A -Nitrosoamines

Meroquinenine, CgHjjOaN (meroquinene), formed by the oxidation of all four alkaloids and of cinchoninone or quininone and by the hydrolysis of quinenine or cinchenine (p. 489), crystallises from methyl alcohol in needles, m.p. 223-4° (dee.), [ajp -f- 27-5° (H2O). It gives a nitrosoamine, m.p. 67°, and a monoacetyl derivative, m.p. 110°, and can be esterified the ethyl ester hydrochloride has m.p. 165°. When oxidised by chromic acid it yields formic and cincboloiponic acids. On reduction with zinc dust and hydriodic acid, it adds on two atoms of hydrogen forming cincholoipon, CgH jOaN, and when heated with hydrochloric acid at 250-60° gives 3-ethyl-4-methylpyridine ()3-collidine). 

A characteristic property of most diazotizations of aminoazoles is the occurrence of a relatively stable transient intermediate (probably the A-nitrosoamine), in contrast with the diazotization of carbocyclic aromatic amines, where A-nitrosoamines have been considered to be unstable intermediates. This problem will be discussed in the context of the mechanism of diazotization in Section 3.4. 

In Sections 3.1 to 3.3 the discussion of the mechanism of diazotization concentrated on the rate-determining part of the reaction which, in most cases, does not include steps occurring after the formation of the A-nitrosoamine. The various pathways of nitrosation are summarized in Scheme 3-35. The transformation of the N-nitrosoamine will be discussed in Section 3.4. 

In principle, the intermediates obtained under these conditions could have the structure of a nitrosoamine such as 3.12, but they could also be one of the isomers, namely a (Z)- or (ii)-nitrosoimine (3.14 or 3.15, respectively), or a (Z)- or (ii)-diazo-hydroxide (3.16 or 3.17, respectively). Analogous isomers exist, of course, for other nitrosation products of heteroaromatic amines. 

The N-diazeniumdiolates are quite photosensitive. Studies of various 02-substi-tuted compounds, both alkyl and aryl, revealed a primary photochemical reaction involving cleavage of the N=N bond to yield a nitrosoamine and an O-substituted nitrene which rearranges to a C-nitroso compound (Scheme 3.31), the latter is often isolated as the oxime [224]. 

More recently, other A-nitrosoamines of heteroaromatic compounds were obtained and characterized by the groups of Butler and of Stepanov102. Therefore, at least the nitrosoamine 33 does appear to be reasonably well documented as an intermediate on the pathway to the diazonium ion. A more extended review on the intermediates of Scheme 7 was published recently7 . 

Secondary amines are converted into the corresponding A-nitrosoamines in high yield (-90%) by sodium nitrite and ALchloro- or A-bromosuccinimide under liquiddiquid two-phase conditions in the presence of lipophilic quaternary ammonium salts [41]. There is evidence that nitrosyl chloride is initially formed, which reacts with the nitrite ion to generate N204. Hydrophilic ammonium salts do not promote the formation of N204 and the final products are the A-haloamines. 

One of the best-knbwn methods for the preparation of aromatic nitroso compounds is the Fischer-Hepp rearrangement of A-nitrosoamines (Eq. 2). In effect, this reaction is the C-nitrosation of secondary aromatic amines. 

Since the neutralization reaction of an amine with nitrous acid may be presumed to be instantaneous while the nitrosation of an amine proceeds at a slower rate, further investigations would be of interest to elucidate the problem of whether nitrite salt formation is a necessary preliminary step to the formation of iV-nitrosoamines or whether the covalent product forms independently. In the latter case, there would be competitive reactions of significantly different reaction rates and mechanisms. The yield of A-nitrosoamines may be influenced by the extent to which the more water-soluble nitrite salts may be present in the course of a preparation. 

Unlike primary amines, secondary amines have an extra R group instead of the tautomeric proton. No tautomer can form. Notice from the diazotization reaction above that, if the A-nitrosoam.ine can t make a tautomer, the reaction will be stopped at the iV-nitrosoamine. When nitrous acid is added to a secondary amine, the product is an A/ -nitrosoamine. 

All three mononuclear amines and 3-amino-2,1-benzisothiazole can be diazotized and coupled to form azo dyes (see Section 4.02.3.5), but 3-amino-1,2-benzisothiazole reacts with nitrous acid to give 3,3 -bis(l,2-benzisothiazoline) (72AHC(14)43), and 5-aminoisothiazoles bearing an electron-withdrawing group at the 4-position form A-nitrosoamines (72AHC(14)1). 

R—N=N. This procedure is called diazotization of an amine. Diazonium salts are the most useful products obtained from the reactions of amines with nitrous acid. The mechanism for diazonium salt formation begins with a nucleophilic attack on the nitrosonium ion to form an A-nitrosoamine. 

Part 1 Attack on the nitrosonium ion (a strong electrophile), followed by deprotonation, gives an A-nitrosoamine. 

Reaction with Secondary Amines Formation of IV-Nitrosoamines Secondary amines react with the nitrosonium ion to form secondary A-nitrosoamines, sometimes called nitrosamines. 

Secondary A-nitrosoamines are stable under the reaction conditions because they do not have the N—H proton needed for the tautomerism (shown in Mechanism 19-6 with a primary amine) to form a diazonium ion. The secondary A-nitrosoamine usually separates from the reaction mixture as an oily liquid. 

Small quantities of A-nitrosoamines have been shown to cause cancer in laboratory animals. These findings have generated concern about the common practice of using sodium nitrite to preserve meats such as bacon, ham, and hot dogs. When the meat is eaten, sodium nitrite combines with stomach acid to form nitrous acid, which can convert amines in the food to A-nitrosoamines. Because nitrites are naturally present in many other foods, it is unclear just how much additional risk is involved in using sodium nitrite to preserve meats. More research is being done in this area to evaluate the risk. 

Acid-catalysed condensation of 1,3-indanedione with a nitrosoaminopyrimidine gives a new pyrazine ring—a type of cyclization sometimes known as the Timmis synthesis. Another indanedione derivative, 2,2-dihydroxy-1,3-Indanedione, condenses with a nitrosoamine with even better results and without the need for acid to be present. 

B-14. Which compound yields an A-nitrosoamine after treatment with nitrous acid (NaN02, HCl) ... 

Pseudoeoniceine is a product of the dehydration of pseudoconhydrine with phosphoric anhydride (191). It is a strongly basic, colorless oil, b.p. 171-172°, d4 0.8776, [ ] + 122.6°, which forms salts (Table 3). It reduces potassium permanganate readily and on treatment of its hydrochloride with nitrous acid gives rise to a nitrosoamine so that it is an unsaturated secondary amine. It readily absorbs hydrogen iodide with the formation of an iodoconiine hydriodide, m.p. 182°, which is different from the derivative obtained by the direct action of fuming hydriodic acid on pseudoconhydrine since the hydriodide of the latter melts at 216-217°. Pseudoeoniceine when reduced either via its iodo derivative (191) or... 

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