Many N-nitrosamines are strictly regulated by environmental and health guidelines due to their carcinogenic nature. Additionally, N-nitrosamines belong to a group of compounds classified by pharmaceutical industry as potentially mutagenic impurities (PMIs). They are occasionally produced when amines react with a nitrosating agent, such as nitrous acid, during the manufacturing of pharmaceutical products. Therefore, reliable and sensitive methodology for the detection and identification of the N-nitrosamino functionality in compounds in complex mixtures is desirable. This issue was addressed by developing a tandem mass spectrometry method based on diagnostic functional-group selective ion-molecule reactions in a linear quadrupole ion trap mass spectrometer. N-nitrosamine model compounds were protonated via positive ion-mode atmospheric pressure chemical ionization. 2-Methoxypropene (MOP) (introduced directly into the ion trap through an external reagent manifold) was found to react with protonated N-nitrosamines in a diagnostic manner via elimination of a 2-propenol molecule. A feasible mechanism for the formation of the diagnostic product ion, [M + H+ + MOP - CH3C(=CH2)OH]+, is proposed based on quantum chemical calculations. All monofunctional and most polyfunctional compounds containing the N-nitrosamine functionality were observed to form this diagnostic product ion with MOP. Three false negative cases were observed for polyfunctional analytes, two of which were due to the compounds containing a more basic functional group than the N-nitrosamino group. This results in protonation of that more basic group instead of the N-nitrosamino group, which prevents the diagnostic reaction. To further evaluate the selectivity of the diagnostic ion-molecule reaction, a variety of protonated analytes containing different functional groups were tested, including carboxylic acids, hydroxylamines, sulfoxides, sulfones, amines and N-oxides. Two false positive results, 2-methoxycarboxylic acid and methyl phenyl sulfoxide, were observed. However, these can ruled out based on their elemental compositions as they do not contain nitrogen.

Identification of the N-nitrosamino functionality by using tandem mass spectrometry based on diagnostic gas-phase ion-molecule reactions

ACS Fall 2021

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