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

Abstract

A study is made of the mass spectral fragmentation pathways of sildenafil, thiosildenafil, and analogous compounds. A prominent gas-phase reaction that occurs during collision-induced dissociation (CID) of thiosildenafil compounds is the transfer of an alkyl group from the piperazine nitrogen atom to the sulfur atom of the thiocarbonyl group. This phenomenon is clearly demonstrated through a comparison of electrospray ionization mass spectral fragmentation patterns of four sildenafil-type compounds and three related thiosildenafil derivatives. Molecular modeling and fragmentation patterns support a direct intramolecular alkyl transfer mechanism rather than an ion-neutral complex mechanism. CID of thiohydroxyhomosildenafil results in a facile hydroxyethyl migration to the sulfur atom followed by a second intramolecular reaction to form a spiro-1,3-oxathiolane ring, which fragments in two directions to generate both carbonyl and thiocarbonyl product ions from this thiocarbonyl compound. While methyl migration to the thiocarbonyl sulfur atom of thiosildenafil is dominant, methyl migration to the carbonyl oxygen atom of sildenafil may occur to a small extent.

Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: A history, analytical aspects and health risks

“…New analogues may have different fragment ions which may not be recognized straightaway. These may even concern 'close' analogues like thiosildenafil analogues (unusual N-S alkyl transfer) [70,71] and amino-tadalafil [17,18,62]. It should be noted that marker ions may differ between collision gasses (He, Ar, N 2 ) [72][73][74].…”

Synthesis and Spectroscopic Analysis of Novel 1H-Benzo[d]imidazoles Phenyl Sulfonylpiperazines

“…The unique mass spectra of the herein reported compounds 2–4 can be considered diagnostic for their identity. In addition, it is worth mentioning that there are reports of detailed MS analyses of sildenafil and other chemically similar compounds [27,28,29] but none of these reports suggested this pattern of fragmentation, which led to the belief that it is novel for these phenylsulfonylpiperazines. Other fragments that were present and their molecular formulae are also shown in Scheme 2.…”

A novel methyl migration to the phosphoryl group with the formation of cyclic aminoacylphosphoramidates in electrospray ionization tandem mass spectra of amino acid ester phosphoramidates of antiviral nucleosides

“…[24] Thus, the rearrangement reaction depended on the distance between the methoxy group of the amino acid residue and the phosphoryl group, which was in agreement with the literature report of N-methyl group migration to the sulfur atom of the thiocarbonyl group. [25] Although the gas-phase reactions in MS involving the methyl group migrations have been observed before, for example, the methyl group migration of trimethyllysine-containing-peptides, [26] the β-methyl migration to an organotin compound, [27] the interfunctional group methyl transfers of dimethyl maleate and dimethyl fumarate, [28] and the unusual seven bondcrossed methyl migration within an aromatic system, [29] it seemed that they went proceeded via different rearrangement mechanisms. For the methyl migration of the amino acid phosphoramidates, the metal ion coordination and the electrophilic effect of the phosphoryl group might position the methoxy group spatially close to the site of migration to allow for reverse side attack on the methyl carbon atom in a traditional nucleophilic substitution.…”