter preferred by
some substrates. The biradical two steps mechanism may be formulated as below for 1, 5-dlene.

It is seen that 1, 6-bond is formed before the breaking of 3, 4-bond. There is yet another suggestion
involving diionic mechanism (Gompper and Ulrich).
Cope rearrangement Is not reversible when there is a hydroxy substituent at 3· or 4-position in
1, 5-dienes since the product tautomerizes to stable aldehyde or ketone.

R ~~ R ~ ~ ~ R=HorAlkyl.
HO~ H~ odJ
This is known as oxyCope rearrangement (Berson and Jones). The reaction has great synthetic
importance.
It is seen that Cope rearrangement of symmetrical 1, 5-dienes gives the product which is
indistinguishable from the starting material. This is known as degenerate Cope rearrangement.

Similarly, degenerate carbocation rearrangement is also known

G) Migration of H G)
CH3-CH2- CH-CH 3 CH3-CH-CH2-CH3
A B

Spectral analysis indicate both A and B exist as equillibrium pair.

o
Cope rearrangement is also observed with conjugated trienes with the difference that the 3, 4-bond
changes f ram double to a single bond.

~
.
C' 1oo·c....._
~
262 REACTIONS, REARRANGEMENTS AND REAGENTS

The reaction has been utilized to prepare biphenyls (Edmunds and Johnstone)

Closely related to the Cope rearrangement is the ring expansion by two carbons of vinylcycloalkanes of
small rings via a four-centered T.S. {Overberger & Borchert)

The driving force of the rearrangement may be the strain in the small rings.
Cope rearrangement does not occur if one of the double bonds Is a part of an aromatic ring e.g.,
4-phenyl-1 ~butene.
 E, ERClSES (CHAPTER 1)

2.. ~ proper signs between the two sets in [Link]\ of the following and describe the phenomena.

0II 01t
-C-C ~--c-<>El

oII e ou
• CH::s-c-cH-c-<>El

3. In which of the two sets is resonance stability greater and what is the <X>nsequence?

//o e;o
{ii) CH3-C,9 ___. CHs-C~
0 0
4. Classify the following reactions and give the mechanisms of the reactions.
H;?S04 llq NHs
Cf;Hs + HNOJ C5H5N~ ; CsHsCl + NaNH2 CsH5NH2

Me 3 CBr + NaOH - MesC(OH) : CHsCHO + NH 20H - CHsCH=NOH

5.

6.

7.

8. What products are obtained o

of HBr to propylene and o ·
9.
10. - C=C
11 .
12. Discuss Hofmann e. How has · been
13. Discuss the stereochemistry of ~ reaction.
15. What predominant products .e., o-1~ o m- are "'7W'"!llff'!l.l!''M'I

of nitrobenzene?
16. Give the energy diagrams o 1 S vs ~
(ii) electrop · lC substitutio · benzene · (a aa1Va1ma
9
17. Explain: (a) The · order halides is I > Br> Cl · protic solvents but 1he order is revelSE!d
in aprotic solvents.
(b) Pure racemic mocfification is not obtained - 1 reaction..
18. Write notes on {i) hybridization,, (ii) · · e effect.. (ii) eledlcwneric effect and fIV) resonance.
19. Give the mechanism of itration of phenol.
20. (a) Arrange the fo k>wing compounds · order
benzene, nrtrobenzene chk>robenzene,
(b) Acetaniltde is ess reactive towards - · than ~
21 . Exp ain: (a) More than one equivalent o 3 Friedel-Crafts (b) Nitrobenzene is the
favoured solvent in Friedel-Crafts reaction {c} Polyacylation is observed · Friedel-Crafts acytation.
22. Give the mechanisms of a and of aromatic
substitution.
23. Place the groups --OH, -a -N~ -N021 -CHO -COOH and -OR - the toHCJWll
- la ttvee catagories:
(i) er/ p-directing with activation
01 e>-/p-directing with deactivation
~ji) m-directing wi1h deactiva1ion
24. Write brief notes on Saytzev and
25. What products are obtained on treatment of ~nan-1"" brorride · (i) alcohol. and - (ii) ~IUI . .
 EXERCISES (CHAPTER 2) 265

ethoxlde? Explain the reactions .

Ellmlnatlon of HCI from the 13-lsomer of hexachlorocyclohexane Is very much slower than from its other
26.
Isomers, why?
( ) Discuss briefly the stereochemlstry of carbocatlon rearrangements. (b) Give all the products obtained
0
· ~ deamlnatlon of (I) cyclobutylamlne and (II) cyclobutylmethylamlne, with HN02.
27

2a. Explain:
(a) Aldehydes are more reactive than ketones.
(b) The enolate form of EAA Is less soluble In water but more soluble in cyclohexane.
(c) o-Hydroxybenzolc acid Is stronger acid than Its other Isomers.
(d) Elimination of HCI from chlorofumaric acid is faster than from chloromaleic acid.
29. Write short notes on E1 , E2 and ElcB mechanisms.
30. Explain:
(a) The stereochemistry of nucleophilic addition to carbonyl group.
(b) The reaction of p-chlorotoluene with strong NaOH at elevated temperature.

EXERCISES (CHAPTER 2)
1. Discuss the mechanism and applications of the following rearrangements:
(a) Allylic, (b) Beckmann and (c) Hofmann.
2. Discuss the acid-catalysed rearrangement of 1 , 2-diols to ketones. Describe its synthetic applications.
3. Define and discuss the mechanism of Cannizzaro reaction and give an account of its applications.
Explain why p-dimethylaminobenzaldehyde does not undergo Cannizzaro reaction.
4. Describe the mechanism and some important applications of any three of the following rearrangements:
(a) Hofmann (b) Wagner-Meerwein (c) Curtius (d) Claisen (e) Pinacol-Pinacolone
5. Explain allylic rearrangement. Discuss SN 1'. SN2' and SNi' reactions involved in allylic rearrangement.
6. Name any three reactions which involve rearrangement of electron-deficient carbon. Discuss the
mechanism and applications of any two of them.
7. Define and discuss Aldol condensation. Give the mechanism of the reaction and its important
applications.
8. (a) Discuss acyloin condensation between esters of monobasic acids and between esters of dibasic
acids. Give the mechanism.
(b) Mention the products obtained when diethyl sebacate is treated with (i) sodium and alcohol and
(ii) sodium in the presence of tolune and then with acetic acid. / ........

9. How will you establish the intermediate formation of a cyclopropanone ring in Favorskii rearrangement?
How does such an intermediate, cyclopropanone ring open when the ring is unsymmetricalty
substituted?
10. Compare Friedel-Crafts alkylation and acylation. With the help of Friedel-Crafts reaction how will you
synthesize naphthalene and phenanthrene? . . .
11 . (i) Give the mechanism of the reactions when benzene is treated with f(a) t~~I chl~ride in the presence
of aluminium trichloride and (b) 2-methyl propylene in the presence o s.u p . unc ac1 . .
when t butyl benzene is treated with bromine in the presence of aluminium
(ii) What products are f orme d . •
trichloride? Suggest the mechanism. . . . . . . .
. h "4 ct ketone complexes with aluminium tnchlonde . This IS a boon
12. (a) 'In Friedel-Crafts acylat1on t e pro)lu • • .(.
 ""'
266 REACTIONS. REARRANGEMENTS AND REAGENTS

rather than a nuisance, why?

(b) More than one molar proportion of aluminium trichloride is required in Friedel-Crafts acylation, why?
(c) Give the synthetic applications of Friedel-Crafts acylation.
13. Discuss Mannich reaction indicating the components and the mechanism of the reaction . Mention some
important synthetic applications.
14. Discuss the mechanism of Wolff rearrangement. How has the reaction been utilized in Amdt-Eistert
homologation of acids.
15. Write explanatory notes on
(a) Clemmensen reduction, (b) Wolff-Kishner reduction and (c) Meerwein-Ponndorf reduction.
Compare their merits.
16. How will you establish that in Beckmann rearrangement, the group trans (syn) to the hydroxyl group
migrates? Mention the important applications of Beckmann rearrangement.
17. Describe Claisen condensation. Give the mechanism of the reaction. Esters having only one a-hydrogen
undergo Claisen condensation only in the presence of a very strong base (e.g., sodium triphenylmethyl),
why? What is the essential difference between Aldol and Claisen condensations?
18. Write the important resonance structures of diazomethane. Give the mechanism and applications of
Arndt-Eistert synthesis and show how diazomethane is used in preparing the intermediates di-
azoketone in this synthesis.
19. Define and discuss the mechanism of Cannizzaro reaction mentioning crossed and intramolecular
Cannizzaro reaction . How has it been established that a direct transfer of hydride ion takes place from
one aldehyde to the other? Give some of its applications.
20. Discuss the mechanism of Claisen condensation. How will you synthesize a 13-ketoester without
ex-hydrogen? Give examples of crossed Claisen condensation between an ester having a-hydrogen and
an ester having no a-hydrogen.
21 . Discuss the mechanism of the following:
(a) Perkin reaction, (b) Benzoin condensation and (c) Mannich reaction.
22. Name the reaction and give the mechanism which involves the conversion of a ketone to an ester with
peracids. How has it been proved that the oxygen of the ketone is present as the carbonyl oxygen of the
ester? Why is trifluoroacetic acid more effective for the transformation than other peracids? Give some
of the applications of this reaction.
23. Discuss the mechanism and applications of any two of the following reactions:
(a) Perkin (b) Michael (c) Wittig (d) Mannich (c) Reimer- Tiemann
24. How is Wittig's reagent prepared? How does it react with aldehydes and ketones? Give the mechanism
and applications of the reaction.
25. Describe Favorskii rearrangement of open chain and cyclic a-haloketones.
Give all the steps for the transformation of 1, 3-dibromo-3-methyl-2-butnone to ~-methyl crotonic acid
under Favorskii conditions.
26. Define, giving the mechanisms of the reactions involved and some important uses of the following:
(a) Claisen condensation, (b) Claisen rearrangement and (c) Claisen-Schmidt reaction.
27. What products are obtained when hydrazoic acid in the presence of sulphuric acid is allowed to react wi1h
(i} carboxylic acids, (ii) aldehydes and (iii) ketones. Name the reaction and give the mechanism in each
case.
28. Mention briefly the types of the two components which may be used in a 4 + 2 cycloaddition reaction to
obtain varied types of six-membered rings. Give the mech~mism involved and the scope of the reaction.
29. Discuss any two of the fo11owing reactions giving the mechanism and some of their important synthetic
applications:
 EXERCISES CHAPTE 3
~ss the preparations and - l$eS tc"~W-
Oiazometflane (b) Peracetic acid c) ,AA_Jt;z,,..._,.,,~ ~ ~~e ~~
- · m hydride
;a 1SS the important [Link] app5ca!lons of :a.l'Jm~r'.J O'ga-le --~
SeJenium oxide {b) Raney eJ c ) [Link] r; Os--11 ~""? ~C);

1e the preparabons ·
! toHo\ · g reagents:
Periodic acid (b ) Lead te~e (c )· -
w rs diazomethane prepared and stoled? ~o:: ;;""-...c:n..r::s d ~ez:;;r-et-.r
re the mechanism of methytation of d ac'1:5 '&2:..r'"ed"a-:e_
cuss the important uses ot the JOJ10W1~[Link]
NBS (b) Fe on's reagent (c )
Sodamjde
·e the preparation of per>ocf.c acid. ~ i..i=i.u ®[Link];;:!fu.c;::_ c~e:;;e i f a::f~
3tzabJe groups and the mechanism tt - :rvnllW='!l'1 - - _ ~t:""Edcr d r e $22
::Se ring of glucose?
le short notes on:
Aluminium isopropo»de (b) c Osm:"'" ~io;:: Pa-.e O<a
Anhydrous alumini um trichk>ride
rcribe the preparations and important app1ications of !he [Link]~ o-pa:o ,,_ ~ r:s:
Sodamide (b) Raney nickel (c) Lead tef>il:il:etale (i u~~JD!:Jm-:fd;:!
~ss the uses of any four of the foilowing::
Hydrogen peroxide (b) [Link] (b) Sodium ~iidt? ~ s ~:11 - ~ c [Link]!
:>eleni um cfio.>cide
trate with [Link] the specific uses of 1he foiDol'[Link]:
Selenium dioxide in the oxidation o1 the ac:fNe n>E~'l"Jelrne ~lr.:.!Cl5.
fdrogenation
::taney [Link] for the syt di eesis of higher fa12y acids
>eriocJj c acid in the determinafion of the size of the o:x1de d ~'~~er
·rrnination of chk>rornycetin
)iazomethafle in methylation of ~ ~ S)lliJ!hesJS P. ire~ en re esd,r::'Ji3!d'co

nino acidS
.ead tetraacetate as acetoxyialing. memyta:fing and oxidrzing ea~
:>isO css the use of perioefic aod - 1tie ' de1e 1n2:fion of ~ SJZ:e s '9i'S
rxidation of exocyctic [Link] bond and (iii) ~rna=·on amino
268 REACTIONS, REARRANGEMENTS AND REAGENTS

(b) How will you detect potassium in the presence of sodium by the use of boron trifluoride?
12. How will you bring about the following transformations by the use of suitable organic reagents?
(a) Cyclohexene to benzene
(b) Ketones to higher ketones and epoxides
(c) Benzene to tropilidene (
(d) Maleic acid to meso-tartaric acid .
(e) o-Diamine to dinitrile
(f) Cyclohexene to hexan-1, 6-diol
13. Write short notes on:
(i) Ziegler-Natta catalysts (ii) Wilkinson's catalyst !Students are <
14. What is meant by the term 'tacticity'? Describe briefly the preparation, mechanism of reaction and some appropriate se
important uses of Ziegler- Natta catalysts. _ the solution.)
15. Describe the preparation of Wilkinson's catalyst and the mechanism of hydrogenation of alkenes by this 1. How will~
catalyst. Give some of its important uses. (a) methy
ODO (b) 1-pro~
(c) diethy
(d) elhan1
(e) 1-bul)
2. Ethyl alC<
3· Compare
4· An alkan
5· AmongS1
6. How Will
7. Mention
8. l'he h
Yd
9roup
9. 1 ~ .
<-dirr
I

Praouct
10. lio .
11 WIS I
. lh
12 e bai
13. ~icte~
14. [Link]('.
• 'Nhich 1
 Simple Problems and Their Solutions

[Students are advised no1 to look up the solutions before trying. In case of difficulty t~ey should look up the
appropriate section in the text, think and then try to solve the problem. Only after this they should look up
the solution.)
1. How will you distinguish between
(a) methyl alcohol and ethyl alcohol
(b) 1-propanol and 2-propanol
(c) diethyl ether and n-butyl alcohol
(d) ethane , ethylene and acetylene
(e) 1-butyne and 2-butyne
2. Ethyl alcohol has a higher boiling point than diethyl ether. Why?
3. Compare the basicity of aliphatic and aromatic 1 ° amines.
4. An alkane of mol. wt. 84 gives one monochloro derivative. What is the structure of the alkane?
5. Amongst a group of isomeric amines, tertiary amine has the lowest boiling point. Why?
6. How will you obtain 1 . 4-pentadiene and trimethyl amine from pyridine?
7. Mention the products formed on treating cyclobutylamine with nitrous acid.
8. The hydrogen atom of the carboxyl group is more easily replaced than the hydrogen of the alcoholic
group.
9. 1. 2-dimethyl propanol(I) on dehydration with sulphuric acid gives 2-methyl butene-2(11) as the major
product. Why?
10. How is methylene cyclohexane obtained from cyctohexanone?
11 . The base strengths of 3° amines are less than that of 2° amines. Explain.
12. Amides are practically neutral. Why?
13. o-hydroxy benzoic acid is a stronger acid than its isomers. Why?
14. Which of the two carbocations is more stable. State reason.
e e
CHr CH-CH 3 CHrCH- CH 2
(1 ) (2)

15. Explain with an example what is meant by ~limination .

16. Give the mechanisms of acid-catalysed and base-catalysed dehydration of an alcohol.
17. Phenol is acidic but ethyl alcohol is neutral. Explain.
18. Arrange the following in order of increasing rates of addition:
CHz=CH 2, MeCH=CHMe , Me2C=CMe 2, CHr-CH-COOH. EtCH=CH2
5
1 2 3 '

269
...

270 REACTIONS, REARRANGEMENTS AND REAGENTS

19. Mention the products and the rule governing the formation of the products.

Mt Cl
I I
Me-C-C-Mo-+? + ?
-HCI

I I
H H
20. N, N-dimethylanlllne undergoes ready coupling but Its 2, 6-dlmethyl derivative does not. Why?
21 . Complete the following reactions:

-HIO
(I)
1
R2 C(OH)-CHOH-R + HI0 4 -1- ? + ?

-HI03
(ii) R-CO-CO-R' + HI0 4 - ? + ?

( ·1·1 ·1) R-CHOH-C~-CHOH-R -HI04 ?

22. How is exocyclic olefinic bond oxidized?

23. How will you bring about the following conversions?
(i) Cyclohexene to cyclohexene-1-one
(ii) Acetic acid to succinlc acid
(iii) Maleic acid to DL-Tartaric acid
(iv) Pyridine to 2-Amino Pyridine
(v) 3, 4-Dimethyl- 1, 5-he~adiene to 2, 6-0ctadiene
24. Acetyl chloride has lower boiling point than acetic acid.

Solutions
1. (a) Ethyl alcohol gives a yellow crystalline precipitate of iod<iaform with alkallne iodine solution while
methyl alcohol does not.
(b) 1-propanol is a 1° alcohol and reacts with Lucas reagent (ZnCl 2 / HCI) to form an alkyl halide only on
heating. 2-propanol is a 2° alcohol and reacts with Lucas reagent after some time (5 minutes) to form an
alkyl halide which being immiscible in 2-propanol forms a cloudy liquld. 3°alcohol reacts Immediately to
give an alkyl halide at room temperature.
(c) n-butyl alcohol reacts with sodium to give bubbles of hydrogen gas due to its OH group. Diethyl ether
does not react with sodium as it has no OH group.
(d) Ethylene and acetylene being unsaturated, add bromine but ethane Is a saturated hydrocarbon and
so does not add bromine. Acetylene gives silver acetylides with AgN0 3 I NH3 solution but ethylene
does not.
(e) A 1-butyne (C2H5C =CH) like acetylene gives a red precipitate with ammonlacal cuprous chloride
solution and a white precipitate with ammoniacal silver chloride solution. 2·butyne (CH3C • CCH3)
having no acidic hydrogen does not react with these reagents.
2. In an alcohol a hydrogen atom is covalently linked to a strong electronegative 0-atom. The a-bond Is thus
(>- 6+
distorted towards the 0-atom resulting in a polar bond. This polarity in the 0-H bond causes association
of alcohol molecules. The unusual high boiling point of an alcohol is due to the energy required to break
the H-bond and vaporize the alcohol molecules. Diethyl ether has no polar bond for association and
hence has a relatively low boiling point.
 EXERCISES (CHAPTER 3) 271

3. The lone pair of N-atom of aromatic amines is involved in ~esonanc~ with the ring and ~enc~ is n?t easily
available for protonation . On the other hand the lone pair of the mtrogen atom of aliphatic amines are
freely avaHable for protonation. Hence aliphatic amines are relatively more basic than aromatic amines.

-Aromatic-am4Ae -
4. The genera\ formula of an open-chain a\kane is C,,H 2n+ 2 and that of a closed-chain alkane is CnH 2rr
When the alkane is an open chain When the alkane is a closed chain
CnH2n + 2 = 84 CnH2n= 84
or 12n + 2n + 2 = 84 or 12n + 2n = 84
or 14n =82. or n = 6.
82
n = 14 (not a whole number).
Hence, the compound is not an Hence the compound is a
open-chain alkane. closed chain of 6 carbons.
Therefore, the compound is cyclohexane which can give only one monochloro derivative as all the twelve
hydrogen atoms are equivalent.

5. Primary and secondary amines having polar bonds ( N-HI

form intermolecular hydrogen bonding, while
tertiary amines havang no hydrogen atom on the N-atom c~nnot form an H-bond. Thus 1° and 2° amines
are associated and need higher energy to break the H-bond and vaporize the liquid. Hence 1° and 2°
amines have higher b.p.'s with respect to 3° amines in a group of isomeric amines.
6. See page 65; Hofmann elimination
7. See page 70.
8. The hydrogen atom of the carboxyl group is easily replaced since the carboxylate ion is resonance
stabilized on the departure of hydrogen.
e
ft..-('~ 0 -----. • q0 / 0
~-"
OH
~ H + R-C,
0
a ~ R-~
0
Hydrogen atom of the alcoholic group is however not eas~y replaced since the charge on the alkoxide ion
is localized and has no factor for stability.
9. See page 18.
10. See page 183; Wittig reaction
11 . The base strength of amines in water is due not ~nly to the el~tron availability on the nitrogen atom. but
also to the extent of solvation by hydrogen bondmg of the cation formed by the uptake of a proton. The
solvation then depends upon the number of hydrogen atoms attached to the nitroge~ atom. It is seen that
the cations of 20 and 30 amines have each two and one hydrogen atom respectively. Therefore. the
basicity order is 2° amine > 3° amine.
R
R (9 H-OH2 le
'N:/ > R-N~ -OH 2
/' I
R -z- H-OH2 R 3•
Proton8t8d amines
 272 REACTIONS, REARRANGEMENTS AND REAGENTS

This is, however, true only in protic solvents. In aprotic solvents (e.g., chlorobenzene) ~ baSf~rfl·
..... . , l<a.1-
V'IJP,!"

is 1° < 2° < 3° amines.

12. The basicity of nitrogeneous compounds depends on the availability of the lone paif of e ~dam
Amides are resonance hybrids of the following structures:
e
CJ~(). ?e
R-C- NH2 - R - C=Nffi

The shift of electrons from nitrogen to oxygen results in a(+) charge on the N-atom. The forre pard
electrons of the N-atom is therefore less available for protonation, i.e.,amfdes are practically eutrat
13. The ionization of o-hydroxy benzoic acid is promoted due to stabilization of its anion by intramolecutar
hydrogen bonding.
o ....... t:'I @
Q c-' 6e
II
: + H

The intramolecular H-bonding is not possible in its other isomers in which the OH amd COOHgroupg,~
far apart for H-bonding.
Hence it is the strongest acid of the three isomers.
14. The stabilities of ions depend upon charge delocalization through inductive effect no bond resonarca
(hyperconjugation) and resonance. In (1) two +I effects are operating for stabilization as afso si;(" eetrli:
hyperconjugative effects. On the other hand cation (2) is stabilized by strong resonance en~, cf OMC
equal energy structures.
e e
CHz=CH-CH2 +--+ CH2-CH=C~
Hence, carboGation (2) is more stable than the carbocation (1 ).
15. Hofmann elimination is known as ~limination. The reaction involves [Link] of a pro ttr:
f3-carbon with the simultaneous expulsion of the leaving group.

6) nH----....
~
M83N-C~-CH-CH 3-M~N! + ~=CH-Of~ + ~O

In case of alternate f}-hydrogen atoms, the most acidic of the two hydrogen atoms is abstl!acfed thE;
base. (For further details see page 64.)
16. See page 82.
17. See page 17 also.
Both phenol and phenoxide ions are resonance hybrids. Charge separation in the resooance st:[Link]:tlJrc5
of phenol makes it less stable than the phenoxide ion where charge cfe{ocafization is ~ ce
phenol prefers ionization, i.e., it is acidic.
The ionization of alcohol gives alkoxide ion which has no stability because the ci1aige ca:mot delacali2E-
e e
R - OH~ RO+H
Hence, alcohol is neutral.
18. See page 35.
19. See page 60.
20. See page 20.
21 . See page 231.
·:---.----------

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'I ,··

._.! :·
.= !

.,

"

," ...... "'r.

.; ..
,'· .
·':.·~~~ .
- . . .. ~·
"":.-·:.
. ~ ·..

·i .:
1,