Amides, nitrosated

Caprolactam is an amide and, therefore, undergoes the reactions of this class of compounds. It can be hydrolyzed, Ai-alkylated, O-alkylated, nitrosated, halogenated, and subjected to many other reactions (3). Caprolactam is readily converted to high molecular weight, linear nylon-6 polymers. Through a complex series of reactions, caprolactam can be converted to the biologically and nutritionally essential amino acid L-lysine (10) (see Amino acids). 

The nitrosation of amides may also be carried out with nitrosyl chloride.2 Related methods of deamination of aliphatic amines are the triazene3 and nitrous acid methods4... 

Nitrosation, of amides with dinitrogen tetroxide, 47, 46 of N phenylglycine, 46, 96 p-Nitrosodimethylamhne, reaction with o nitrobenzylpyndimum bro mide, 46,82... 

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... 

The N-nitrosation of these amides was subsequently studied as a function of pH and temperature (78). There was no apparent pH maximum for the reaction, N-nitrosamide formation increasing with increasing hydrogen ion concentration. The rates of N-nitrosation decreased rapidly as the pH increased and little reaction occurred above pH 3. A unit drop in pH from 2 to I increased the rate of N-nitrosation by a factor of 5-8 times. 

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-... 

Under appropriate conditions, they are readily N-nitrosated. The authors tentatively concluded that the major contribution of N-substituted amides, if they were present in foods, could be as precursors of N-nitroso compounds formed by vivo N-nitrosation reactions ... 

Hard evidence for the first category seems to be nonexistent. An educated guess on the potential hazards would combine residue technology [how much of a secondary amine (or amide, urea, carbamate, etc.) might a person consume or otherwise be exposed to ], nitrosation chemistry (what would be the yield of in vivo nitrosation of the pesticide thus consumed ), and toxicology (what would be the toxicological effect and potency of the nitroso compound thus formed ). Frequently, these questions, which simplify to, "What dose—eg., in mg/kg—of a pesticide-derived nitroso compound might a person be exposed to and what would be the result if he were " are not carefully considered. 

Furoxanes 321 can be prepared from amide oximes in one step by nitrosation of hydroxylamines in the presence of H2S04 (Equation 70) <2002RCB1504>. 

Nitrosation of primary amides results in deamination to produce carboxylic acid and nitrogen as products. Secondary amides, when nitrosated, give the corresponding nitrosamides in a reversible process [51]. In order to obtain good yields of the nitrosamides, it is best to add a base to remove the acid formed (Scheme 3.2). This reaction also occurs with ureas and carbamates. 

The nitrosation of amides, such as methylurea and methylurethane, follows the kinetic expression ... 

The main nitrosating agent is probably nitrous acidium ion (NO OH2+). There is no simple rule, as there is for secondary amines, relating the ease of nitrosation to the properties of the amide. 

Of numerous other preparations for which nitrile oxides have been invoked as intermediates, one of the most synthetically useful is that developed by Shimizu et al. which employs alkyl esters of a-nitroalkanoic acids as precursors <87BCJ1948). The method is suitable for aliphatic, amide, and ester derivatives, and involves themolysis in an inert solvent to generate the nitrile oxide with con-commitant expulsion of carbon dioxide and alkanol. Other reactions leading to furoxans via nitrile oxides include treatment of a-bromo-a-nitrotoluene with triphenylphosphine <84TL2029), nitrosation... 

Nitrosamine formation is not the only conceivable fragmentation mechanism for compounds of structure I. By analogy to the nitrosative dealkylation reactions discussed above, one might predict that such compounds could also undergo cis elimination of nitroxyl in amide-forming reactions. Such a transformation has possibly been observed (14). During an attempt to synthesize the nitrosamino aldehyde VIII from immonium ion IX, Hecht coworkers were able to isolate only 5-10% of the desired product. The major product proved to be N-methyl-2-pyrrolidone, as shown in Fig. 10. We interpret this as evidence that an intermediate such as li can fragment not only by the Fig. 1... 

In view of the various possible pathways for nitrosation of amines as well as of amine derivatives (amides, ureas, carbamates, etc. ), it is not unexpected then for N-nitroso compounds to be found in many different areas of the human environment (11). It is possible that N-nitroso compounds may represent a carcinogenic exposure which most people experience on a daily basis. The list of items that have now been demonstrated to have measurable levels of various N-nitroso compounds present within them has grown considerably over the past decade (, 11, 12). A portion of this list would include air, water, soil, cheese, meats, fish, eggs. 

The total amount of 1750 ml. of acetic acid is necessary to dissolve the amide completely at lower temperatures. With less acetic acid, it is difficult to secure complete nitrosation, even with very efficient stirring of the suspension. 

General Procedure for Nitrosation of Amides with Dinitrogen Tetroxide. . 439... 

The nitrosation products of amides have been studied extensively. 

Five methods for the nitrosation of amides will be mentioned here. Of these, the methods using dinitrogen tetroxide appears to have the widest applicability in terms of the classes of amides which can be nitrosated and the purity of the products obtained. However, the other methods also have special utility. 

---