Formation and Non Formation of Nitrosamine

Nitrosamine

Nitrosamine or more specifically n-nitrosamine refers to a molecule containing the nitroso functional group (R-N=O). Any compound containing the secondary amine functional group is expected to react with nitrosating agents to produce nitrosamine. These molecules are of concern because nitrosamine impurities are probable human carcinogens.

Formation of Nitrosamines

• Presence of Secondary Amines: Nitrosamines are formed when secondary amines, which contain a lone pair on the nitrogen atom, react with nitrosating agents. The lone pair on the nitrogen is crucial for the reaction, as it allows the formation of the nitroso functional group (R-N=O).

• Concentration and Reactivity: The likelihood and extent of nitrosamine formation depend on several factors, including the concentration of the secondary amine and the nitrosating agent present. Additionally, the structural characteristics of the amine can influence the reaction rate, determining how readily nitrosamines are formed.

• Environmental Conditions: Certain environmental conditions, such as pH level and temperature, can also influence the formation of nitrosamines. These conditions can affect the reactivity of the amines and the nitrosating agents, potentially facilitating or hindering the formation process.

Reaction 

Why Nitrosamines Do Not Form on Amide Groups?

Electron-Withdrawing Properties: Amides contain a carbonyl group (C=O) attached to the nitrogen. This carbonyl group has electron-withdrawing properties, which reduce the reactivity of the nitrogen's lone pair. Essentially, the electron density around the nitrogen is decreased, making it less likely to engage in reactions with nitrosating agents.

Lower Reactivity: Due to the electron-withdrawing effect of the carbonyl group, amides exhibit significantly lower reactivity towards common nitrosating agents compared to secondary amines. This diminished reactivity is why nitrosamine impurities are not typically formed from amide groups.

 Why nitrosamines do not form on Imidazole ?

Imidazole is a five-membered aromatic molecule containing two annular nitrogen atoms. Both nitrogen atom of imidazole are part of the aromatic ring the nitrogen NH group is secondary amine, but it is non-basic in nature as the lone pair of electrons is part of the aromatic structure.

For a non-basic nitrogen it is difficult or not possible to form nitrosamine, and if it does, it cannot have the same carcinogenic mechanism as other typical nitrosamines.

Imidazole's unique structure, especially the involvement of its nitrogen's lone pair in the aromatic system, makes it an exception in terms of basicity and reactivity compared to more conventional secondary amines. These differences significantly reduce the likelihood of nitrosamine formation and suggest a divergent potential mechanism for carcinogenicity, setting imidazole and its derivatives apart from the typical concerns associated with nitrosamines.

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