Low‐energy collision‐induced dissociation of sildenafil thiono analogues: gas‐phase intramolecular nucleophilic substitution through ion‐neutral complexes between a cationic substrate and a thione‐containing neutral nucleophile

Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs

“…The MS-MS spectrum on the protonated molecular ion of thiosildenafil recorded on an ion trap mass spectrometer in our laboratory differs from the one recorded on a triple quadrapole mass spectrometer by Zou et al [17], but is practically identical to the spectrum recorded on an ion trap instrument by Lee [19].…”

“…The sildenafil product ion at m/z 377 results from fragmentation of the S-N sulfonamide bond with a hydrogen transfer, and the other sildenafil product ions listed in Table 1 are also devoid of the piperazine ring moiety [3,9,15,18]. Major product ions from compound 1 (thiosildenafil) are 30 Da higher than those seen in sildenafil (Table 1), 16 mass units attributed to the presence of a thioketone instead of a ketone and 14 mass units resulting from migration of the methyl group on the piperazine nitrogen atom to the thiocarbonyl sulfur atom, a phenomenon that has been previously reported [19]. On the other hand, the major product ions in compound 2 are 16 Da higher than those from sildenafil (Table 1), which supports the replacement of an oxygen atom with sulfur, and further indicates that the additional mass of 14 Da in compound 2 is in the piperazine moiety of the molecule, which is lost during fragmentation, and that there is no alkyl group on the piperazine nitrogen atom with which to migrate.…”

Direct intramolecular gas‐phase transfer reactions during fragmentation of sildenafil and thiosildenafil analogs in electrospray ionization mass spectrometry

“…In the current study, the fragmentation of seven sildenafil and thiosildenafil related compounds are compared in order to establish the fragmentation pathways for these compounds. As previously observed, 11 N-alkyl migration to the sulfur atom of a thiocarbonyl analog does occur. However, data presented in this paper will demonstrate that a direct intramolecular transfer reaction is geometrically feasible and is more compatible with certain fragmentation patterns than an ion-neutral complex mechanism.…”

“…An interesting phenomenon occurs during collision-induced dissociation (CID) of the sulfur analogs of sildenafil -an alkyl group migrates from the nitrogen atom in the piperazine ring to the sulfur atom of the thiocarbonyl group. This phenomenon was first reported by Lee et al, 11 who investigated the fragmentation pattern of thiosildenafil compounds by ESI-MS and clearly demonstrated that an N-methyl or N-ethyl group on the piperazine ring of a thiosildenafil compound migrates to the sulfur atom on the pyrimidine ring, a phenomenon that reportedly is not observed in their corresponding oxygen analogs. These authors 11 recognized that the interatomic distance between the N-alkyl carbon atom and the sulfur atom was too large for an intramolecular transfer to occur.…”

“…This phenomenon was first reported by Lee et al, 11 who investigated the fragmentation pattern of thiosildenafil compounds by ESI-MS and clearly demonstrated that an N-methyl or N-ethyl group on the piperazine ring of a thiosildenafil compound migrates to the sulfur atom on the pyrimidine ring, a phenomenon that reportedly is not observed in their corresponding oxygen analogs. These authors 11 recognized that the interatomic distance between the N-alkyl carbon atom and the sulfur atom was too large for an intramolecular transfer to occur. To rationalize the N-alkyl migration to sulfur, they proposed the formation of an ion-neutral complex followed by a transfer of the alkyl group from one pair of the complex to the other.…”