Nitrosamines synthesis

The occurrence and determination of aliphatic amines have received a great deal of attention in recent years [42-44]. These foul-smelling compounds have been found in a number of ambient environments [45-47] and become a source of serious social and psychological problems. They are also involved in nitrosamine synthesis in air [48], because methylamines react with nitrogen oxides (NO ) and O2. 

Liu, R.H., Jacob, J.R., Tennant, B.D., Hotchkiss, J.H. (1992). Nitrite and nitrosamine synthesis by hepatocytes isolated from normal woodchucks (Marmota monax) and woodchucks chronically infected with woodhuck hepatitis vims. Cancer Res. 52,4139-4143. 

Synthesis. The classic laboratory synthesis of /V-nitrosamines is the reaction of a secondary amine with acidic nitrite [14797-65-0] at ca pH 3. The primary nitrosating intermediate is N2O2 arising from nitrous acid [7782-77-6] (48). 

Biochemical Functions. Ascorbic acid has various biochemical functions, involving, for example, coUagen synthesis, immune function, dmg metabohsm, folate metaboHsm, cholesterol cataboHsm, iron metaboHsm, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting direcdy with nitrites, and consequently may potentially reduce cancer risk. 

Evidence exists that the relative solubility of amines and inhibitors in heterogeneous oil-water systems could be decisive in formation of nitrosamines and blocking these reactions, Nitrosopyrrolidine formation in bacon predominates in the adipose tissue despite the fact that its precursor, proline, predominates in the lean tissue (5,6,7). Mottram and Patterson (8) partly attribute this phenomenon to the fact that the adipose tissue furnishes a medium in which nitrosation is favored, Massey, et al, (9) found that the presence of decane in a model heterogeneous system caused a 20-fold increase in rate of nitrosamine formation from lipophilic dihexylamine, but had no effect on nitrosation of hydrophilic pyrrolidine. Ascorbic acid in the presence of decane enhanced the synthesis of nitrosamines from lipophilic amines, but had no effect on nitrosation of pyrrolidine. The oil-soluble inhibitor ascorbyl palmitate had little influence on the formation of nitrosamines in the presence or absence of decane. 

Commercially produced amines contain Impurities from synthesis, thus rigid specifications are necessary to avoid unwanted Impurities In final products. Modern-day analytical capability permits detection of minute quantities of Impurities In almost any compound. Detection In parts per million Is routine, parts per billion Is commonplace, and parts per trillion Is attainable. The significance of Impurities In products demands careful and realistic Interpretation. Nltrosatlng species, as well as natural amines, are ubiquitous In the environment. For example, Bassow (1976) cites that about 50 ppb of nitrous oxide and nitrogen dioxide are present In the atmosphere of the cities. Microorganisms In soil and natural water convert ammonia to nitrite. With the potential for nitrosamine formation almost ever-present In the envlronmeit, other approaches to prevention should Include the use of appropriate scavengers as additives In raw materials and finished products. 

As described 1 Eizember and Vogler (1980), many inorganic halides are effective in removal and destruction of nitrosamine impurities during in the synthesis of dinitroanilines. Nitrosamine destruction occurs during the synthesis of oryzalin and fluchloralin. Structures of oryzalin and fluchloralin are shown. 

The nitrosation of oximes can also serve to produce N-hydroxy-N-nitrosamines (Scheme 3.9). The acidified nitrite procedure can be applied to oximes derived from terpenes [132] and hydroxyguanidine [133] for the synthesis of N-hydroxy-N-nitrosamines. However, some a, 5-uri saturated oximes were converted into pyrazole-1,2-dioxides [134]. The alkyl nitrites under basic conditions have produced interesting results. Quinone dioximes yielded only monodiazeniumdiolates [135], while simple aliphatic oximes gave products resulting from addition to the imine double bond... 

There are several routes for nitrosamine contamination in pesticides use of contaminated chemicals during synthesis, side reactions, use of nitrite as a preservative and corrosion inhibitor of metal containers and by reactions with environmental nitrosating agents. Over 300 formulations were shown to be contaminated with nitrosamines however, the main contamination was confined to 2,6-dinitroaniline herbicides, dimethylamino salts of phenoxyalkanoic acid herbicide, diethanolamine and triethanolamine salts of acid... 

Other reagents have been used for the direct nitration of amines under nonacidic conditions. Mandel reported the synthesis of methylnitramine, dimethylnitramine and diisopropy-Initramine from the reaction of nitryl fluoride with the parent amine. The presence of an excess of amine appears to be of prime importance given that other reports give the nitrosamine as a major by-product. 

The high performance nitramine explosive known as CL-20 (5) has been synthesized via a two-stage nitrolysis starting from the key intermediate (83). The first stage uses dinitrogen tetroxide or nitrosonium tetrafluoroborate for nitrosolysis. The second step, involving nitrolysis of the acetamide and nitrosamine bonds, is achieved with nitronium tetrafluoroborate (>90 %) or mixed acid at 75 °C to 80 °C (93 %). The synthesis of CL-20 is discussed in more detail in Chapter 6. 

Krimmel and co-workers ° have reported the synthesis of 2,4,6-tris(trifluoromethyl)-l,3,5-trinitro-l,3,5-triazacyclohexane (123) from the nitrolysis of the nitrosamine (122). 

In view of the highly carcinogenic nature of many nitrosamines any experiments involving their isolation must be discouraged, and for this reason, this section has only been written for completeness. This high toxicity is unfortunate because the preparation of nitrosamines from the parent amines is often facile and they provide a route to highly pure nitramines. Other equally useful methods for the synthesis of nitramines, such as the chloride-catalyzed nitration of secondary amines, also suffer from the formation of nitrosamines in appreciable amounts and must also be viewed with caution. 

Strategies used for the synthesis of polyazapolycyclic-caged nitramines and nitrosamines are the subject of an excellent review by A. T. Nielsen. Nielsen identified three routes to such compounds "... 

Reactions of the Nitroso Group. Up until recently, the chemistry of N-nitrosamines was restricted to the reaction involving the nitroso group. It was not until the usefulness of N-nitros-amines in synthesis [concept of "Umpolung (3.)] was demonstrated, that the long-known denitrosation of N-nitrosamines became impor-... 

The second part will report on the hydrolysis of a -acetoxy N-nitrosamines and the consequenses thereof. Finally the attempted synthesis of -phosphates of N-nitrosamines and their relationship to the thermal behavior of a -functionalized N-nitrosamines will be discussed. 

Since 1971, we have been engaged in the synthesis of g-substituted dialkyl N-nitrosamines, namely -hydroxy N-nitrosamines. Because of the presumed high reactivity of these alcohols, it seemed desirable to have them in a stabilized form, e.g. as esters. In 1970 Franck and his group reported a method to convert tertiary amines into dialkyInitrosamines in the presence of 2-nitropropane, cuprous ion and oxygen 9). If the amine is substituted with different alkyl groups, these groups are cleaved statistically (Eq. 1). 

In 1972, Eiter and his group reported the synthesis of a-alkoxy dialkyl N-nitrosamines (11),which can be obtained easily in 20-50 g quantities. This synthetic scheme works well when formaldehyde was used. In those cases when higher aliphatic aldehydes are used (e.g. acetaldehyde), the yields decreased to 3-5%. The a -alkoxy dialkyInitrosamines always contained the trimeric paraldehyde as impurity. When acetaldehyde and... 

Although a number of problems remains to be solved, the method seems to offer promise for the synthesis of protected glucosides and glucuronides of a -hydroxy-lated nitrosamines. 

The g-amino nitrosamines however, also defied isolation in the pure state and, hence, they were isolated as the corresponding ureas. The synthesis of the ureas was accomplished in several steps starting with the ester of an appropriate N-nitrosamino acid (here illustrated by N-nitrososarcosine) (10). 

Roller, P.P., Shimp, D.R. and Keefer, L.K., "Synthesis and Solvolysis of Methyl (acetoxymethy 1) nitrosamine. Solution Chemistry of the Presumed Carcinogenic Metabolite of Dimethylnitros-amine". Tetrahedron Letters, 1975, 2065-2068. 

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