Reactions of Synthetic Importance

Mr. Sayad ImranY B Chavan College of Pharmacy

Clemmensen Reduction

Clemmensen reduction

The Clemmensen reduction is an organic reaction used to reduce an aldehyde or ketone to an

alkane using amalgamated zinc and hydrochloric acid.

* In Clemmensen reduction, the amalgamated zinc in HCl is used as reducing agent.

* The C=O group is converted to -CH2- group.

MECHANISM OF CLEMMENSEN REDUCTION

The Clemmensen reduction occurs over the surface of zinc catalyst. The probable mechanism is

shown below.

* There is a net flow of

electrons from zinc to the

carbonyl compound.

* As there is no formation of alcohol during the reaction, this method is not useful to reduce alcohols to alkanes.

3) In the following reaction, along with the reduction of carbonyl group, the -OH group is substituted by

the -Cl group (side reaction). However this side reaction can be avoided by employing Wolff-Kishner

method.

Wolff Kishner Reduction

In Wolff-Kishner reduction, the carbonyl compounds which are stable to strongly basic conditions can

be reduced conveniently to alkanes. The C=O group is converted to CH2 group.

The carbonyl compound is first treated with excess of hydrazine to get the corresponding hydrazone

which upon heating, in presence of a base, furnishes the hydrocarbon.

A high-boiling hydroxylic solvent, such as diethylene glycol (DEG), is commonly used to achieve the

temperatures needed.

MECHANISM OF WOLFF KISHNER REDUCTION

The Wolff-Kishner reduction of acetone gives………….

The cyclohexane is formed upon Wolff-Kishner reduction of cyclohexanone.

The Wolff-Kishner reduction is best suited for the reduction of carbonyl compounds containing groups

stable to strongly basic conditions. In the following example, the alcohol group is not affected during the

reduction.

The base sensitive groups may be affected during Wolff-Kishner reduction. In the following case, the

halogen group undergoes dehydrohalogenation under strongly basic conditions.

This side reaction can be avoided by using Clemmensen reduction.

Higher temperatures encourage elimination

Birch Reduction

Birch reduction

In Birch reduction, aromatic rings are reduced to 1,4-dienes as an unconjugated cyclohexadienes

by alkali metals (Na, Li) in liquid ammonia and in presence of alcohols.

*

MECHANISM OF 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 single electron transfer from the metal to the aromatic ring, forming an anion, and abstraction

of a proton from the alcohol results in the final cyclohexadiene product and two equivalents of metal

alkoxide salt as a byproduct.

REGIOSELECTIVITY IN BIRCH REDUCTION

The positions of protonation on substituted benzenes depend on the nature of the group

* EWG: The electron-withdrawing groups promote ipso & para reduction. These groups

activate the ring towards birch reduction. Initially the protonation occurs para to the EWG.

E.g. -COOH, -CONH2, aryl group etc.,

REGIOSELECTIVITY IN BIRCH REDUCTION

* EDG: The electron-donating groups promote ortho & meta reduction. They deactivate the ring for

overall reduction compared to the EWG.

E.g. -R, -OR, -NR2, -SR, PR2, -CH2OH, -CHO, -C(O)R, CO2R etc.,

The birch reduction of benzoic acid,

The protonation occurs at ipso and para positions relative to -COOH group on the benzene ring.

Beckmann Rearrangement

Beckmann Rearrangement

The Beckmann rearrangement is an acid catalyzed rearrangement of an oxime to an N-substituted

amide.

Conc.H2SO4, HCl, PCl5, PCl3, SOCl2, ZnO, PPA (Poly phosphoric acid) etc., are commonly

employed in Beckmann rearrangement.

Cyclic oximes give lactams (cyclic amides).

Mechanism Of Beckmann Rearrangement

Initially the -OH group of the oxime is protonated.

Then 1,2 shift of alkyl group (R1) onto electron deficient nitrogen and the cleavage of N-O bond

occurs simultaneously.

the alkyl group which is 'anti' to the -OH group on nitrogen undergoes 1,2 shift which indicates

the concerted nature of the beckmann rearrangement.

T.

Beckmann Rearrangement

Industrial conversion of cyclohexanone to caprolactam, which is used in the manufacture of

Nylon-6, involves Beckmann rearrangement.

Beckmann Rearrangement

The relative migratory aptitudes of different groups in Beckmann rearrangement is illustrated

below.

The 1,2 shift of phenyl group is faster than that of alkyl groups. It is due to formation of

phenonium ion. Hence the anti isomer reacts faster than the syn isomer.

cyclododecanone can be converted to the corresponding lactam, the monomer used in the production of Nylon 12; Beckmann rearrangement can be rendered catalytic using cyanuric chloride and zinc chloride as a co-catalyst.

Oppenauer-Oxidation

Oppenauer Oxidation

is the process of conversion of secondary alcohols to ketones by selective oxidation. Oxidation

reaction takes place in the presence of Aluminium triisopropoxide [Al(i-Pro)3] in excess of

acetone.

• Acetone acts as a hydrogen acceptor, and it is transformed into 2-propanol. The presence of excess of acetone

drives the reaction towards the oxidation product.

• The use of inert solvent such as benzene, toluene or dioxane minimizes the side products.

Oppenauer Oxidation Mechanism

The alcohol (1) coordinates to the aluminium to form a complex (3),

In the second step, complex (3) gets deprotonated by an alkoxide ion (4)

Oppenauer Oxidation Mechanism

In the third step, both the oxidant acetone (7) and the substrate alcohol are bound to the

aluminium. The acetone is coordinated to the aluminium which activates it for the hydride transfer

from the alkoxide. The aluminium-catalyzed hydride shift from the α-carbon of the alcohol to the

carbonyl carbon of acetone proceeds over a six-membered transition state (8). The desired ketone

(9) is formed after the hydride transfer.

Mechanism

The reaction is performed by refluxing a secondary alcohol with acetone in the presence of

Al(OiPr)3. The latter serves only to form the aluminium alkoxide of the alcohol that is

oxidized through a cyclic transition state at the expense of acetone to a ketone and 2-

propanol.

Dakin Oxidation

Dakin oxidation is an organic redox reaction in which an ortho- or para-hydroxylated phenyl

aldehyde (2-hydroxybenzaldehyde or 4-hydroxybenzaldehyde) or ketone reacts with hydrogen

peroxide in base to form a benzenediol and a carboxylate.

Overall, the carbonyl group is oxidized, and the hydrogen peroxide is reduced.

Reaction Mechanism

Nucleophilic addition of a hydroperoxide anion to the carbonyl carbon, forming a tetrahedral

intermediate (2).

[1,2]-aryl migration, hydroxide elimination, and formation of a phenyl ester (3).

The phenyl ester is subsequently hydrolyzed:

nucleophilic addition of hydroxide from solution to the ester carbonyl carbon forms a second tetrahedral intermediate (4),

Now eliminating a phenoxide (5) and forming a carboxylic acid.

Finally, the phenoxide extracts the acidic hydrogen from the carboxylic acid, yielding the products (6)

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