19.25:
2° Amines to N-Nitrosamines: Reaction with NaNO2
Secondary amines—including alkyl and aryl—upon treatment with NaNO2 and a strong acid yield secondary N-nitrosamines.
Recall that an acidified solution of NaNO2 generates HNO2. The unstable HNO2 further undergoes protonation and subsequent dehydration to form the nitrosonium ion—an electrophile.
The nitrosyl cation, generated in situ, is attacked by the nucleophilic secondary amines to form an N-nitrosammonium ion.
The ion, upon deprotonation by solvent molecules, results in the formation of secondary N-nitrosamines.
Unlike primary N-nitrosamines—derived from primary amines—secondary N-nitrosamines are stable because the absence of the N–H proton prevents further tautomerism and eventual diazonium formation.
They usually separate as oily liquids from the reaction mixture.
In general, secondary N-nitrosamines have rare synthetic applications. However, many of them are known carcinogens found in processed food or tobacco.
19.25:
2° Amines to N-Nitrosamines: Reaction with NaNO2
Secondary amines react with nitrous acid to form N-nitrosamines, as depicted in Figure 1. Nitrous acid, a weak and unstable acid, is formed in situ from an aqueous solution of sodium nitrite and strong acids, such as hydrochloric acid or sulfuric acid, in cold conditions. In the presence of an acid, the nitrous acid gets protonated. The subsequent loss of water results in the formation of the electrophile known as nitrosonium ion.
Figure 1. The nitration reaction of secondary amines
The secondary amine acting as a nucleophile reacts with the nitrosonium ion to give another ion known as the N-nitrosammonium ion. The resulting ion is then deprotonated by water to form secondary N-nitrosamines. This mechanism of the reaction is illustrated in Figure 2. The secondary N-nitrosamines are separable from the reaction mixture as oily yellow liquids.
Figure 2. The mechanism of nitration followed by dehydration
Usually, secondary N-nitrosamines are less significant for commercial use. However, they are studied due to their potent carcinogenic properties. In Norway (1962), an outbreak of food poisoning in sheep was attributed to nitrite-treated fish meal. Sodium nitrite is used to preserve various types of food and meat. In the stomach, they react with stomach acid to form nitrous acid. The nitrous acid then reacts with secondary amines in the food to give highly carcinogenic N-nitrosamines. For this reason, the usage of sodium nitrite has been limited by FDA to 50 to 125 ppm in meat preservation. N-nitrosamines are also found in cigarette and tobacco smoke.