Hofmann’s reaction

The synthesis of meconin has been referred to already (p. 201). Cotarnine has been synthesised by Salway from myristicin (I) as a starting-point. This was transformed into jS-3-methoxy-4 5-methylenedioxy-phenylpropionic acid (II), the amide of which was converted by Hofmann s reaction into )S-3-methoxy-4 5-methylenedioxyphenylethylamine, and the phenylacetyl derivative (HI) of this condensed, by heating it in xylene solution with phosphoric oxide, giving rise to the two possible dihydroiso-quinoline derivatives. The first of these substances, 8-methoxy-6 7-methylenedipxy-1-benzyl-3 4-dihydroiioquinoline (IV), on conversion into the methochloride and reduction with tin and hydrochloric acid, gave... 

HOFMANN S REACTION. Reaclion used lor preparation of a primary amine from an amide by treatment with a halogen (usually bromine) and caustic soda. The resulting amine has one fewer carhon atom than the amide used. 

Hofmann s Reaction.—One more important reaction of the acid amides is that known as Hofmann s reaction. When an acid amide is treated with bromine in an alkaline solution the final product is an alkyl ami/ie containing one less carbon than the amide. The steps in the reaction are represented in the case of acetamide as... 

As substitution-products of ammonium iodide which contain two, three, and four alkyl groups are obtained along with methylammonium iodide by the action of ammonia on methyl iodide—a fact explained below—the compound is most readily prepared in the pure condition from acetamide by what is known as Hofmann s reaction. When an amide is treated with bromine and an aqueous solution of sodium hydroxide, the first reaction which takes place consists in the replacement of one of the hydrogen atoms in the amido group by bromine. The equation for the reaction in the case of acetamide is,—... 

It will be remembered that the monobromamides are formed in the preparation of amines by Hofmann s reaction. 

When warmed with an aqueous solution of an alkali, A-bromoacet-amide is converted into methylamine (Hofmann s reaction) —... 

Aminobenzoic Acids, NH2.C6H4.COOH.—The most important of the aminobenzoic acids is the ortho compound, which is called anthranilic acid. It was first obtained from indigo anil). It is manufactured on the large scale in the synthetic preparation of indigo by a method which is an application of Hofmann s reaction for the preparation of amines. It will be recalled that acetamide is converted by a solution of bromine in sodium hydroxide into methylamine —... 

In addition to its uses in photography and medicine, iodine and its compounds have been much exploited in volumetric analysis (iodometry and iodimetry, p. 864). Organoiodine compounds have also played a notable part in the development of synthetic organic chemistry, being the first compounds used in A. W. von Hofmann s alkylation of amines (1850), A. W. Williamson s synthesis of ethers (1851), A. Wurtz s coupling reactions (1855) and V. Grignard s reagents (1900). 

In 1878, Hofmann reported that treatment of D-l-bromo-2-propylpiperidine (3) with hot sulfuric acid gave rise to a tertiary amine 4, D-octahydroindolizine. In the ensuing decade, Loffler and Freytag extended the reaction to simple secondary amines and found it to be a general way to synthesize pyrrolidines as exemplified by transformation of N-bromo-A-methyl-2-butylaminylpyridine 5 to nicotine (6). The Hofmann-Loffler-Freytag reaction is sometimes referred to as Loffler s method, Hofmann-Loffler reaction, Loffler-Hofmann reaction, as well as Loffler-Freytag reaction. 

This reaction then is exactly analogous to Hofmann s preparation of the corresponding chloro compound from chloroacet-amide.2 Toxicity by injection into mice showed a l.d. 50 of about 60 mg. /kg. 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

Pyridine (and quinoline) which in so many respects are aromatic and comparable to benzene, lose this character completely on hydrogenation to piperidine (and hydroquinoline), which are entirely of the same nature as secondary aliphatic amines. The completely hydrogenated heterocyclic bases undergo degradation reactions which have become important particularly in the investigation of the constitution of alkaloids. A. W. Hofmann s method of opening rings by means of exhaustive methylation may be illustrated with piperidine. By thermal decomposition of the quaternary ammonium base a C—N-link-age is broken and at the same time water is eliminated. 

I) Carbylamlne reaction (III) Hofmann s bromamide reaction (v) Ammonolysis... 

A -Oxides give alkenes via a -elimination under heating. This reaction obeys Hofmann s Rule. 

In this example, 1-pentene and 2-pentene are possible products. The reaction produces almost exclusively 1-pentene, the less highly substituted product. This elimination reaction follows Hofmann s rule ... 

This elimination reaction follows Hofmann s rule, so the less substituted alkene should be the major product. 

Hofmann s rule (Section 9.4) The major product of an elimination reaction has fewer alkyl groups bonded to foe carbons of the double bond (foe less highly substituted product). The Hofmann elimination follows this rule. 

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