Unit V: Reaction of synthetic importance as per PCI Syllabus of POC-III

Reaction of synthetic Importance
Mr. Mote G. D
ADCBP, Ashta
1

INDEX
1. METAL HYDRIDE REDUCTION (NABH4 AND LIALH4)
2. CLEMMENSEN REDUCTION
3. BIRCH REDUCTION
4. WOLFF-KISHNER REACTION
5. OPPENAUER OXIDATION
6. DAKIN REACTION
7. BECKMANN REARRANGEMENT
8. SCHMIDT REARRANGEMENT.
9. CLAISEN-SCHMIDT CONDENSATION
2

Metal hydride reduction (NaBH4 and LiAlH4)
The most common sources of the hydride Nucleophile are lithium aluminum hydride
(LiAlH4) and sodium borohydride (NaBH4).
The hydride anion is not present during this reaction; rather, these reagents serve as a
source of hydride due to the presence of a polar metal-hydrogen bond
Because aluminium is less electronegative than boron, the Al-H bond in LiAlH4 is
more polar, thereby, making LiAlH4 a stronger reducing agent.
Addition of a hydride anion (H:-) to an aldehyde or ketone gives an alkoxide anion,
which on protonation yields the corresponding alcohol .
Aldehydes produce 1°-alcohols and ketones produce 2°-alcohols.
Al
H
H H
H
Li B
H
H H
H
Na H

Metal hydride reduction by LiAlH4 and NaBH4
R C
O
H
LiAlH4
R C
H
OH
H LiOH
+ + AlH3
R C
O
H
NaBH4
R C
H
OH
H NaCl
+ + BH3
HCl
H2O

Mechanism of Metal hydride reduction by LiAlH4
R C
O
H + Al
H
H
H
H
Li R C
O
H
H
Li+
+ AlH3
1. Nucleophilic attack by hydride
2.Protonation of Alkoxide ion
R C
O
H
H
Li+
+ H OH R C
OH
H
H
+ LiOH

Mechanism of Metal hydride reduction by NaBH4
R C
O
H + B
H
H
H
H
Na R C
O
H
H
Na+
+ BH3
1. Nucleophilic attack by hydride
2.Protonation of Alkoxide ion
R C
O
H
H
Na+
+ H Cl R C
OH
H
H
+ NaCl

Examples of Metal hydride reduction by LiAlH4&bNaBH4
H3C C
O
H
LiAlH4
H3C C
H
OH
H LiOH
+ + AlH3
H3C C
O
H
NaBH4
H3C C
H
OH
H NaCl
+ + BH3
HCl
H2O
acetaldehyde
acetaldehyde ethanol
ethanol
H3C C
O
CH3
LiAlH4
H3C C
H
OH
LiOH + AlH3
H3C C
O
CH3
NaBH4
H3C C
H
OH
CH3 NaCl + BH3
HCl
H2O
Acetone
acetone
CH3
+
+
propan-2-ol
propan-2-ol

Application
1. Aldehydes are converted into primary alcohol(Alcohol preparation)
2. Ketones are converted into secondary alcohol (Alcohol Preparation)
3. Identification Class of alcohol

INTRODUCTION
 This reaction was first reported by Clemmensen of Park Davis in 1913.
 It is the reduction of carbonyl groups ( in aldehyde and ketone) to
methylene group.
 This reaction done with zinc amalgam and hydrochloric acid and it is
generally known as Clemmensen reduction.
 The Clemmensen reduction is particularly effective at reducing aryl- alkyl
ketones,such as those formed in a Friedel-Crafts acylation.
4

GENERAL REACTION
R1=Alkyl,Aryl
R2= H,Alkyl, Aryl
5

CHOLESTANE-3-ONE
MODIF CATION
CHOLESTANE
7

APPLICATIONS
🠶
This reaction has widely used to convert a carbonyl group into a
methylene group.
🠶
Also important application in the preparation of polycyclic
aromatics and aromatics containing unbranched side hydrocarbon
chains.
🠶
To reduce aliphatic and mixed aliphatic-aromatic carbonyl
compounds
8

Birch Reduction
The reduction of aromatic substrates with alkali metals, alcohol in liquid
ammonia is known as "Birch reduction
This reaction is named after a Australian chemist Sir Arthur John Birch.
The Birch reduction is an organic reaction where aromatic rings undergo a
1,4-reduction to provide unconjugated cyclohexadienes .
The reduction is conducted by sodium or lithium metal in liquid ammonia
and in the presence of an alcohol.

Birch Reduction
The mechanism begins with a Single Electron Transfer (SET) from the
metal to the aromatic ring, forming a radical anion.
The anion then picks up a proton from the alcohol which results in a neutral
radical intermediate.
Another SET, and abstraction of a proton from the alcohol results in the
final cyclohexadiene product and two equivalents of metal alkoxide salt as a
by-product.

Birch Reduction
benzene
Na
NH3
, 2CH3OH
cyclohexa-1,4-diene
+ CH3ONa

Mechanism of Birch Reduction
Na NH3 2Na+ 2e-
e-
H
H
H
H
HO CH3
2
H
H
H
e-
H
H
H
HO CH3
H
H
H
H
-CH3O
-CH3O
CH3 O + 2Na
2 2CH3ONa

Application of Birch Reduction
1) Naphthalene can be reduced to 1,4,5,8-tetrahydronaphthalene by
using Birch reduction conditions.
Na, NH3(Liq)-78
°C
EtOH, Et2O
1,4,5,8-tetrahydronaphthalene
2) In the birch reduction of benzoic acid, the protonation occurs at ipso and para positions
relative to -COOH group on the benzene ring.
COOH
Na, NH3
C2H5OH
COOH
cyclohexa-2,5-dienecarboxylic acid
benzoic acid

INTRODUCTION
 The Wolff– Kishner reduction was discovered independently by N. Kishner
in 1911 and L. Wolff in 1912.
 TheWolff–Kishner reduction is a reaction used in organic chemistry to convert
carbonyl functionalities into methylene groups.
 The Wolff-Kishner reduction is an organic reaction used to convert an
aldehyde or ketone to an alkane using hydrazine, base, and thermal
conditions
 Because the Wolff–Kishner reduction requires highly basic conditions, it is
unsuitable for base-sensitive substrates.

Unit V: Reaction of synthetic importance as per PCI Syllabus of POC-III

MODIFICATION
🠶
The reaction has been extensively modified.
🠶
One of the modification uses the Huang Minlon modification using
distillation to remove excess water and also used 85% hydrazine and
solvent used is ethylene glycol.
🠶
In addition, the Wolff- kishner reduction has been carried out in
DMSO instead of hydroxylic solvent by addition of hydrazones into
anhydrous DMSO containing freshly sublimed potassium tert-
butoxide at 250C.
🠶
Moreover,it has been reported that the Wolff-Kishner reduction can
occur in a very short period of time in a microwave irradiation,
affording product with high purity.
13

APPLICATIONS
🠶
This reaction has very broad application in organic synthesis,
especially for the multiwalled carbon nanotubes.
🠶In 2011, Pettus and Green reduced a tricyclic carbonyl compound
using the Huang Minlon modification of the Wolff–Kishner
reduction.Several attempts towards decarbonylation of tricyclic
allylic acetate containing ketone failed and the acetate functionality
had to be removed to allow successful Wolff–Kishner reduction.
Finally, the allylic alcohol was installed via oxyplumbation.
🠶
The Wolff–Kishner reduction has also been used on kilogram scale
for the synthesis of a functionalized imidazole substrate.
14

INTRODUCTION
Named after Rupert Viktor Oppenauer.
It is a gentle method for selectively oxidizing secondary alcohols to
ketones.
The reaction is the opposite of Meerwein– Ponndorf –Verley
reduction.
The alcohol is oxidized with aluminium isopropoxide in excess acetone.
This shifts the equilibrium toward the product side.

 The oxidation is highly selective for secondary alcohols and does not
oxidize other sensitive functional groups such as amines and sulfides,
 Though primary alcohols can be oxidized under Oppenauer conditions,
primary alcohols are seldom oxidized by this method due to the
competing aldol condensation of aldehyde products.
 The Oppenauer oxidation is still used for the oxidation of acid labile
substrates.
Cont……

MODIFICATION
Woodward modification
🠶In the Woodward modification, Woodward substituted potassium tert-
butoxide for the aluminium alkoxide.
🠶The Woodward modification of the Oppenauer oxidation is used
when certain alcohol groups do not oxidize under the standard
Oppenauer reaction conditions.
🠶For example, Woodward used potassium tert-butoxide
and benzophenone for the oxidation of quinine to quininone, as the
traditional aluminium catalytic system failed to oxidize quinine due
to the complex formed by coordination of the Lewis-
basic nitrogen to the aluminium centre.
28

Cont……
Other modifications
• Several modified aluminium alkoxide catalysts have been also reported
• For example, a highly active aluminium catalyst was reported by Maruoka and
co-workers which was utilized in the oxidation of carveol to carvone (a member
of a family of chemicals called terpenoids) in excellent yield (94%)
29

APPLICATIONS
The Oppenauer oxidation is used to prepare analgesics in the pharmaceutical
industry such as morphine and codeine. For instance, codeinone is prepared
by the Oppenauer oxidation of codeine.

Cont……
The Oppenauer oxidation is also used to synthesize hormones.
Progesterone is prepared by the Oppenauer oxidation of
pregnenolone.

Cont……
The Oppenauer oxidation is also used in the synthesis of lactones
from 1,4 and 1,5 diols.

6. Dakin Reaction
Dakin Reaction is the replacement of the aldehyde group of ortho and para hydroxy and
ortho amino-benzaldehyde (or ketone) by a hydroxyl group on reaction with alkaline
hydrogen peroxide.
H2O2
NaOH
OH
C
O
H
OH
OH
+ H-COOH
Catechol
Salicylic acid

6. Dakin Reaction- Mechanism
NaOH OH + Na HO OH
OH-
H2O
OH
C
O
H
HO O
O OH
OH
C
O
H
O OH
Na
-NaOH
OH
O
C
O
H
H-OH
OH
OH
Catechol
+ HCOOH
salicylic acid
1 2.
3.

Applications of Dakin oxidation reaction
1. Synthesis of Pyrro gallol mono methyl ether- Anesthetic agent
2. Synthesis of Hydroquinone-Treatment of acne
3. Phenol preparation
CHO
OH
OCH3
H2O2
NaOH, H2O
OH
OH
OCH3
2,3 Dihydroxy anisole
(Pyrrogallol monomethyl ether)
C OH
CH3
O
H2O2
NaOH, H2O
HO OH
p-hydroxyacetophenone Hydroquinone
-2-hydroxy, 3-3methoxy
benzaldehyde

Beckmann rearrangement
• The acid-catalysed conversion of ketoximes to amides is known as
the Beckmann rearrangement
• The Beckmann rearrangement, named after the German chemist
Ernst Otto Beckmann (1853–1923)
• This rearrangement is occurs in both cyclic and acyclic compounds
.
• Aldoximes are less reactive.
• Cyclic oximes yield lactams and acyclic oximes yield amides
2

Beckmann rearrangement
Reagents:-Conc.H2SO4, HCl, PCl5,PCl3, SOCl2, ZnO, SiO2, PPA (Poly
phosphoric acid) etc., are commonly employed in Beckmann
rearrangement.
Oxime
4
3
Amide

Reaction mechanism
The first step in the process is formation of an oxime from the aldehyde or ketone,
4
4

Reaction mechanism
This rearrangement take place an alkyl migration with expulsion of the hydroxyl
group to form a nitrilium ion followed by hydrolysis.
4
5

Migratory aptitude
• The relative migratory aptitudes of different groups in Beckmann rearrangement
is illustrated below.
4
6

Applications in drug synthesis:-
• An alternative industrial synthesis method for Paracetamol. It is involves direct
acylation of phenol with acetic anhydride catalyzed by HF, conversion of the
ketone to a ketoxime with hydroxylamine, followed by the acid-catalyzed Beckmann
Rearrangement to give the amide
7
Paracetamol

48
Applications in drug synthesis:-
• The Beckmann rearrangement is also used in the synthesis
of
1. DHEA
2. Benazepril
3. Etazepine etc.

Applications in polymer synthesis:-
• Beckmann rearrangement can be rendered catalytic using cyanuric chloride and
zinc chloride as a co-catalyst. For
example, cyclododecanone can be converted to the corresponding lactam,
the monomer used in the production of Nylon 12
49

Applications in polymer synthesis:-
• The Beckmann rearrangement is also used in the
synthesis of Nylon 6
50

Schmidt Rearrangement
The Schmidt reaction is an organic reaction in which an azide reacts with a carbonyl derivative, usually an aldehyde, ketone, or
carboxylic acid, under acidic conditions to give an amine or amide, with expulsion of nitrogen.
The reaction is superior to the Curtius or Hofmann rearrangement because it directly converts an acid or ester to amine, without
making the acid derivatives.
The reaction is limited to acid insensitive compounds.
The reaction is effective with carboxylic acids to give amines, and with ketones to give amides.

The reaction proceeds with faster rate with sterically hindered acids which forms acyl cation in presence of acids, even
without heating.
Crowding around the a-center of the “R” group facilitates the formation of acyl cation, thus enhances the rate.
Acids that do not form acyl cation react through the protonation of the acid under heating, as shown previously.
acyl cation

Examples
Cyclic ketones gives lactams with expansion of the ring

Schmidt Rearrangement for ketone

Formation of the carbocation step (6) in Schmidt reaction can be evidenced by the formation of the tetrazole (A) and the
substituted urea (B), which are often isolated from the reaction medium when excess of azide is used. These products are
obtained from the intermediate carbocation as the amide does not react with hydrogen azide in the reaction condition.
(A)
(B)
(6)
Evidence for the carbocation intermediate formation
Unsymmetrical ketone gives a mixture of two product

Application of Schmidt Rearrangement
1. Preparation of Primary Amines
COOH
H3C +NH3
H2SO4
NH2
H3C
Toludine
Tolueic acid
2. Preparation of Capro-lactams and polymerisation of caprolactam with base to form nylone
O
+ NH3
H2SO4
NH
O
Lactam
Cyclohexanone

Application of Schmidt Rearrangement
3. Synthesis of Acetanilide from acetophenone- Analgesic, Antirhuematic
4. Synthesis of Benzanilide from Benzophenone- Perfume and dye
C
O
CH3
+ NH3
H2SO4
acetophenone
NH C
O
CH3
Acetanilide
C
O
+ NH3
H2SO4
NH C
O
benzophenone
Benzanilide

Claisen–Schmidt Condensation Reaction
The reaction between an aldehyde or ketone having an alpha-hydrogen with an
aromatic carbonyl compound lacking an alpha hydrogen is called the Claisen–
Schmidt condensation.
In cases where the product formed still has reactive alpha hydrogen and a hydroxide
adjacent to an aromatic ring, the reaction will quickly undergo dehydration leading to the
condensation product
C
O
H
+ CH3
C
O
CH3
NaOH, Aq. EtOH
H
C CH
C
O
C
H
H
C
Dibenzal acetone
Benzaldehyde
2

Mechanism
H2C C
O
CH3
H
OH-
H2C C
O
CH3
C
O
H
C
O
H
C
H2
C
O
H3C
H2O
H/H2O
C
OH
H
CH
C
O
H3C
H
H
C
CH
C
O
H2C
H

Mechanism H
C
C
H
C
O
H2C
H
OH
H2O
H
C
C
H
C
O
H2C
+
C
O
H
H
C
C
H
C
O
H2
C
C
H
O
H+
/H2O
H
C
C
H
C
O
H
C
C
H
OH
H
H
C
C
H
C
O
C
C
H
H
Dibenzal acetone

Application
1. A reaction employed for preparation of unsaturated aldehydes and ketones
by condensation of aromatic aldehydes with aliphatic aldehyde or ketone in presence of
sodium hydroxide. E.g. synthesis of cinnamaldehyde which is used in perfumery industry
C
O
H
+ CH3 C
O
H
H
C
H
C C
O
H
10% NaOH
Cinnamaldehyde
Bezaldehyde
2. Synthesis of Dibenzalacetone which is used as sun protecting agent in sun screen lotion
C
O
H
+ CH3
C
O
CH3
NaOH, Aq. EtOH
H
C CH
C
O
C
H
H
C
Dibenzal acetone
Benzaldehyde
2

Application
3. Synthesis of Chacone
4. This reaction also used to synthesis of natural products such as ionone, Flavonone,
piperine etc
C
O
CH3
+ H C
O
C
H
C CH
10% NaOH
Chalcones
Acetophenone
O
Benzaldehyde
ethanol

Unit V: Reaction of synthetic importance as per PCI Syllabus of POC-III

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Unit V: Reaction of synthetic importance as per PCI Syllabus of POC-III