We report a collision-induced dissociation (CID) based gas phase rearrangement study using quadrupole time-of-flight mass spectrometry coupled with liquid chromatography on a novel endothelin and angiotensin II receptor antagonist, sparsentan. We performed tandem mass spectrometry to identify precursor and fragment ion relationships and assigned structures for major fragment ions. We propose a benzyl migration mechanism based on bond length measurements in density functional theory (B3LYP/6-31+G*) optimized geometries of protonated sparsentan and its m/z 547 fragment. Protonated sparsentan undergoes loss of ethanol, which yields a resonance-stabilized benzylic cation with m/z 547, which further fragments into m/z 353 via benzyl migration, where the benzylic cation migrates to one of the nucleophilic nitrogen atoms followed by proton transfer from the sulfonamide nitrogen to a carbonyl oxygen, resulting in a neutral loss of mass 194. Further fragmentation of m/z 353 results in m/z 258, which undergoes radical and neutral loss to yield m/z 193 and 194, respectively. The proposed mechanism of generation of m/z 353 was confirmed by CID of deuterated sparsentan. Considering the importance of gas phase rearrangements of organic molecules in structural identifications as well as the novelty of the molecule, these findings will be helpful for future studies to predict gas phase benzyl migration in sparsentan analogs and for degradation product and metabolite identification of sparsentan and its analogs using LC-MS.
Keywords: benzyl migration; collision-induced dissociation; density functional theory; sparsentan.
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