Aromatic nitrogen "Is it possible for aromatic nitrogen to convert nitrosamine?"- Indole

Dear All,

Nice to discuss to you all about nitrosamines. Today like to keep point regarding aromatic nitrogen “Is it possible for aromatic nitrogen to convert nitrosamine?” Specially Indole.


Is any research article or possibility formation N-Nitrosamine impurities from Indole (Aromatic, Heterocyclic, organic compound) compound with Nitrating agent like Nitromethane at acidic condition.

Note: Indole is a planar molecule and follows Huckel’s rule [(4n+2) π electrons ]. All atoms in indole are sp2 hybridized and each of them possesses one unhybridized p-orbital.

Please check and need to discuss.

Thanks and Regards,
Dr. Dinkar Gagare


Please find the similar request regarding N-Nitroso Melatonin.
Ref: AI for en Indole struktur (N-Nitroso melatonin) - #4 by Amanda

According to European Medicines Agency
12 October 2023; EMA/451665/2023
Page-2: Potency categorisation approach does not apply to N-nitrosamines where the N-nitroso group is attached to a nitrogen within a hetero aromatic ring (e.g., nitrosated indole).

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It can nitrosate, but the resulting nitroso-compound is not a nitrosamine.
Please check Redirecting, Fig.8.


According to the article below, indoles do not form nitrosamines in acidic media in the presence of nitrites, but only 1Hindazole-3-carboxaldehyde.

RSC Adv., 2018, 8, 13121
An optimized procedure for direct access to 1Hindazole- 3-carboxaldehyde derivatives by
nitrosation of indoles†

Arnaud Chevalier, Abdelaaziz Ouahrouch, Alexandre Arnaud,
Thibault Gallavardin * and Xavier Franck


Depends on what you are calling the aromatic nitrogen. Molecules like indole, are extremely well known to form nitrosamines. So, may be you can see that if the nitrosation would destroy the aromaticity of the ring, then nitrsamine will not form. If you google, N-nitrosoindole, you will find a lot of data. The most famous example is Nitroso-tryptophan, which is present in beer and other drinks. Similarly N-nitroso imidazole derivatives are well known. By the way, CPCA does not apply to these. You will need to do a true read-across and find a surrogate.


Thank you for your example-based response.

Does a compound’s having aromaticity have the ability to reject a nitration reaction or the creation of nitrosamine?

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Dinkar, I think you are mixing up nitrosation and nitration. These are two different reactions and should not be mixed up. It is difficult to say anything without knowing what you are looking for.


The conditions for the formation of N-nitrosoindoles are extremely specific, therefore, for a drug manufacturing process such as wet granulation, it is unlikely.
What do you think in this context?


I agree. But the weird thing is that we know so little about the mechanism of nitrosation in solid matrix that we are seeing in finished products, as if we have stepped in a mine field.
So it may be good to check one time if the nitroso-indole is formed it is formed, especially if the pH falls a bit low druing the granulation. However, one has to remember that nitroso-indole is a different class and should not mixed up with nitrosamines. All the current publications on nitrosamines do not apply to it.


Thank you for your comprehension and clarification.I was considering the case no. 1 below and the aromaticity relationship for “Indole compounds”:

Case 1: Nitrosation is a process that converts organic compounds into nitroso derivatives.

Case 2: Nitration is a chemical process that replaces one or more hydrogen atoms in a compound with one or more nitro groups.

Sir, If in the API amine group is present, no nitro group involved in any excipients, but water contains nitrates & nitrites within acceptable limit, then is there any chance of formation of nitrosamines in the finished formulation?