Secondary amines and nitrous acid

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. 

We have seen that Af-nitroso compounds are formed from secondary amines and nitrous acid ... 

Since the synthesis of N-nitroso compounds is accomplished through reaction of secondary amines and nitrous acid, it was demonstrated that nitrosamines could be produced biochemically by the naturally acidic conditions in the stomach with ingestion of secondary amines (2). The nitrosating agent would be formed by the reaction of gastric juice with nitrite compounds that are widely used as food preservatives and for food color enhancement (2). Vitamin C was found to be a potent inhibitor of this reaction (I). 

Nitrosamines, which are the amides of nitrous acid, are more stable and are derived from secondary amines with nitrous acid. iV-nitrosamides are substances which have a carbonyl group attached to a nitrogen-bearing NO group, e.g. iV-nitrosamides, iV-nitrosocarbamates and /V-nitrosoLireas see Figure 10. 

Amino groups possessing replaceable hydrogen atoms react with nitrous acid. The tertiary amines are not affected, except for the formation of a salt (nitrite). Secondary amines with nitrous acid yield nitrosoamines. The nitrosoamine can be easily reduced back to the secondary amine by zinc and acid. 

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. 

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 ). 

Recently [35a] it has been found that, contrary to common belief, tertiary aliphatic amines react with aqueous nitrous acid to undergo dealkylation to form a carbonyl compound, a secondary nitrosoamine, and nitrous oxide. Base-weakening groups markedly reduce nitrosative cleavage, and quaterniza-tion prevents it completely. Several examples of this reaction are shown in Table II. 

Reaction between secondary amines or amides and nitrous acid 5-30 Addition of NOC1 to olefins... 

Reaction CXXIV. Action of Nitrous Acid on Secondary Amines, and subsequent Rearrangement of the Products. 

A kinetic study has been reported recently for the nitrosation of many symmetrical tertiary amines in aqueous acid-acetate buffers (Gowenlock et al., 1979). One experimental difficulty in tertiary amine nitrosations generally is that the reactions are much slower than for the analogous secondary amines, and are more conveniently studied at a higher temperature, typically 75°C, where the decomposition of nitrous acid is quite rapid. In this study, rate constants were obtained from the less accurate method of initial rate measurements. Nevertheless, for acidities less than pH 3.1, rate eqn (16) was established. The acid dependence is complicated by the protonation of the... 

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). 

Nitrosamine and para Nitroso Methyl Aniline.—The reaction with nitrous acid is characteristic of secondary amines and yields phenyl methyl nitrosamine, the nitroso group entering the amino radical. This, however, undergoes rearrangement with the transference of the nitroso group to the ring yielding a nitroso benzene compound. 

Treatment of a primary aliphatic amine with nitrous acid or its equivalent produces a diazonium Ion which results in the formation of a variety of products through solvent displacement, elimination and solvolysis with 1,2-shift and concurrent elimination of nitrogen. The stereochemistry of the deamination-substitution reaction of various secondary amines was investigated as early as 1950, when an Swl-type displacement was suggested. Thus, the process can hardly be utilized for the preparation of alcohols except in cases where additional factors controlling the reaction course exist. Deamination-substitution of a-amino acids can be utilized for the preparation of chiral alcohols. 

The nitrosation of several secondary and tertiary amines can be blocked in vitro by the addition of vitamin C. The vitamin appears to compete for the nitrite, thus inhibiting nitrosation. It has been demonstrated that vitamin C does not react with amines, nor does it enhance the rate of nitrosamine decomposition. However, it reacts very rapidly with nitrite and nitrous acid. It has been suggested that the vitamin decreases the available nitrite by reducing nitrous acid to nitrogen oxides, leading to inhibition of the nitrosation reaction ... 

Tert-Amines - sec-amines.1 When a tertiary amine in pyridine is shaken with 2-nitropropane and CuCl under oxygen, it is converted into a nitrosamine (5), which can be isolated in yields of 15-65% and then reduced to a secondary amine. The reaction proceeds through oxidation to an amine oxide (2) with conversion of (1) into 2-nitro-2-propanol (3). This decomposes into acetone and nitrous acid. The nitrous acid traps the secondary amine formed from the amine oxide (2) after rearrangement to the carbinolamine (4). It is noteworthy that even... 

Nitroso derivatives are valuable for characterizing secondary amines and can be used as starting points for the synthesis of A,iV-disubstituted hydrazines. Nitrosamines are usually prepared by the action of nitrous acid on aliphatic... 

The reaction which takes place between dimethylamine and nitrous acid is of importance, as it is an example of a general reaction used to distinguish secondary amines from the other classes of amines. Nitrous acid reacts with dimethylamine and forms a substance which belongs to the class known as nitroso compounds —... 

The behavior of aromatic amines with nitrous acid is characteristic. The reagent serves to distinguish not only primary, secondary, and tertiary amines from one another, but aromatic amines from aliphatic amines in the case of primary and tertiary compounds. 

In this process, 3° alcohols react faster than 2° alcohols. Heterolytic bond cleavage of a halide or sulfonate ester (C-X, X = Br, Cl, I, OMs, OTs, etc.) in aqueous solvents (usually with heating) generates tertiary cations easily, secondary alcohols with difficulty, and primary cations with extreme difficulty. Reaction of aldehydes and ketones with an acid catalyst gives the oxygen-stabilized cation (see 1 and 4). Reaction of amines with nitrous acid (HNO2) initially gives a diazonium salt (5, also see sec. 13.9.B) but alkyl diazonium salts readily decompose to cations. ... 

This reaction has been applied in the determination of secondary amines, and their mixtures with other classes of amines. Although the latter react with nitrous acid in a different way (sections II.C.IO and II.F.3) the one-to-one stoichiometry is preserved. The determinations can be carried out by direct titration of the organic sample with standardised sodium nitrite back titration of the excess reagent or by measuring the nitrosamine... 

Tertiary amines are degraded to secondary amines by a combination of an organic hydroperoxide and nitrous acid the reagent fulfilling both requirements, 2-nitroprop-2-yl hydroperoxide, is prepared by catalysed oxygenation of 2-nitropropane. Reaction with tertiary amines proceeds as shown in Scheme 111, the secondary amine produced being trapped as its jV-nitroso-derivative by the generated nitrous acid. 

The Behavior of Amines Towards Nitrous Acid is also occasionally of value to differentiate between the three classes of amines. In these reactions, primary amines behave somewhat differently from the secondary aminos. Ammonia also reacts, and, indeed, we have here simply an example of the method of preparing nitrogen which was studied in inorganic chemistry. 

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 ... 

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