Hofmann Reaction

Hofmann degradation: The Hofmann degradation is the

organic reaction of a primary amide to a primary amine with
one fewer carbon atoms. This reaction is also sometimes
called the Hofmann rearrangement reaction.
• Hofmann degradation is the reaction of a primary amide with a
halogen (chlorine or bromine) in strongly basic (sodium or potassium
hydroxide) aqueous medium, which converts the amide to a primary
amine. For example:
Mechanism
of Reaction
 It is used to prepare:

Anthranilic acid

3-Aminopyridine
Applications
4-Aminopyridine

Phentermine (Phentermine, sold under the brand name Ionamin among

others, is a medication used together with diet and exercise to treat obesity.)
 Applications of Hofmann reactions
Synthesis of anthranilic acid from sodium salt of phthalamic
: acid by Hofmann rearrangement reaction

Pharmaceutical uses:
Anthranilic acid is used to produce-
 Saccharin, a sweetening agent
 Loop diuretics such as furosemide
 Outlawed euphoric sedative drug methaqualone
 Benzene and its derivatives.
 It is the precursor of tryptophan.
 Anthranilic acid derivatives are used to inhibit the formation of
advanced glycation end products to reduce complications in diabetes.

Other uses:
 In preparing perfumes to imitate jasmine and orange.
 An intermediate in the production of azo dyes.
 Corrosion inhibitors for metals .
 Mold inhibitors in soya sauce.
 Anthranilate esters could be efficient insect repellents.
 Preparation of indigo from anthranilic acid.
 Synthesis of 3-Aminopyridine from
nicotinamide by Hofmann degradation:

Pharmaceutical uses: 3- Amino pyridine is used as-

 Pharmaceutical intermediates
 Intermediate of colorant.
 In the menufacturing of Piroxicam , Tenoxicam, and Ampiroxicam.
 In the synthesis of organic ligand 3-pyridylnicotinamide.
Other uses:
 An intermediate for agrochemicals.
 As chelate ligands to form a complex with a transition metal ion.
 Aminopyridine is used as a monomer for polymerization.
 3-Aminopyridines are involved in photosensitizer chemistry, luminescent
materials, metal complex chemistry and liquid crystal.

Precautions:
3-Aminopyridine can easily be absorbed through the skin. It is fatal if swallowed or
absorbed through the skin. High concentrations can be extremely destructive to the
tissues of mucous membranes and upper respiratory tract eyes and skin. Symptoms
may also include convulsions and death. It also causes damage to the nervous system.
Thermal decomposition leads to evolution of toxic gases such as carbon monoxide
and oxides of nitrogen.
 Synthesis of 4-Aminopyridine from pyridine-4-
carboxamide via the Hofmann rearrangement.

NaOCl

Pharmaceutical uses: There are various applications of 4-Aminopyridine in

pharmacy such as,
 as a precursor to the drug pinacidil, which affects potassium ion channels.
 In the laboratory, 4-AP is a useful pharmacological tool in studying various
potassium conductance in physiology and biophysics.
 At very low concentration it selectively and reversibly inhibits Shaker
channels without significant effect on other sodium, calcium, and potassium
conductance.
 As a drug, to manage some of the symptoms of multiple sclerosis, and is
indicated for symptomatic improvement of walking in adults with several
variations of the disease.
 4-Aminopyridine is a potent convulsant and is used to generate seizures in
animal models for the evaluation of antiseizure agents.
 Clinically used in Lambert-Eaton myasthenic syndrome and multiple sclerosis.
 To improve visual function and motor skills and relieve fatigue in patients with
multiple sclerosis.
 4-AP works as a potassium channel blocker and a potent calcium channel
activator.
 Spinal cord injury patients have also seen improvement with 4-AP therapy.
 As an antidote for tetrodotoxin poisoning.
 Treatment of Parkinson's Disease.
 Synthesis of drug, Phentermine, by Hofmann
degradation reaction:
Friedel-Craft’s alkylation
And acylation NaNH2
Sodamide

Hofmann
degradation

Phentermine

Phenetermine is a sympathomimetic agent employed as an anorectic in the treatment of

obesity.
Dose: Usual, adult 15to 30mg at breakfast.
 Synthesis of methyl amine from acetamide by
Hofmann degradation reaction.
CH3CONH2+Br2+4NaOH CH3NH2+Na2CO3+2NaBr+2H2O

• As intermediates to make pharmaceutical products.

• To make analgesics.
• To make xanthine derivatives, such as caffeine.
Pharmaceutica • To make intermediates for lorazepam tranquilizers,
nortryptylene antidepressant, isometheptene
l uses: Methyl veterinary smooth muscle relaxant.
• Sympathomimetic drugs are made from MA ,such as
amine is used- adrenaline, ephidrine, neosynephrine, vanedrine, and
veritol.
• In the synthesis of local anesthetics, such as
amethocaine, procaine, and pontocaine.
 Determination of alkaloid structure by
Hofmann reaction:
The Hofmann degradation has been a useful tool in structure determination of
alkaloids. The correct structure of lobelia alkaloids, of which lobelanine is typical,
was first deduced from the Hofmann degradations of the quaternary hydroxide.

lobelanine