Nitration secondary amines

Many activations involve compounds which are used as pesticides. In the case of N-nitrosation, the precursors are secondary amines and nitrate. The former are common synthetic compounds and the latter is an anion found in nearly all solid and aqueous phases. The N-nitrosation of a secondary amine [R-NH-R ] occurs in the presence of nitrite formed microbiologically from nitrate. The product is an N-nitroso compound (i.e., a nitrosamine [RR -N-N=0]). The reason for concern with nitrosamines is their potency, at low concentrations, as carcinogens, teratogens, and mutagens. 

Amine. Catalyzed Nitration. A series of papers, on this subject, were published in CanJRes 26B (1948) by the following investigators l)W.J.Chute et al, pp 89-103 (Dinitroxydiethyl-nitramine) 2)G.E.Dunn et al, pp 104-113 (Relative Basicity of Secondary Amines in Acetic Acid) 3)W.J.Chute et al, pp 114-137 (TKff Esse of Nitration Among AlipHatic Secondary Amines) 4)J.C.MacKenzie et al, pp 138-153 (The Role of Electropositive Chlorine in the Nitration of Lysidine) 5)... 

Primary and secondary amines are nitrated by NO2 BF4 in sulfolane or SO2 solution to yield nitramines. 

Figure 1, Nitrosamine Formation from a Secondary Amine and Nitrate in an Acid Environment.

The carcinogenicity of nitrosamines has created widespread concern over the safety of food products that are significant sources of nitrates and nitrites. Nitrosamines are readily formed by reaction of secondary amines with nitrites at acid pH, conditions which may occur in the gastrointestinal tract. 

Inhibition of Nitrosamine Formation. Nitrites can react with secondary amines and A/-substituted amides under the acidic conditions of the stomach to form /V-nitrosamines and A/-nitrosamides. These compounds are collectively called N-nitroso compounds. There is strong circumstantial evidence that in vivo A/-nitroso compounds production contributes to the etiology of cancer of the stomach (135,136), esophagus (136,137), and nasopharynx (136,138). Ascorbic acid consumption is negatively correlated with the incidence of these cancers, due to ascorbic acid inhibition of in vivo A/-nitroso compound formation (139). The concentration of A/-nitroso compounds formed in the stomach depends on the nitrate and nitrite intake. 

Where direct nitration results in degradation, a primary amine can be acylated, nitrated directly to form a secondary niiramine, which is then hydrolyzed to form the primary nitramine as exemplified in the following reaction sequence ... 

With such a diversity of N-nItrosatlon pathways theoretically possible. It Is comforting to note that only a few combinations of circumstances have been Implicated In environmental nitrosamlne formation thus far. Two of these are so facile and prevalent that, as of 20 years ago, they were the only recognized mechanisms of N-nItrosatlon. They Involve the Interaction of di-or trisubstituted ammonia derivatives with a nitrite Ion, as Illustrated In Figure 1 for the secondary amines, under the catalytic Influence of acid. Note the Important special cases of nucleophilic displacement of water from the nitrous acldlum Ion, H20-N0 , by a second nitrite Ion to yield NoOo (as in the reaction at the top of Figure 1), and by nitrate (bottom of Figure... 

N-Nitrosamines, formed principally from the reaction of naturally occurring secondary amines with nitrites that may be added to foods or produced by bacterial reduction of nitrates, have been identified in many food systems including cured meat products, nonfat dried milk, dried malt and beer. In addition, the presence of less volatile and non-volatile N-nitroso compounds or their precursors in foods have been suggested from a number of model system studies. 

The LCM baths use a mixture of nitrate/nitrite eutectic salts. As it contains up to 40% sodium nitrite the salt system is toxic and can cause water pollution, and also cause nitrosation of volatile secondary amines. 

Secondary aliphatic amines, such as diethylamine, pyrrolidine or piperidine, react with the electron-poor nitrate ester 2-(trifluoromethyl)-2-propyl nitrate (369) under neutral conditions to afford the corresponding W-nitro derivatives 370412. 

Pbotolytic. Low et al. (1991) reported that the photooxidation of aqueous secondary amine solutions by UV light in the presence of titanium dioxide resulted in the formation of ammonium and nitrate ions. 

Barton and Narang" have prepared nitrate esters by treating primary and secondary alky-lamines with dinitrogen tetroxide in the presence of an amidine base like DBU. Wudl and Lee " conducted deamination reactions without any amidine base and reported much lower yields of nitrate ester product. The use of an amidine base is not necessary if the amine substrate... 

Nitrations of aromatic amines often involve the intermediate formation of N-nitramines, although these are rarely seen under the strongly acidic conditions of mixed acid nitration (Section 4.5). N,2,4,6-Tetranitro-N-methylaniline (tetryl) is an important secondary high explosive usually synthesized from the nitration of N,N-dimethylaniline or 2,4-dinitro-N-methylaniline. ° The synthesis of tetryl is discussed in Section 5.14. 

Aryloxy groups are much easier to displace compared to primary and secondary alkox-ide anions and so, aryl ethers are generally more useful in displacement reactions. Amine nucleophiles react with unsymmetrical aryl ethers to form the amine of the heavier nitrated moiety.Accordingly, 2,4,6-trinitrodiphenyl ether reacts with ammonia to expel phenoxide... 

The direct nitration of a primary amine to a nitramine with nitric acid or mixtures containing nitric acid is not possible due to the instability of the tautomeric isonitramine in strongly acidic solution (Equation 5.1). Secondary amines are far more stable under strongly acidic conditions and some of these can undergo electrophilic nitration with nitric acid in a dehydrating medium like acetic anhydride. 

If nitration under acidic conditions could only be used for the nitration of the weakest of amine bases its use for the synthesis of secondary nitramines would be severely limited. An important discovery by Wright and co-workers " found that the nitrations of the more basic amines are strongly catalyzed by chloride ion. This is explained by the fact that chloride ion, in the form of anhydrous zinc chloride, the hydrochloride salt of the amine, or dissolved gaseous hydrogen chloride, is a source of electropositive chlorine under the oxidizing conditions of nitration and this can react with the free amine to form an intermediate chloramine. The corresponding chloramines are readily nitrated with the loss of electropositive chlorine and the formation of the secondary nitramine in a catalytic cycle (Equations 5.2, 5.3 and 5.4). The mechanism of this reaction is proposed to involve chlorine acetate as the source of electropositive chlorine but other species may play a role. The success of the reaction appears to be due to the chloramines being weaker bases than the parent amines. 

Unlike the direct nitration of amines under acidic conditions, nucleophilic nitration is an excellent route to both primary and secondary nitramines. In these reactions the amine or the conjugate base of the amine is used to attack a source of NO2. This source may be a nitrogen oxide, nitronium salt, cyanohydrin nitrate, alkyl nitrate ester or any other similar source of nitronium ion. 

More recently, Polish chemists have reported a synthesis of both aryl and aliphatic secondary nitramines by treating amine substrates with ethyl magnesium bromide followed by reaction with n-butyl nitrate (Equation 5.8). This method, which uses nonpolar solvents like hexane or benzene, has been used to synthesize aliphatic secondary nitramines, and At-nitro-A-methylanilines which otherwise undergo facile Bamberger rearrangement in the presence of acid. The direct nitration of At-unsubstituted arylamines usually requires the presence of an electron-withdrawing group. Reactions are retarded and yields are low for sterically hindered amines. 

Ordinarily, alkyl nitrate esters will not nitrate amines under neutral conditions. However, Schmitt, Bedford and Bottaro have reported the use of some novel electron-deficient nitrate esters for the direct At-nitration of secondary amines. The most useful of these is 2-(trifluoromethyl)-2-propyl nitrate, which nitrates a range of aliphatic secondary amines to the corresponding nitramines in good to excellent yields. Nitrosamine formation is insignificant in these reactions. 2-(Trifluoromethyl)-2-propyl nitrate cannot be used for the nitration of primary amines, or secondary amines containing ethylenediamine functionality like that in piperazine. Its use is limited with highly hindered amines or amines of diminished nucleophilicity due to inductive or steric effects. 

Emmons and co-workers prepared a series of aliphatic secondary nitramines by treating amines with a solution of dinitrogen pentoxide in carbon tetrachloride at —30 C (Equation 5.9). The amine component needs to be in excess of two equivalents relative to the dinitrogen pentoxide if high yields of nitramine are to be attained. This is wasteful because at least half the amine remains unreacted. However, yields are high and there is no reason why the amine cannot be recovered as the nitrate salt. The method is particularly useful for the nitration of hindered secondary amines substrates such as those with branching on the a carbon. 

The reaction of dinitrogen pentoxide with primary aliphatic nitramines and amines leads to deamination and the formation of a nitrate ester as the major product. Consequently, dinitrogen pentoxide cannot be used for the synthesis of primary nitramines. In contrast, both primary and secondary arylamines undergo efficient A-nitration with dinitrogen pentoxide in chlorinated solvents. ... 

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