Exhaustive methylation, amine

Chemical Properties. Reactions of quaternaries can be categorized iato three types (169) Hoffman eliminations, displacements, and rearrangements. Thermal decomposition of a quaternary ammonium hydroxide to an alkene, tertiary amine, and water is known as the Hoffman elimination (eq. la) (170). This reaction has not been used extensively to prepare olefins. Some cycHc olefins, however, are best prepared this way (171). Exhaustive methylation, followed by elimination, is known as the Hoffman degradation and is important ia the stmctural determination of unknown amines, especially for alkaloids (qv) (172). 

The preparation of an alkene 3 from an amine 1 by application of a /3-elimination reaction is an important method in organic chemistry. A common procedure is the Hofmann elimination where the amine is first converted into a quaternary ammonium salt by exhaustive methylation. Another route for the conversion of amines to alkenes is offered by the Cope elimination. 

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. 

The open-chain unsaturated tertiary amine is again exhaustively methylated and its quaternary ammonium base, in its turn, decomposed as before. 

Problem 18.30 Deduce the structures of the following amines from the products obtained from exhaustive methylation and Hofmann elimination, (a) C,H jN (A) reacts with 1 mol of CH,I and eventually yields propene. (6) CjHjjN (B) reacts with 2 mol of CHjI and gives ethene and a 3° amine. The latter reacts with 1 mol of CH,I and eventually gives propene. 

Problem 18.58 An optically active amine is subjected to exhaustive methylation and Hofmann elimination. The alkene obtained is ozonized and hydrolyzed to give an equimolar mixture of formaldehyde and butanal. What is the amine ... 

The present preparation of methylenecyclohexane is an example of an amine oxide pyrolysis. This route from amines to olefins in many cases yields pure olefins where the alternative method, the Hofmann exhaustive methylation reaction, is accompanied by some rearrangement to more stable isomeric olefins. 

With amines, the first step is generally exhaustive methylation. 

Silver hydroxide is used in exhaustive methylation, a process often utilised in order to obtain an unsaturated cyclic hydrocarbon from an amine by treating it with methyl iodide aud silver hydroxide the triniethyl-ammonium hydroxide obtained is then decomposed by distillation. 

Antihistaminics, being tertiary amines, are analysed after reaction with an analogous reagent [566] with pentafluorobenzyl chloroformate a derivative is formed with a high ECD response and good GC properties, e.g., on OV-17. Hucker and Miller [567] subjected amitriptyline and other tertiary amines to exhaustive methylation and analysed the products from the reaction (Hoffman). Whereas the initial substances gave considerable tailing on 3% of QF-1, the derivatives provided sharp and symmetric peaks. 

An amino group can be converted to a good leaving group by exhaustive methyla-tion, which converts it to a quaternary ammonium salt that can leave as a neutral amine. Exhaustive methylation is usually accomplished using methyl iodide. 

For example, when butan-2-amine is exhaustively methylated, converted to the hydroxide salt, and heated, elimination takes place to form a mixture of but-l-ene and but-2-ene. 

Hofmann elimination of exhaustively methylated butan-2-amine. The most stable conformation of the C2—C3 bond has no proton on C3 in an anti relationship to the leaving group. Along the Cl —C2 bond, however, any staggered conformation has an anti relationship between a proton and the leaving group. Abstraction of a proton from Cl gives the Hofmann product. 

Predict the major products formed when the following amines undergo exhaustive methylation, treatment with Ag20, and heating. 

Thermal decomposition of quaternary ammonium salts and bases is most valuable in structural investigations of amines, particularly heterocyclic secondary amines (Hofmann exhaustive methylation). The course of the elimination (A or B) is determined by the nature of the four alkyl groups on the nitrogen atom. The reaction has found little use in the synthesis of pure olefins. The yields are low even when three of the alkyl groups are methyl radicals. Carbon-skeleton rearrangement does not occur. Thus, the only olefin obtained by pyrolysis of pinacolyltri-methylammonium hydroxide, (CHj),CCH(CHj)N(CHj)j OH, is /-butylethylene (50%). ... 

Apart from the reactions of diazonium salts, a number of other reactions are known in which the C-N bond is broken. The best known of these is the Hofmann elimination of quaternary ammonium hydroxides (Scheme 2.37). An amine is converted by methylation with methyl iodide to the quaternary ammonium salt ( exhaustive methylation ). The iodide, on treatment with moist silver oxide, forms the quaternary ammonium hydroxide which undergoes a bimolecular elimination to form an alkene. The bimolecular elimination of onium salts yields the least alkylated alkene. This substitution pattern is determined by the ease with which a hydrogen atom can be attacked by the base. 

The formation of quaternary ammonium salts, followed by an elimination of the kind just described, is very useful in the determination of the structures of certain complicated nitrogen-containing compounds. The compound, which may be a primary, secondary, or tertiary amine, is converted into the quaternary ammonium hydroxide by treatment with excess methyl iodide and silver oxide. The number of methyl groups taken up by nitrogen depends upon the class of the amine a primary amine will take up three methyl groups, a secondary amine will take up two, and a tertiary amine only one. This process is known as exhaustive methylation of amines. 

The alkylation of amines (including polyamines formed by reduction of polypeptides) was a highly popular method of derivatization in peptide chemistry before the appearance of contemporary mass-spectro-metric techniques for analysis of nonvolatile compounds (FFAB, MALDI, etc.). Direct alkylation of amines by alkyl halides (Hoffman reaction) can lead to the final nonvolatile ammonium salts and, hence, other soft reagents must be used. For example, exhaustive methylation can be provided by the mixtures CH20/NaBH4/H+ or CH20/formic add. 

In 1851, A.W. Hofmann discovered that when trimethylpropylammonium hydroxide is heated, it decomposes to form a tertiary amine (trimethylamine), an olefin (propene), and water. Widespread use of this transformation did not occur until 1881, when Hofmann applied this method to the study of the structure of piperidines and nitrogen-containing natural products (e.g., alkaloids). " The pyrolytic degradation of quaternary ammonium hydroxides to give a tertiary amine, an olefin and water is known as the Hofmann elimination. The process involves three steps 1) exhaustive methylation of the primary, secondary or tertiary amine with excess methyl iodide to yield the... 

An example of a reaction that shows this latter regiochemistry is the Hofmann exhaustive methylation, which is sometimes called, rather ambiguously, the Hofmann degradation (this is a term best avoided, because it is sometimes also used to describe the Hofmann rearrangement). In this reaction, an amine is methylated with methyl iodide until the quaternary ammonium iodide is formed. This is then treated with moist silver oxide to convert the iodide to the hydroxide. Write out the final elimination step that occurs on heating. 

Hofmann exhaustive methylation The treatment of an amine with excess methyl iodide to form the quaternary ammonium iodide, which is then converted into the hydroxide by treatment with moist silver oxide on heating in an aqueous or alcoholic solution, it decomposes to give an alkene. Also called the Hofmann degradation. 

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