Nitroso compounds Tertiary

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 ... 

Tertiary aliphatic - aromatic amines, unlike those of the aliphatic series, react with nitrous acid with the formation of G-nitroso compounds the nitroso group enters almost exclusively in the para position if available, otherwise in the ortho position. Thus dimethylaniline yields />-nitrosodiniethylaniline ... 

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). ... 

Dimeric nitroso compounds with tertiary alkyl groups show more tendency toward dissociation into the monomers. For example, 2-methyl-2-nitrosopropane is so volatile in the form of the monomer that it can hardly be isolated from organic solvents. For the prepara-... 

All attempts to isolate primary and secondary nitroso compounds result only in the formation of oximes. Tertiary nitroso compounds, however, are stable. Explain. 

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-... 

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 ... 

Alkyl and aryl C-nitroso compounds contain a nitroso group (-N=0) directly attached to an aliphatic or aromatic carbon. As compounds with a nitroso group attached to a primary or secondary carbon exist primarily as the oxime tautomer, the stable examples of C-nitroso compounds contain nitroso groups attached to tertiary carbons, such as 2-methyl-2-nitroso propane (1, Fig. 7.1) or nitroso groups attached to carbons bearing an electron-withdrawing group (-CN, -N02, -COR, -Cl, -OAc, Fig. 7.1). Oxidation of alkyl and aryl hydroxylamines provides the most direct route to alkyl and... 

Apart from rare exceptions, the only nitroso-compounds known are those in which the NO-group is united to a tertiary carbon atom, as in nitrosobenzene. Nitrosoisobutane (H3C)3 C.NO, for example, is a representative from the aliphatic series. 

Aliphatic nitro compounds exhibit rather different behavior from nitroaromatic compounds. Secondary and primary nitro compounds tend to produce oximes because the intermediate nitroso compound quickly tautomerizes to the oxime (equation 1). Under aprotic conditions the radical anions of primary and secondary nitro compounds are relatively stable those derived from tertiary nitro compounds, on the other hand, eject nitrite ion relatively readily (equation 2)8. 

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 reaction of tertiary amine oxides with nitrous acid has also been shown to produce N-nitroso compounds. The mechanism for the amine oxides is similar to that for the tertiary amines (26). 

Aliphatic nitro compounds with the nitro group on a tertiary carbon were reduced to amines with aluminum amalgam [146 or iron [559]. 2-Nitro-2-methylpropane afforded ferf-butylamine in 65-75% yield [146. Even some secondary nitroalkanes were hydrogenated to amines. fra s-l,4-Dinitrocy-clohexane was converted to frans-l,4-diaminocyclohexane with retention of configuration. This may be considered as an evidence that the intermediate nitroso compound is reduced directly and not after tautomerization to the isonitroso compound [560] (see Scheme 54). 

Tertiary and aromatic nitroso compounds are not readily accessible consequently not many reductions have been tried. Nitrosobenzene was converted to azobenzene by lithium aluminum hydride (yield 69%) [592], and o-nitrosobiphenyl to carbazole, probably via a hydroxylamino intermediate, by treatment with triphenylphosphine or triethyl phosphite (yields 69% and 76%, respectively) [298]. Nitrosothymol was transformed to amino-thymol with ammonium sulfide (yield 73-80%) [245], and a-nitroso-/J-naphthol to a-amino-/J-naphthol with sodium hydrosulfite (yield 66-74%) [255]. 

Tertiary and aromatic nitroso compounds react with aryl Grignard or aryl-lithium reagents giving the corresponding hydroxylamines . This reaction is useful for preparation of alkyl- and aiylhydroxylamines (e.g. 109, equation 80 and 110, equation 81) and can be considered as complementary to arylation of hydroxy lamines with activated aryl halides. It has been used for functionalization of cyclophanes with the hydroxy amino group. The main limitation of the reaction is the relatively restricted choice of available aliphatic nitroso components, so most of reactions were done with 2-nitroso-2-methylpropane. There is no literature data about the possibility of removal of the tert-butyl group from these compounds. 

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. 

The situation with regard to aliphatic nitroso compounds was confused by the observation that oximes were frequently isolated from nitrosation reactions. In fact, many oximes were called isonitroso compounds. Until the middle 1950s, without adequate experimental evidence, it was generally believed that only tertiary aliphatic nitroso compounds (which obviously could not rearrange to oximes) had reasonable stability. More recent work has shown that a wide variety of aliphatic nitroso compounds can be produced and that they exhibit adequate stability. It was also discovered that many nitroso compounds are dimeric in nature. 

The field of reductive preparations for the formation of nitroso compounds has not yet been adequately explored. For example, only indirect evidence exists that the electrolytic reduction of f-nitroalkanes to tertiary alkyl-hydroxylamines proceeds by way of nitroso compounds. 

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]. 

It is natural to presuppose that the reduction of nitro compounds should lead to the nitroso compounds, at least as an intermediate stage. Until quite recently, no reductive processes for the formation of nitrosoalkanes were known [3], More recently, some indirect evidence is said to show that, on electrolytic reduction of tertiary aliphatic nitro compounds, the final t-alkyl-hydroxylamines are produced by the intermediate formation of nitroso compounds which were not isolated [99]. 

On treatment of certain other tertiary aromatic amines with nitrous acid, it has been found that either C-nitroso compounds, nuclear nitro compounds, or jV-nitrosoamines are formed with loss of an alkyl group. In the case of the nitrodimethylanilines, the latter two types of reaction may occur. The formation of nitro-jV-nitrosomethylanilines predominate at room temperature, whereas the formation of polynitro compounds predominates at more elevated temperatures. The formation of nitrosoamines from iVW-dimethylanilines appears to be particularly favored when both ortho positions are occupied by nitro groups, although /V-nitroso compounds were also obtainable from other nitrodimethylanilines. The product of the reaction, of course, is an /V-nitroso secondary amine. 

Treatment of aliphatic active methylene compounds with such reagents normally leads to oxime formation. An exception is the nitrosation of compounds with active tertiary carbon atoms such as ethyl isopropyl ketone which are convertible into C-nitroso compounds. 

The nitrosation of aliphatic carbon atoms, particularly of carbon atoms activated by adjacent carbonyl, carboxyl, nitrile, or nitro groups, has been reviewed in great detail [2]. Judging from this review, with few exceptions, nitrosation of active methylene compounds leads to the formation of oximes (unfortunately termed isonitroso compounds in the older literature). The few exceptional cases cited in which true nitroso compounds (or their dimers) were formed involved tertiary carbon atoms in which no hydrogen atoms were available to permit tautomerism to the oxime or involved a reaction which was carried out under neither acidic nor basic conditions. 

Nitroso Compounds Primary and secondary aliphatic C-nitroso compounds are usually unstable and rearrange to oximes or dimerize. Tertiary and aromatic nitroso compounds are reasonably stable, existing as monomers in the gaseous phase or in dilute solution and as dimers in neat samples. Monomeric, tertiary, aliphatic nitroso compounds show N=0 absorption in the 1585-1539 cm1 region aromatic monomers absorb between 1511 and 1495 cm-1. 

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