Loss of atomic nitrogen from even‐electron ions? A study on benzodiazepines

Abstract

The fragment spectra of protonated nitro-substituted benzodiazepines show an unusual fragment [M + H - 14] , which is shown by accurate mass measurement to be due to the loss of a nitrogen atom. Our investigations show that this apparent loss of atomic nitrogen is rather an attachment of molecular oxygen to the [M + H - NO ] ion, which is the main fragment ion in these spectra. The oxygen attachment is exothermic, and rate constants have been derived. MS spectra show that it is not easily reversible upon fragmentation of the adduct ion and that it is also observed with some secondary and tertiary fragments, which allows to limit the attachment site to the aromatic ring annulated to the diazepine moiety. Fragments of the oxygen adduct ion indicate that the O molecule dissociates in the adduct formation process, and the two oxygen atoms are bound to different sites of the ion. Comparison with radical cations generated by fragmentation of non-nitro-substituted benzodiazepines, none of which showed an oxygen attachment, and the fragmentation mechanisms involved in their formation indicates that the [M + H - NO ] ion is a distonic ion with the charge and radical site neighbored on the aromatic ring. From these results, we derive a proposal for the formation and structure of the [M + H - NO + O ] ion, which explains the experimental observations. Copyright © 2015 John Wiley & Sons, Ltd.

Fragmentation studies of selected drugs utilized in palliative care

“…the elimination of the NO radical and substitution of O 2 to the radical cation resulting in the formation of the ions at m/z 302. 18 Moreover, existence of these ions clearly shows that the initial elimination of CO from the protonated molecule is not the only possible primary loss as it was suggested by Niessen and Correa. 26 Although tandem mass spectrum of clonazepam is not fragment ion rich, sufficient number of abundant ions can be found for its quantitation.…”

“…[11][12][13][14] The aim of this study was to get more detailed insight into the fragmentation of selected drugs used in palliative care, as for some of them, there is only limited information available. While the most widely used morphine is described in many papers and its fragmentation is fully characterized, [15][16][17] clonazepam, midazolam and metoclopramide are described to a lesser extent [18][19][20][21] and fragmentation schemes of fentanyl, tramadol, levomepromazine, hyoscine butylbromide and haloperidol are rarely published and present structures of main fragments only. [22][23][24] Therefore, the fragmentation of [MþH] þ ions was studied to supply more detailed insight into this topic.…”

An intriguing “reversible reaction” in the fragmentation of deprotonated dicamba and benzoic acid in a Q‐orbitrap mass spectrometer: Loss and addition of carbon dioxide

“…This mechanism can explain why, as the collision energy increases, the relative abundance of the precursor ion becomes higher (Table 1). We speculated that the CO 2 probably comes from background air or the collision gas, as the addition of residual gases (N 2 , O 2 and H 2 O) to gas‐phase ions in mass spectrometry has been reported several times 7–12 . It is well known that carbanions react with CO 2 yielding the corresponding carboxylate anions in the gas phase and this reaction is known to proceed without an activation barrier and with very high efficiency 17–19 .…”

“…It is worth noting that the product ions sometimes do not directly reflect the structure of the precursor ion. In the fragmentation reactions, skeleton rearrangements, 3,4 intermediate‐mediated reactions, 5,6 ion‐molecule reactions with background gases (water, nitrogen and oxygen) 7–12 and solvent (acetonitrile and methanol) addition 13,14 will lead to the formation of some unexpected product ions, which may lead to complicated MS/MS spectra and wrong structural assignments. Although such examples are not common, they are very important for structural analysis and gas‐phase ion chemistry, and have been recognized by the mass spectrometry community.…”

An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: The microscale syntheses of nitrazolam and clonazolam for use as reference materials, utilizing polymer‐supported reagents

“…The chromatographic peaks displayed good from the protonated molecule, has been previously reported. 37 3.4 | X-ray crystallography of clonazolam (vendor sample)…”