Nitrosation tertiary amine

The reaction of aromatic amines with nitrous acid is of considerable importance and the formation of diazonium salts from the primary amines is discussed in detail in Section 8.6. Reaction of nitrous acid with secondary amines does not give diazonium salts, but results instead in A -nitrosation. Tertiary amines such as A, A -dimethylaniline do not N-nitrosate, but undergo electrophilic substitution by the nitrosonium cation (NO ) to give A, A -dimethyl-4-nitrosoaniline (Scheme 8.8). 

Butler recently reviewed the diazotization of heterocyclic amines (317). Reactions with nitrous acid yield in most cases N-exocyclic compounds. Since tertiary amines are usually regarded as inen to nitrosation, this... 

Tertiary alkylamines illustrate no useful chemistry on nitrosation Tertiary aryl-amines undergo nitrosation of the ring by electrophilic aromatic substitution... 

Fluoroaromatics are produced on an industrial scale by diazotization of substituted anilines with sodium nitrite or other nitrosating agents in anhydrous hydrogen fluoride, followed by in situ decomposition (fluorodediazoniation) of the aryldiazonium fluoride (21). The decomposition temperature depends on the stabiHty of the diazonium fluoride (22,23). A significant development was the addition of pyridine (24), tertiary amines (25), and ammonium fluoride (or bifluoride) (26,27) to permit higher decomposition temperatures (>50° C) under atmospheric pressure with minimum hydrogen fluoride loss. 

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... 

The mechanism of nitrosation is essentially the same as in 12-47 up to the point where 33 is formed. Since this species cannot lose a proton, it is stable and the reaction ends there. The attacking entity can be any of those mentioned in 12-47. The following has been suggested as the mechanism for the reaction with tertiary amines ... 

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-... 

Precursors and Formation. Tobaccos used for commercial products in the U.S.A, contain between 0,5 and 2,7% alkaloids. Nicotine constitutes 85-95% of the total alkaloids (14,26,27). Important minor alkaloids are nornicotine, anatabine, anabasine, cotinine and N -formylnornicotine (Figure 6), Several of these alkaloids are secondary and tertiary amines and, as such, amenable to N-nitrosation. The N-nitrosated alkaloids identified to date in tobacco and tobacco smoke include N -nitrosonornico-tine (NNN), 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) and N -nitrosoanatabine (NAT Figure 7). In model experiments, nitrosation of nicotine also yielded 4-(methylnitrosamino)-4-(3-pyridyl)butanal (NNA 28). 

We thus assume, that the biochemical processes during tobacco curing may be different from the ui vitro N-nitrosation of secondary and tertiary amines (30). 

Prevention of nitrosamine formation in other important commercial dinitroanilines such as trifluralin, benefin, isopropalin, profluralin, ethalfluralin and other tertiary amines is approached first eliminating sources of nitrosating agents from the reaction mixture prior to amination. 

R3N—N=0, but this then readily undergoes C—N fission to yield relatively complex products. With aromatic tertiary amines, ArNR2, nitrosation can take place not on N but at the activated p-position of the nucleus (cf. p. 137) to yield a C-nitroso compound ... 

Tertiary amines. Tertiary amine type compounds, react with nitrous acid to yield secondary-amine type N-nitroso compounds. The myth that tertiary amines do not nitrosate to yield N-nitroso compounds, is a remarkable feat of misinformation that has persisted for over 100 years (23, 24, 25). 

The mechanism for the N-nitrosation of tertiary amines assumes that the un-... 

The first clues that compounds of structure I might be involved in nitrosamine-forming reactions came during the study of tertiary amine nitrosations. Smith and Loeppky had proposed ( ) in their detailed, classical investigation of the mechanism of this reaction that the first steps involve nitrosammonium ion formation followed by elimination of nitroxyl (HNO). The resulting immonium ion was postulated to hydrolyze to the secondary amine, which reacted with nitrosating agent to form the observed product. These mechanistic proposals are summarized in Fig. 2a. 

Figure 2. Nitrosative dealkylation of tertiary amines (a) mechanism postulated by Smith and Loeppky (2) (b) composite of proposals by Lijinsky et al. (S) and...

The Smith-Loeppky mechanism [2) convincingly rationalized much of what was known about tertiary amine nitrosations. However, there was some evidence in the literature that there might be more to the mechanistic story. For one thing, it was not clear why the nitrosation of tertiary amines should have a higher pH optimum than that of secondary amines (2). Even more troubling was the somewhat controversial later report by Mai ins (15) that dimethylnitrosamine formed at pH 6 more readily from trimethyl amine than from dimethyl amine. If that report is correct, then free dimethylamine and the corresponding ammonium ion could not be the only kinetically significant intermediates in the trimethyl amine nitrosation. 

A similar mechanism was invoked by Ohshima and Kawabata (2) to account for their results in the nitrosation of tertiary amines and amine oxides. In applying these concepts to the nitrosative dealkylation of tetraalkyltetrazenes, Michejda al. 5) introduced an interesting variant by suggesting that immonium ions could be formed in two successive one-electron oxidation steps (for example by ferric ion oxidation of tertiary amine to the radical cation followed by radical abstraction of a hydrogen atom from the alpha position), rather than exclusively through the one-step removal of a hydride ion as nitroxyl. The resulting immonium ion was again considered to react directly with nitrite to produce the N-nitroso derivative. These reactions are summarized in Fig. 2b. 

Thus the postulate that a-amino nitrite esters could form and fragment to nitrosamines has provided a useful construct for explaining some aspects of the nitrosative dealkylation of tertiary amines and their derivatives. 

Assuming that the above rationale for tertiary amine nitrosation was valid, we predicted 3) that the reaction of secondary amines with nitrite at milder pH s should be catalyzed by electrophilic carbonyl compounds, since secondary amines are known to form immonium ions on admixture with appropriate aldehydes and ketones. The prediction turned out to be true. Formaldehyde was shown to promote nitrosamine formation from a... 

Lijinsky, W. Keefer, L. Conrad, E. Van de Bogart, R. Nitrosation of tertiary amines and some biologic implications. J. Natl. Cancer Inst.. 1972, (5), 1239-1249. 

As a result of our previous work on the scope and mechanism of tertiary amine nitrosation (X), we became interested in the behavior of N-alkylaziridines toward nitrous acid. Possible modes of reaction are illustrated in Scheme 1. The operation of either path A or C would be consistent with our previous studies of oxidative dealkylation of tertiary amines (1 ), while pathway B would be akin to the observed cheleotropic transformation of N-nitroso-aziridines (2). 

Since nicotine is the major precursor to NNN in tobacco and tobacco smoke, the reaction of nicotine with sodium nitrite was studied to provide information on formation of other tobacco specific nitrosamines, especially NNK and NNA, which could arise by oxidative cleavage of the l -2 bonds or l -5 bond of nicotine followed by nitrosation (26). The reaction was investigated under a variety of conditions as summarized in Table I. All three nitrosamines were formed when the reaction was done under relatively mild conditions (17 hrs, 20 ). The yields are typical of the formation of nitrosamines from tertiary amines (27). At 90 , with a five fold excess of nitrite, only NNN and NNK were detected. Under these conditions, both NNK and NNA gave secondary products. NNK was nitrosated a to the carbonyl to yield 4-(N-methyl-N-nitrosamino)-2-oximino-l-(3-pyridyl)-1-butanone while NNA underwent cyclization followed by oxidation, decarboxylation and dehydration to give l-methyl-5-(3-pyridyl)pyrazole, as shown in Figure 4. Extensive fragmentation and oxidation of the pyrrolidine ring was also observed under these conditions. The products of the reaction of nicotine and nitrite at 90 are summarized in Table II. 

Lijinsky, W., Keefer, L., Conrad, E., van de Bogard, R., "Nitrosation of Tertiary Amines and Some Biologic Implications",... 

Chemists have long been aware that amines can react with various nitrosating agents, under a variety of conditions, to form a wide array of N-nitroso derivatives (1 ). It was generally assumed that only secondary amines can effectively form stable N-nitrosamines. However, it has now become apparent that primary and tertiary amines, as well as tetraalkylammonium salts, can all form N-nitroso derivatives under the appropriate reaction conditions (2-10). It has also become apparent that there are several mechanisms possible for the formation of the most common N-nitroso derivatives. Thus, in addition to the more customary reaction of an amine with nitrous acid, N-nitroso derivatives can also form via the reaction of an amine with NO (NO2, N2O3, N2O4) ( ). Amines can also be transnitrosated with already formed N-N-nitroso or C-nitro compounds via a transnitrosation reaction, they can be converted into their N-nitroso derivatives ). 

Many pharmaceutical products on the market contain primary, secondary, and/or tertiary amines or amine derivatives, and several drugs have been shown to readily form N-nitroso compounds when nitrosated in vitro and/or in vivo (27-33). With the exception of aminopyrine in Germany (23) and the antibiotic studied by Schoenhard et, (26), there appears to be no information available with regard to the possible presence of N-nitroso impurities present in pharmaceutical products. 

As indicated above, tertiary aromatic amines are directly C-nitrosated. The usual reagents are sodium nitrite and dilute hydrochloric acid, sodium nitrite and glacial acetic acid containing concentrated hydrochloric acid, and nitrite esters with hydrochloric acid [21a, 27]. While tertiary amines with such complex alkyl groups as found in A,A-di(3,5,5-trimethylhexyl)aniline are readily nitrosated [25], of the four A-butyl-A-methylaniline isomers, JV-r-butyl-A-methylaniline does not undergo the reaction, and even the nitroso compounds which did form were only unstable oils [27]. 

The nitrosation of phenols proceeds in a manner similar to that of tertiary amines. For example, l-nitroso-2-naphthol has been prepared from the sodium salt of /9-naphthol by treatment with sodium nitrite and sulfuric acid near 0°C [29], This general procedure, suitably modified, has been used to prepare other nitrosophenols such as p-nitrosophenol (m.p. 135°-136°C) [30]. 

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