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Mass Spectrometry and Theoretical Studies on N-C Bond Cleavages in the N-sulfonylamidino Thymine Derivatives

Mass Spectrometry and Theoretical Studies on N-C Bond Cleavages in the N-sulfonylamidino Thymine Derivatives

Authors :
Snježana Kazazić
Biserka Žinić
Borislav Kovačević
Luka Krstulović
Miroslav Bajić
Zoran Glasovac
Renata Kobetić
Publication Year :
2015

Abstract

The reactivity of new biologically active thymine derivatives substituted with 2-(arylsulfonamidino)ethyl group at N1 and N3 position was investigated in the gas phase using CID experiments (ESI-MS/MS) and by density functional theory (DFT) calculations. Both derivatives show similar chemistry in the negative mode with a retro-Michael addition (Path A(-)) being the most abundant reaction channel, which correlate well with the fluoride induced retro-Michael addition observed in solution. The difference in the fragmentation of N-3 substituted thymine 5 and N-1 substituted thymine 1 in the positive mode relates to the preferred cleavage of the sulfonyl group (m/z 155, Path B) in N-3 isomer and the formation of the acryl sulfonamidine 3 (m/z 309) via Path A in N-1 isomer. Mechanistic studies of the cleavage reaction conducted by DFT calculations give the trend of the calculated activation energies that agree well with the experimental observations. A mechanism of the retro-Michael reaction was interpreted as a McLafferty type of fragmentation, which includes Hβ proton shift to one of the neighboring oxygen atoms in a 1,5-fashion inducing N1(N3)-Cα bond scission. This mechanism was found to be kinetically favorable over other tested mechanisms. Significant difference in the observed fragmentation pattern of N-1 and N-3 isomers proves the ESI-MS/MS technique as an excellent method for tracking the fate of similar sulfonamidine drugs. Also, the observed N-1 and/or N-3 thymine alkylation with in situ formed reactive acryl sulfonamidine 3 as a Michael acceptor may open interesting possibilities for the preparation of other N-3 substituted pyrimidines.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....530ca686959dd68f7f08a4f8dbdd9f33