Study of n-alkyl derivatives of theophylline by gas chromatography-mass spectrometry

In the study fragmentation under electron ionization of 7-allyl-, 7-propargyl-, 7-(2-(4-bromophenyl)-2-hydroxy-oxoethyl)-, 7-methallyl-, 7-(2-bromoethyl)-, 7-(2-hydroxyethyl)-, 7-[2-(2-chloroethoxy)ethyl]-, 7-[2-(2-hydroxyethoxy)ethyl]-, 7-(2,3-dibromopropyl)theophylline and 7,7'-ethane-1,2-diylbis(theophylline) was investigated by gas chromatography-mass spectrometry analysis, the main mass fragmentation ways were revealed. 7-(2,3-Dibromopropyl)theophylline was prepared by the addition of bromine to the double bond of 7-allyl-thophylline in acetic acid at room temperature for 24 hours. 7-[2-(2-Chloroethoxy)ethyl]- and 7-[2-(2-hydroxyethoxy)ethyl] theophyllines were obtained by the interaction of theophylline with 2,2'-dichlorodiethyl ether in DMF in the presence of anhydrous potassium carbonate under reflux for 8 h. 7-Methallyltheophylline was synthesized by the interaction of theophylline with a methallylchloride in DMF in the presence of anhydrous potassium carbonate under reflux for 6 h. The structure of 7-methallyltheophylline was confirmed by 1H NMR spectroscopy. The mass spectra of all studied compounds contain peaks characteristic for the fragmentation of theophylline. In almost all mass-spectra there are peaks of theophylline cation radical with m/z 180. This indicates a disruption of the N-CH2 bond. In the cases of 7-propargyl- and 7-(2-(4-bromophenyl)-2-oxoethyl)theophyllines this peak is absent. In the cases of 7-allyl- and 7-methallyltheophyllines peaks with m/z 180 have low intensity, because of higher stability of the N-alkyl bond. 7-Methallyl- and 7-propargyltheophyllines are thermally rearranged under chromatographic conditions in a spectrometer. There is characteristic distribution of isotope peaks of the molecular ion in the mass spectra of halogen-containing compounds: a doublet with an intensity ratio of approximately 1:1 for compounds with one bromine atom, a triplet of peaks in the case of two bromine atoms, and a doublet with an intensity ratio 3:1 for chlorine-containing derivatives. These multiplets usually have low intensity. The peak of the bromo radical detachment in the case of 7-(2-bromoethyl)- and 7-(2,3-dibromopropyl)-theophyllines has maximum intensity. The elimination of methyl isocyanate, carbon monoxide and hydrogen cyanide molecules is a characteristic feature of all studied mass spectra.