Differentiating Toxic and Nontoxic Tricresyl Phosphate Isomers Using Ion-Molecule Reactions with Oxygen

Amiri, Roshanak, Bissram, Meera J, Hashemihedeshi, Mahin, Dorman, Frank L, Megson, David ORCID: https://orcid.org/0000-0002-8881-3860 and Jobst, Karl J (2023) Differentiating Toxic and Nontoxic Tricresyl Phosphate Isomers Using Ion-Molecule Reactions with Oxygen. Journal of the American Society for Mass Spectrometry, 34 (4). pp. 640-648. ISSN 1044-0305

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Abstract

Ortho-substituted isomers of tricresyl phosphates (TCPs) and their toxic metabolites (e.g., CBDP: cresyl saligenin phosphate) can cause neurotoxic effects in humans. When TCP is introduced to an atmospheric pressure chemical ionization source using gas chromatography, radical cations M^•+ are formed by charge exchange. The mass spectrum of an ortho-substituted isomer displays two intense peaks that are absent in the spectra of non-ortho-substituted isomers, leading us to propose structure-diagnostic ion-molecule reactions between ions M^•+ and oxygen species present in the source. However, the mechanisms of these reactions have not yet been established. In this study, we propose a mechanism and provide support through computational and experimental analyses using density functional theory and cyclic ion mobility-mass spectrometry. The mechanism consists of a multistep reaction starting with the rearrangement of the molecular ion into a distonic isomer followed by an oxidation step and then decomposition into [CBDP-H]⁺. This proposal is consistent with the results obtained from a series of isotopically labeled analogues. Cyclic ion mobility experiments with a tri-<i>o</i>-cresyl phosphate standard reveal the presence of at least two hydrogen shift isomers of the product ion [CBDP-H]⁺ that are connected by a low-lying barrier. The selectivity of the ion-molecule reactions toward ortho-substituted cresyl TCP isomers provides us with an identification tool that can select potentially neurotoxic triaryl phosphate esters present in complex mixtures that are produced in large volume by industry.