Nitrosation 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... 

Primary amines. The nitrosation of primary amine type compounds yields small amounts of secondary amine type N-nitroso compound (14, 15, 16). The reaction mechanism is not well understood. 

MS is not the only highly sensitive and selective detection system that can be interfaced with GC. For example, consider another compound class of special safety concern as extractables/leachables, A-nitrosamines.f A-Nitrosamines are formed during mixing and vulcanization of certain types of rubber, by the reaction of various secondary amines with nitrosating agents " and can be found at trace levels (ng/g) in components fabricated from these rubbers. 

The A-nitrosamines are formed from different precursors and under a wide variety of conditions. They can be formed by the reaction of secondary amines with nitrosating agents, such as... 

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. 

Again, abnormal behaviour in nitrosation is observed with certain complex molecules. Thus, pelletierine (42) fails to undergo iV-nitrosa-tion, although it yields the corresponding acetamide and benzam-ide , and on the other hand, the tertiary amine codeine (43) yields iV-nitrosonorcodeine by displacement of the iV-methyl group Analysis of secondary amines via nitrosation is further discussed elsewhere... 

Some recent general reviews deal with the mechanism of N-nitrosation in aqueous solution (345), the nitrosation of secondary amines (346). the effect of solvent acidity On diazotization (347) and the reactivity of diazonium salts (1691). Therefore, a complete rationalization of the reactivity of amino azaaromatics would be timelv. 

Nitrosamines are formed whenever nitrosating agents come m contact with secondary amines Indeed more nitrosamines are probably synthesized within our body than enter it... 

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). 

Secondary aromatic amines form /V-nitrosamines and tertiary aromatic amines undergo ring nitrosation to yield C-nitroso products. 

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

W-Nitroso amine (Section 22.15) A compound of the type R,N—N=0. R may be alkyl or aryl groups, which may be the same or different. A-Nitroso amines are formed by nitrosation of secondary amines. 

A number of benzodiazepines have heterocyclic rings anne-lated to them. One such is the tranquilizer midazol am (94). Nitrosation (HONO) of secondary amine leads to the ] -nitroso analogue Nitrosoamidines, in the presence of carbanions,... 

Research into the mechanism of diazotization was based on Bamberger s supposition (1894 b) that the reaction corresponds to the formation of A-nitroso-A-alkyl-arylamines. The TV-nitrosation of secondary amines finishes at the nitrosoamine stage (because protolysis is not possible), but primary nitrosoamines are quickly transformed into diazo compounds in a moderately to strongly acidic medium. The process probably takes place by a prototropic rearrangement to the diazohydroxide, which is then attacked by a hydroxonium ion to yield the diazonium salt (Scheme 3-1 see also Sec. 3.4). 

Schmolukowski in 1917, a diffusion-controlled bimolecular reaction in solution at 25 °C can reach a value for th second-order rate constant k as high as 7 x 109 m 1s-1. Nitrosations of secondary aliphatic amines also have rates which are relatively close to diffusion control (see Zollinger, 1995, Sec. 4.1). 

It is appropriate to add here some comments on diazotization in anhydrous carboxylic acids. They may be relevant for the diazotization of heteroaromatic amines carried out in acetic acid/propionic acid mixtures (Sec. 2.2). Extensive studies by Casado et al. (1983, 1984) showed that in nitrosation of secondary amines the nitrosyl ion, nitrosyl acetate, and dinitrogen trioxide are formed, and all three may act as nitrosating agents. The results do not, however, account for the considerable improvement that is claimed in the patent literature (Weaver and Shuttleworth, 1982) to result from the addition of carboxylic acids in the diazotization of heteroaromatic amines. 

There is no reference to the formation of the ortho nitroso amine in the benzene series, indeed the formation and characterisation of ortho nitroso amines from any reaction has only been reported once or twice79. When the para position is blocked by a substituent, de-nitrosation so the secondary amine can occur80 a certain amount (which depends on the conditions) of denitrosation occurs also, concurrently with the rearrangement81, so that N-nitroso-N-methylaniline (XLVII) yields N-methylaniline (XLVIII) as well as the rearrangement product p-nitroso-N-methylaniline XLIX, viz. 

LI. On the basis of the evidence of trans-nitrosation and on the apparent specific catalysis by hydrochloric acid, a mechanism first proposed by Houben85 has become generally accepted 8 86,87. This involves a reversible de-nitrosation forming the secondary amine and nitrosyl chloride followed by C-nitrosation in ... 

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... 

In classical organic chemistry, nltrosamlnes were considered only as the reaction products of secondary amines with an acidified solution of a nitrite salt or ester. Today, it is recognized that nitrosamines can be produced from primary, secondary, and tertiary amines, and nltrosamides from secondary amides. Douglass et al. (34) have published a good review of nitrosamine formation. For the purposes of this presentation, it will suffice to say that amine and amide precursors for nitrosation reactions to form N-nitroso compounds are indeed ubiquitous in our food supply, environment, and par-... 

Safe" secondary amines resulting in non-carcinogenic N-nitroso compounds after nitrosation (German Patent Application No P 3029 318 6)... 

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