Nitrous acid secondary amines

Nitrosation (Section 22 15) The reaction of a substance usu ally an amine with nitrous acid Pnmary amines yield dia zonium 10ns secondary amines yield N nitroso amines Tertiary aromatic amines undergo nitrosation of their aro matic ring... 

In the aliphatic series, primary amines are deaminated by nitrous acid, secondary aliphatic amines are A-nitrosated, while tertiary aliphatic amines form salts in the acidic medium followed by secondary reactions such as dealkylation [1, 21a, b]. 

Nitrosation of amines is best illustrated by examining what happens when a secondary amine reacts with nitrous acid. The amine acts as a nucleophile, attacking the nitrogen of nitrosyl cation. The intermediate that is formed in the first step loses a proton to give an /V-nitroso amine as the isolated product. 

Nitrosation The reaction of a substance, usually an amine, with nitrous acid. Primary amines yield diazonium ions secondary amines yield A-nitroso amines. Tertiary aromatic amines undergo nitrosation of their aromatic ring. 

With nitrous acid, primary amines are diazotised (equation 58), secondary amines undergo iV nitrosation (section II.C.2.e), and tertiary aliphatic or alicyclic amines fail to react while tertiary aromatic amines may undergo C-nitrosation. 

In Summary Nitrous acid attacks amines, thereby causing N-nitrosation. Secondary amines give Ai-nitrosamines, which are notorious for their carcinogenicity. Ai-Nitrosamines derived from primary amines decompose through SnI or Sn2 processes to a variety of products. Ai-Nitrosation of N-methylamides results in the corresponding N-nitrosamides, which liberate diazomethane upon treatment with hydroxide. Diazomethane is a reactive substance used in the methylesterification of carboxylic acids and as a source of methylene for the cyclo-propanation of alkenes. 

The most important reaction of the diazonium salts is the condensation with phenols or aromatic amines to form the intensely coloured azo compounds. The phenol or amine is called the secondary component, and the process of coupling with a diazonium salt is the basis of manufacture of all the azo dyestuffs. The entering azo group goes into the p-position of the benzene ring if this is free, otherwise it takes up the o-position, e.g. diazotized aniline coupled with phenol gives benzeneazophenol. When only half a molecular proportion of nitrous acid is used in the diazotization of an aromatic amine a diazo-amino compound is formed. 

Secondary amines of both the aliphatic and the aromatic series react similarly with nitrous acid, giving nilrosamines ... 

Secondary amines upon treatment with nitrous acid yield nitrosamiues, which are stable, neutral yellow liquids (or low melting point solids), for example ... 

Secondary and tertiary amines are not generally prepared in the laboratory. On the technical scale methylaniline is prepared by heating a mixture of aniline hydrochloride (55 parts) and methyl alcohol (16 parts) at 120° in an autoclave. For dimethylaniline, aniline and methyl alcohol are mixed in the proportion of 80 78, 8 parts of concentrated sulphuric acid are added and the mixture heated in an autoclave at 230-235° and a pressure of 25-30 atmospheres. Ethyl- and diethyl-anihne are prepared similarly. One method of isolating pure methyl- or ethyl-aniline from the commercial product consists in converting it into the Y-nitroso derivative with nitrous acid, followed by reduction of the nitroso compound with tin and hydrochloric acid ... 

Some reference to the use of nitrous acid merits mention here. Primary aromatic amines yield diazonium compounds, which may be coupled with phenols to yield highly-coloured azo dyes (see Section IV,100,(iii)). Secondary aromatic amines afford nitroso compounds, which give Liebermann a nitroso reaction Section IV,100,(v). Tertiary aromatic amines, of the type of dimethylaniline, yield p-nitroso derivatives see Section IV,100,(vii). ... 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Synthesis. The classic laboratory synthesis of /V-nitrosamines is the reaction of a secondary amine with acidic nitrite [14797-65-0] at ca pH 3. The primary nitrosating intermediate is N2O2 arising from nitrous acid [7782-77-6] (48). 

Cycloaliphatic amines are strong bases with chemistry similar to that of simpler primary, secondary, or tertiary amines. Upon reaction with nitrous acid,... 

Reaction with Nitrous Acid. Primary, secondary, and tertiary aromatic amines react with nitrous acid to form a variety of products. Primary aromatic amines form diazonium salts. ... 

If primary or secondary amines are used, A/-substituted amides are formed. This reaction is called aminolysis. Hydra2ines yield the corresponding hydra2ides, which can then be treated with nitrous acid to form the a2ides used in the Curtius rearrangement. Hydroxylamines give hydroxamic acids. 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

Ring nitrosation with nitrous acid is normally carried out only with active substrates such as amines and phenols. However, primary aromatic amines give diazonium ions (12-47) when treated with nitrous acid, " and secondary amines tend to give N-nitroso rather than C-nitroso compounds (12-49) hence this reaction is normally limited to phenols and tertiary aromatic amines. Nevertheless secondary aromatic amines can be C-nitrosated in two ways. The N-nitroso compound first obtained can be isomerized to a C-nitroso compound (11-32), or it can be treated with another mole of nitrous acid to give an N,C-dinitroso compound. Also, a successful nitrosation of anisole has been reported, where the solvent was CF3COOH—CH2CI2. " ... 

When secondary amines are treated with nitrous acid, N-nitroso compounds (also called nitrosamines) are formed. The reaction can be accomplished with dialkyl-, diaryl-, or alkylarylamines, and even with mono-N-substituted amides RCONHR -I-HONO RCON(NO)R. Tertiary amines have also been N-nitrosated, but in these cases one group cleaves, so that the product is the nitroso derivative of a secondary amine.The group that cleaves appears as an aldehyde or... 

Reaction between secondary amines or amides and nitrous acid... 

With such a diversity of N-nItrosatlon pathways theoretically possible. It Is comforting to note that only a few combinations of circumstances have been Implicated In environmental nitrosamlne formation thus far. Two of these are so facile and prevalent that, as of 20 years ago, they were the only recognized mechanisms of N-nItrosatlon. They Involve the Interaction of di-or trisubstituted ammonia derivatives with a nitrite Ion, as Illustrated In Figure 1 for the secondary amines, under the catalytic Influence of acid. Note the Important special cases of nucleophilic displacement of water from the nitrous acldlum Ion, H20-N0 , by a second nitrite Ion to yield NoOo (as in the reaction at the top of Figure 1), and by nitrate (bottom of Figure... 

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