A PresentAtion on

PhArmAceuticAl And synthetic APPlicAtions of hofmAnn reAction

Submitted by: Arabindu kha Roll no: 121112 & MD. Sohanur RahamanRoll no: 121113

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 Reactions

Hofmann elimination: Hofmann elimination, also known as exhaustive

methylation, is a process where an amine is reacted to create a tertiary amine and an alkene by treatment with excess methyl iodide followed by treatment with silver oxide, water, and heat.

Applications of Hofmann reactions

:

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.

Synthesis of anthranilic acid from sodium salt of phthalamic acid by Hofmann rearrangement reaction

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.

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.

NaOCl

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.

Other uses:

4-Aminopyridine is also used in bird control bait. It causes convulsions

and, infrequently, death, depending on dosage. If the dose is sub-

lethal, the birds will recover after 4 or more hours without long-term

ill effect. The amount of bait should be limited so that relatively few

birds are poisoned, causing the remainder of the flock to be frightened

away with a minimum of mortality. A lethal dose will usually cause

death within an hour.

Synthesis of drug, Phentermine, by Hofmann degradation reaction:

Friedel-Craft’s alkylationAnd 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

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.

Figure: Structure of lobelanine

Physiological importance of Hofmann elimination reaction:

The design of atracurium, a neuromuscular-blocking drug or skeletal muscle relaxant was based on the structure of tubocurarine and suxamethomum but superior to both because of its lack of cardiac side effects and self destruction mechanism into blood by Hofmann elimination reaction.

Figure: Hofmann elimination of Atracurium.

References

1. Chemistry of Natural Products, S.V. Bhat, B.A. Nagasampagi, M. Sivakumar.

2. Medicinal Chemistry, Ashutosh kar.

3. An Introduction to Medicinal Chemistry, Graham L. Patrick.

4. Organic Chemistry, Stereochemistry and The Chemical natural Products, I.L. Finar.

5. www.wikipedia.com