Loknete Dr.

Balasaheb Vikhe Patil (Padma Bhushan Awardee)

Pravara Rural Education Society
Arts, Science & Commerce College Kolhar

Structure, Stability and Reactions of

Reactive Intermediates
Class- M.Sc.-I
Mr. A. K. Kharde
Asst. Professor Dept. of Chemistry
A. S. C College, Kolhar
Structure, Stability and Reactions of Reactive Intermediates
Carbocation:-
A carbocation is molecule having a carbon atom bearing three
bonds and a positive formal charge. Carbocations are generally
unstable because they do not have eight electrons to satisfy the
octet rule.

C Open valence shell on carbon

Methyl carbocation
Classification of Carbocations:-
i) Primary carbocation (1o):- A primary carbocation is one in
which there is one carbon (alkyl group) directly attached to the
carbon bearing the positive charge.
H H H H H H C H
H C C C H C C
H H H H H

ii) Secondary Carbocation (2o):- A secondary carbocation is one

in which there are two carbons (alkyl groups) directly attached to
the carbon bearing the positive charge
H
H3 C C
CH3
 iii) Tertiary Carbocation (3o):- A tertiary carbocation is one in
which there are three carbons (alkyl groups) directly attached to
the carbon bearing the positive charge.
CH3
H3 C C
CH3

iv) Allylic Carbocation:- When carbon bearing the positive charge

is immediately adjacent to a carbon-carbon double bond, the
carbocation is termed as allylic carbocation.

General allylic R H
carbocation R C C C R H C C CH2 allyl carbocation
structure R R
H
 v) Benzylic carbocation:- When the carbon bearing the positive
charge is immediately adjacent to benzene ring, the carbocation is
termed as benzylic carbocation.
R R
R H
General benzylic C Benzyl carbocation
R C
carbocation structure
R H
R R

vi) Vinylic Carbocation:- When the carbon bearing the positive

charge is part of an alkene the carbocation is termed as vinylic
carbocation.

General Vinylic
carbocation structure
R C C R H C C Vinyl carbocation
R H H
 vii) Aryl Carbocation:- When the carbon bearing the positive
charge is part of a benzene ring the carbocation is termed as aryl
carbocation.
R R
General aryl
carbocation structure R Phenyl carbocation
R R

Stability of Carbocation:- Tertiary carbocation is more stable

than secondary and secondary carbocation is more stable than
primary carbocation because of inductive and resonance effect.

3o > 2o > 1o > CH3 Stability order of carbocation

Allyl cation and benzyl cation are more stable than most other
carbocations.

R C C C R R C C C R
R R R R R R

CH2 CH2 CH2 CH2

Reactions of Carbocations:-
i) Nucleophilic attack:- R R
R C + Nu R C Nu
R R
Nu = ROH, RSH, X- , alkene (Produces new carbocation), Ar
ii) β-elimination:-
H
C C C C

iii) Rearrangements:-

H C C H C C
Carbanion:-
A carbanion is an anion in which carbon is trivalent and bears a
formal negative charge. Formally carbanion is a conjugate base of
carbon acid.
R R
R C H+B R C + HB
R R
R
R C
R
Carbanions are typically nucleophilic and basic. The basicity and
nucleophilicity of carbanions are determined by the substituents
on carbon. These includes
i) The inductive effect, electronegative atoms adjacent to the charge will
stabilize the charge.

ii) The extent of conjugation of the anion, resonance effect can stabilize
the anion.

Halogen stabilize carbanions in the order of Br > Cl > F

Carbanions are trivalent with SP3 hybridization. The loan pair of

electrons occupies one of the SP3 orbitals. The geometry is thus trigonal
pyramidal.

Stabilization of Carbanions:- The negative charge on carbanion is

stabilized by neighbouring electron withdrawing groups (EWG) such as
carbonyl, nitron and sulfone.
EWG: C=O, NO2, CN, SO2

O O
C C C C

O O O O O O
C C C C C C C C C

When carbanions are formed in unsymmetrical ketones two

carbanions is possible. One the more substituted carbanion is
called the thermodynamic anion, while the least substituted and
first formed anion is called kinetic anion. LDA is a base of choice
for formation of kinetic product, while hydroxide and alkoxides
gives the thermodynamic anion.
 O H2 O H2 O H
H3C C C CH3 H2C C C CH3 H3C C C CH3
Kinetic Thermodynamic
LDA 71 29
t-BuOK 20 80

Stability of Carbanion:- A carbanion is a nucleophile,

which stability and reactivity determined by several factors: The
greater the s-character of the charge-bearing atom, the
more stable the anion; The extent of conjugation of the anion.
Resonance effects can stabilize the anion.
Allylic, benzylic > 1o > 2o > 3o
sp > sp2 > sp3
Reactions of Carbanion:-
i) Aldol condensation reaction:- Aldehydes and ketones containing
α-hydrogen react with base to form enolate which react with
another molecule of aldehyde to form product are called aldol
condensation reaction.
O O O H2O O
OH
+
OH
ii) Claisen Condensation:-

The α-hydrogen of ester is removed by base to give the enolate.

The enolate reacts with another molecule of the ester in an
addition-elimination reaction resulting product is β-ketoester. The
reaction is known as the claise condensation.
iii) Michael Reaction:- Enolates may also be alkylated with α, β
unsaturated carbonyl substrates. The enolates add in the 1,4 fashion
to give a product this reaction is known as Michael reaction.
iv) Robinson Ring-forming Reaction:- Robinson annulation is a
chemical reaction used in organic chemistry for ring formation. It
is unique reaction that produces a new ring containing an α,β-
unsaturated ketones. When an enolate derived from a ketone react
with methyl vinyl ketone, the enolate add like Michel reaction,
then a second enolate in the ketone product is formed that cyclizes
in an Aldol condensation to give the final product.
 O O

+ OH H
O C O O O
O
Carbene:- In chemistry a carbene is a molecule containing a
neutral carbon atom with a two valence and two unshared valence
electrons. The general formula is where R represents
substituent or hydrogen atom. The compound H2C: are called
methylene. Well studied carbene is dichlorocarbene Cl2C:
Structure and Bonding:-

The two class of carbenes are singlet and triplet carbenes. Singlet
carbene are spin paired. Triplet carbenes have two unpaired
electrons.
Reactivity:- Singlet and triplet carbenes exhibit divergent
reactivity. Singlet carbenes generally participate in cheletropic
reactions as either electrophilic or nucleophilic. Singlet carbenes
with unfilled p-orbital should be electrophilic. Triplet carbenes can
be considered to be diradicals, and participate in stepwise radical
additions. Triplet carbenes have to go through an intermediate with
two unpaired electrons whereas singlet carbene can react in a
single concerted step. Due to these two modes of reactivity,
reactions of singlet methylene are stereospecific whereas those of
triplet methylene are stereoselective.
Reactions of Carbene:-
i) Cyclopropanation:- Carbene add to double bonds to form
cyclopropanes. A concerted mechanism is available for singlet
carbenes.
e.g.
ii) C-H insertion:-
H H
H3C C H + CH2 H3C C CH3
CH3 CH3
Carbene insertion
iii) Carbene dimerization:- Carbenes and carbenoid precursors can
undergo dimerization reactions to form alkenes.

R R R
N N N
2
N N N
R R R
iv) Wolff Rearrangement:- Wolff rearrangement is also proceed
via formation of carbene as intermediate.

v) Arndt-Eistert homologation:- In Arndt-Eistert homologation

carboxylic acid first converted to acid chloride followed by Wolff
rearrangement to give higher carboxylic acid homologue.
Nitrene:- In chemistry a nitrene or imine (R-N) is the nitrogen
analogue of a carbene. The nitrogen atom is uncharged and
univalent, so it has only 6 electrons in its valence level two
covalent bonded and four non-bonded electrons. It is therefore
considered an electrophile due to the unsatisfied octet. A nitrene is
reactive intermediate and is involved in many chemical reactions.
The simple nitrene, NH is called imidogen.

Nitrenes are so reactive, they are not isolated, they are formed as
reactive intermediates during a reaction.
Generation of Nitrene:- Most common method of generation of
nitrene is thermolysis or photolysis of azides.

Generation from isocyanate

Types of nitrenes:- Nitrenes are of two types singlet nitrene and

triplet nitrene.
Reactions of Nitrene:-
i) Insertion reaction:-

CH3 CH3 CH3 CH3 CH3 CH3

HH
CH3 C C CH3
R N
CH3 C C CH3 + CH3 C C C NR
H
CH3 H CH3 N H CH3 H
R
ii) Addition to π-system:- As with carbene, addition of nitrenes to
alkenes is stereospecific with singlet nitrenes, and non-
stereospecific with triplet nitrenes.

iii) Curtius rearrangement or acyl azides:-

iv) Hoffman Rearrangement:- In Hoffman rearrangement there is
formation of nitrene as a intermediate.
O O
Br2 OH R NH2
R C N H R C N
H
v) Lossen Rearrangement:-

vi) Schmidt Rearrangement:-

vii) Beckmann Rearrangement:-

viii) Neber Rearrangement:-

Free Radicals:- A free radical is an atom, molecule or ion that has
an unpaired valence electron. These unpaired electron make
radical highly chemically reactive. Many radicals spontaneously
dimerize. Most organic radicals have short life time.
Hydroxyl radical
HO•

Radicals may be generated in number of ways, these methods

involve redox reactions, ionizing reactions, heat, electrical
discharge and electrolysis.

Radicals are important in combustion, atmospheric chemistry,

polymerization, plasma chemistry, biochemistry and many other
chemical processes.
Radical formation from spin-paired molecules:-

Homolysis:- Homolysis make two new radicals from spin paired

molecule by breaking a covalent bond, leaving each of the
fragments with one of the electrons in the bond. Breaking of bond
requires energy therefore homolysis occur under the addition of
heat or energy.

Homolysis of a bromine molecule producing two bromine radicals

Homolysis of dibenzoyl peroxide producing two benzoyloxy radicals

Reduction:- Radicals can also form when a single electron is added
to spin-paired molecule, resulting in an electron transfer. This
reaction usually takes place with an alkali metal, metal donating an
electron to another spin paired molecule.

Reduction of a ketone to form a ketyl radical

Radical formation from other radicals:-

Abstraction:- Hydrogen abstraction describes when a

hydrogen atom is removed from a hydrogen donor molecule
with its one electron. Abstraction produces a new radical and a
new spin-paired molecule. This is different from homolysis,
which results in two radicals from a single spin-paired
molecule and doesn’t include a radical as its reactant.
Radical abstraction between a benzoyloxy radical and a hydrogen
bromide molecule, resulting in the production of a benzoic acid
molecule and a bromine radical.

Addition:- When radical is added to a spin-paired molecule to form

a new radical. The addition of bromine radical to an alkene. Radical
addition follows the Anti-Markovnikov rule, where the substituent
is added to the less substituted carbon atom.
Elimination:-

Radical elimination can be viewed as the reverse of radical addition.

In radical elimination, an unstable radical compound breaks down
into a spin-paired molecule and a new radical compound. Where a
benzoyloxy radical breaks down into phenyl radical and a carbon
dioxide molecule.
Stability of free radicals:-

Free radicals do not have formal charge but are unstable because of
an incomplete octet. Groups that donate electrons towards the free
radicals will help to stabilize it. Free radical and carbocations are
both electron deficient and they follow a similar order of stability.

Like carbocations, radicals can be stabilized by resonance.

Factor affecting stability of free radicals:-

Four factor which affect the stability of free radical

i) Conjugation

ii) Hybridisation

iii) Hyperconjugation

iv) Captodative effect

i) Conjugation:- It is a system of connected p-orbitals with

delocalized electrons in compounds with alternating single and
multiple bonds, which in general may lower the overall energy of
the molecule and increase stability.
ii) Hybridisation:- The stability of free radicals decreases as the
orbital is held closer to the nucleus.
iii) Hyperconjugation:- Hyperconjugation is the interaction of the
electrons in a sigma bond (usually C-H or C-C) with an adjacent
empty or partially filled non-bonding p-orbital or antibonding π
orbital or filled π orbital, to give an extended molecular orbital that
increases the stability of the system. Unstable charge on molecule
are dispersed over the structure or due to presence of hydrogen
attached to stabilize the molecule.
iv) Captodative effect:- The captodative effect is the effect on the
stability of a carbon centered radical that is determined by the
combined action of a captor (electron-withdrawing) and a dative
(electron-donating) substituent, both attached to the radical centre.

When electron donating group and electron with drawing group are
near the radical center, the stability of radical center increases.
The substituents can kinetically stabilize radical centers by
preventing molecules and other radical centers from reacting with
the center.

Reactions of free radicals:- There are four principal propagation

reactions.
i) Abstraction of another atom or group, usually a hydrogen atom.
Free radicals proceed reactions with saturated organic molecules by
abstracting an atom from carbon.
The selectivity of the free radicals towards C-H bonds of different
types is determined by bond dissociation energy and polar effects.
The rate of the abstraction process increases as bond dissociation
energy decreases.
ii) addition to multiple bond:- Free radicals undergo addition to
carbon-carbon double bonds. The reaction is generally selective. For
example, addition to CH2=CHX takes place exclusively at the
methyl group, irrespective of the nature of X.
iii) Decomposition:- This can be illustrated by the decomposition
of the benzoyloxy radical.

iv) Combination and Disproportionation:- Two free radicals can

combine by dimerization or disproportionation.

These reactions are generally fast, some having negligible

activation energy.
v) Rearrangement:-

Neighbouring Group Participation:-

Neighbouring group participation (NGP) also known as anchimeric
assistance. In organic chemistry NGP has been defined by IUPAC as
the interaction of a reaction centre with lone pair of electrons in an
atom or the electrons present in σ bond or π-bond contained within
the parent molecule but not conjugated with the reaction centre.
NGP increase the rate of reaction.
Characteristics of NGP:-
i) In case of certain substrate it is occasionaly found that rate of
reaction is greater than expected.
ii) The configuration at chiral carbon is retention not inverted or
racemic.
iii) In this cases there is usually a group with an unshared pair of
electron on adjacent carbon or β-carbon.
The mechanism operating in such cases is called neighbouring
group mechanism which consist essentially two SN2 substitution
which causing an inversion so the net result is retention of
configuration.
 General Mechanism:-
Z R3 Z Z R3

SN2 - SN2
R1 C C R4 R1 C C R3 + X R1 C C R4
NGP by
Z group R2 R4 Y R2 Y
R2 X

R S R

The important evidence for the existence of this mechanism was the
retention of configuration can occur if the substrate is suitable.

Important Neighbouring group:-

-COO- (not COOH), -COOR, -COAr, -OCOR, -OR, -OH, O- ,
-NH2, -NHR, -NR2, -NHCOR, -SH, -SR, S, I, Br, Cl
The decreasing order of the effectiveness of halogens as neighbouring
group is I > Br > Cl
i) NGP by heteroatom loan pairs:- A classic example of NGP is the
reaction of a sulfur or nitrogen mustard with a nucleophile, the rate
of reaction is much higher for the sulfur mustard and a nucleophile
than it would be for a primary alkyl chloride without a heteroatom.

R R2 NR2
N
OH
R 2N HO
R SN2
Cl R
hydroxide water opens
opens here here
H2O

OH
H2O
R 2N R2N
R SN1
R
Hydroxide ion is a stronger nucleophile than water. SN2 reactions are
faster at primary carbons and they depend on the nucleophile. Thus a
stronger nucleophile (like OH-) opens the aziridinium ion at the primary
carbon i.e at less hindered side. The weak nucleophile water can readily
take part in SN1 reaction, because their rates are independent of
nucleophile. Since the primary cation is too unstable to form. Water opens
the aziridinium ion at the more hindered site i.e at the secondary carbon
which forms stable cation.

ii) NGP by alkene (C=C):- The π orbitals can stabilize a transition state by
helping to delocalize the positive charge of the carbocation. For instance
the unsaturated tosylate will react more quickly ( 1011 times faster for
aqueous solvolysis) with a nucleophile than the saturates tosylate.
The carbocationic intermediate will be stabilized by resonance
where the positive charge is spread over several atoms as shown
below.

Cation formed is stabilized by delocalization of π-orbitals.

In saturated tosylate carbocation is not stabilized by delocalization
of π-orbitals. Due to this reason unsaturated tosylate react 1011
times faster than saturated tosylate.

iii) NGP by a cyclopropane, cyclobutane or a homoallyl group:-

Cyclopropylmethyl chloride is reacted wtih ethanol and water then

a mixture of 48% cyclopropylmethyl alcohol, 47% cyclobutanol
and 5% homoallyl alcohol (but-3-enol) is obtained. This is because
the carbocationic intermediate is delocalized onto many different
carbons through a reversible ring opening.
 OH
Cl EtOH OH+ + OH
H2O

Cl

iv) NGP by an aromatic ring:- Aromatic ring in β position can function as

neighbouring group. In the case of a benzyl halide the reactivity is higher
because the SN2 transition state enjoys a similar overlap effect to that in
the allyl system. An aromatic ring can assist the formation of a
carbocationic intermediate called a phenonium ion by delocalizing the
positive charge.
v) NGP by aliphatic C-C or C-H Bonds:- Aliphatic C-C or C-H
bonds can lead to charge delocalization if these bonds are close and
antiperiplanar to the leaving group.
e.g. 2-norbornyl system.

vi) NGP by methyl group:- Methyl group in the above reaction

show NGP because after living I- primary carbocation is formed
which is not stable but after migration of methyl group stable
tertiary carbocation is formed.
Neighbouring group can accelerate substitution reactions:-

Compare the rate of following substitution reactions. Substitution of

the leaving group (OTs or Cl) by solvent, known as the solvolysis.
Nearby group increases the rate of substitution reaction
significantly.