Nitrites, reaction with amines

Thiocyanate, an anion normally secreted in human saliva, also catalyzes the nitrosation of amines by nitrite (22). The mechanism of the reaction is thought to proceed through the formation of nitrosylthiocyanate and subsequent reaction with amine to form the nitrosamine. This reaction, originally investigated to assess the... 

Since nitrosamines and their precursors are present in the food, exposure to nitrosamines cannot be avoided. Flowever, recent studies have shown that ingestion of adequate quantities of vitamin E and selenium may reduce the risk of cancer. It is known that carcinogenic nitrosamines are formed from the reaction of some amines with nitrites and nitrates present in the diet. Vitamin E and selenium have been found to minimize or prevent the reaction of nitrites/ nitrates with amines and hence prevent or reduce the formation of carcinogenic nitrosamines. 

The brown color of old meat is the result of oxidation of blood and is objectionable to many consumers. Nitrites and nitrates are added to food to retard this oxidation and also to prevent growth of botulism bacteria. Nitrate ions, N03, are reduced to N02 ions, which are then converted to NO. This in turn reacts with the brown oxidized form of the heme in blood. This reaction keeps meat red longer. Controversy has arisen, however, concerning the possibility that nitrites combine with amines under the acidic conditions in the stomach to produce carcinogenic nitrosoamines. 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alky] nitrite (jsoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and IIT36. 

Nitrosamines are readily produced from the reaction of amines with nitrous acid, i.e., acidified nitrite (3), and are also produced vivo when amines and nitrite are administered, as reflected by tumor induction [reviewed in (3)], and the in vivo appearance of nitrosamines (2> ) Challis and Kyrtopoulos (5) showed that gaseous NO2 reacts directly with amines in neutral or alkaline aqueous solutions to produce nitrosamines and nitramines. The kinetics of the extremely rapid reaction of... 

A strain of Escherichia coli produces a naphthotriazole from 2,3-diaminonaphthalene and nitrite that is formed from nitrate by the action of nitrate reductase. The initial product is NO, which is converted by reactions with oxygen into the active nitrosylating agent that reacts chemically with the amine (Ji and Hollocher 1988). A comparable reaction may plausibly account for the formation of dimethylnitrosamine by Pseudomonas stutzeri during growth with dimethylamine in the presence of nitrite (Mills and Alexander 1976) (Figure 2.2f). 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Inhibitors of nitrosation generally function by competing with the amine for the nitrosating agent. An inhibitor would thus react with nitrite at a faster rate than with amines. The inhibition reaction has recently been reviewed ( 35). The ability of ascorbate to act as a potent inhibitor of nitrosamine formation has resulted in the use of the vitamin in nitrite-preserved foods and pharmaceuticals. Furthermore, the effectiveness of ascorbate in inhibiting nitrosamine formation is dependent on (1) the concentration of ascorbate (an excess is required) (2) pH (ascorbate is nitrosated 240 times more rapidly than ascorbic acid) (3) the reactivity of the amine toward nitrosation and (4) the extent of oxygenation of the system. 

Nitration of the amine (139) with mixed acid yields the energetic nitramine (140). The same reaction with sodium nitrite in sulfuric acid, or with nitrosyl fluoride in methylene chloride, yields the nitrosamine (141), which is also an energetic high explosive. ... 

In Table 1 is a list of the environmental secondary and tertiary amines which have been tested by feeding to rats together with nitrite. Of these, several react very readily with nitrite in acid solution, but some, for example phenmetrazine (2 , 27), give rise to a noncarcinogenic N-nitroso derivative. On the other hand, aminopyrine reacts extremely readily with nitrous acid, although it is a tertiary amine, and forms the potent carcinogen nitrosodimethylamine in high yield (28, ). The other amines vary considerably in the extent to which they form N-nitroso derivatives by reaction with nitrous acid, especially at the relatively low concentrations which model human exposure more closely... 

Other, more sensitive, tests have been suggested for the evaluation of potential carcinogenic risk of exposure to chemicals. These include the bacterial mutagenesis test devised by Dr. Bruce Ames ( ). This test has been applied to many of the amines listed in Table 1, both alone and after reaction with nitrite in weakly acid solution, followed by neutralization and application to the bacteria. In Table 3 are given the results of a number of such tests, together with comparison of the results of chronic... 

---