Novel product ions of 2-aminoanilide and benzimidazole Ag(I) complexes using electrospray ionization with multi-stage tandem mass spectrometry

ArticleinRapid Communications in Mass Spectrometry 26(9):1115-22 · May 2012with10 Reads
DOI: 10.1002/rcm.6210 · Source: PubMed
Abstract
The 2-aminoaniline scaffold is of significant value to the pharmaceutical industry and is embedded in a number of pharmacophores including 2-aminoanilides and benzimidazoles. A novel application of coordination ion spray mass spectrometry (CIS-MS) for interrogating the silver ion (Ag(+)) complexes of a homologous series of these compounds using multi-stage tandem mass spectrometry is described. Unlike the ubiquitous alkali metal ion complexes, Ag(+) complexes of 2-aminoanilides and benzimidazoles were found to yield [M - H](+) ions in significant abundance via gas-phase elimination of the metal hydride (AgH) resulting in unique product ion cascades. Sample introduction was by liquid chromatography with mass spectrometry analysis performed on a hybrid linear ion trap/orbitrap instrument capable of high-resolution measurements. Rigorous structural characterization by multi-stage tandem mass spectrometry using [M +  H](+), [M - H](-) and [M - H](+) precursor ions derived from ESI and CIS experiments was performed for the homologous series of 2-aminoanilide and benzimidazole compounds. A full tabular comparison of structural information resulting from these product ion cascades was produced. Multi-stage tandem mass spectrometry of [M - H](+) ions resulting from Ag(+) complexes of 2-aminoanilides and benzimidazoles in CIS-MS experiments produced unique product ion cascades that exhibited complementary structural information to that obtained from tandem mass spectrometry of [M  +  H](+) and [M - H](-) ions by electrospray ionization (ESI). These observations may be broadly applicable to other compounds that are observed to form Ag(+) complexes and eliminate AgH.
    • With the high vacuum and feasible interface to the liquid phase, ESI-MS has long served as the gas-phase medium in which to form gaseous key ions and, hence, probe reaction mechanisms and establish intrinsic reactivity orders. In the gas-phase chemistry of numerous argentinated organic ligands, product ions retaining the silver ion are generally observed2324252627 except when elimination of AgR (R = CH 3 , ph) [27, 28] or AgH24252627282930 takes place. In the case of argentinated amines, aminocarboxylic acids, ethers, or compounds possessing at least one α-hydrogen to the amino nitrogen or ether oxygen, the α-hydrogen tends to cleave with the silver in a 1,2-elimination282930.
    [Show abstract] [Hide abstract] ABSTRACT: The fragmentations of argentinated N-allylbenzamides have been exhaustively studied through collision-induced dissociation and through deuterium labeling. The intriguing elimination of AgOH is certified as the consequence of intramolecular cyclization between terminal olefin and carbonyl carbon following proton transfer to carbonyl oxygen, rather than simple enolization of amide. Linear free energy correlations and density functional theory (DFT) calculations were performed to understand the competitive relationship between AgOH loss and AgH loss, which results from the 1,2-elimination of α-hydrogen (to the amido nitrogen) with the silver.
    Full-text · Article · Feb 2015
    • [4] [23] [24] Metal complexation not only increases the ionization efficiency in ESI-MS, but also alters fragmentation pathways in MS n . [25] [26] [27] [28] [29] [30] [31] Many positional isomers [32] [33] [34] [35] [36] [37] [38] [39] and enantiomers [40] [41] [42] [43] [44] [45] have been successfully distinguished by comparing structurally distinctive product ions resulting from dissociation of metal complexes in MS n .
    [Show abstract] [Hide abstract] ABSTRACT: RATIONALEDevelopment of mass spectrometry (MS)-based methods for isomeric differentiation remains a challenging analytical task, and has attracted the interest of many research groups. It is relevant to develop a general method to differentiate the isomeric halogenated phenylmethylidene hydrazinecarbodithioates (MX, X = F, Cl, Br).METHODS Diluted CH3CN solutions containing NiCl2 and a title isomer (MX) were analyzed by electrospray ionization tandem mass spectrometry (ESI-MSn) in a quadrupole ion trap instrument equipped with an ESI source. Theoretical calculations were performed using the density functional theory (DFT) method at the uB3LYP/6-31+G(2d,p) level.RESULTSIn MS3 experiments, the complex [MX + SCH3 + Ni]+ ion, resulting from dissociation of the ESI-generated complex [2MX – H + Ni]+ ion, undergoes ligand-exchange reactions with residual gas molecules, such as water, acetonitrile, and nitrogen in the ion trap, and the o-isomers [Mo-X + SCH3 + Ni]+ were found to undergo the characteristic HX elimination reactions to afford several unique ions. Each set of three isomers [MX + SCH3 + Ni]+ show significantly different reactivity, which has been corroborated by MS4 experiments and theoretical calculations.CONCLUSIONSA rapid method based on metal complexation and tandem mass spectrometric (MSn) analysis has been developed to differentiate three sets of positional isomers of halogenated phenylmethylidene hydrazinecarbodithioates (MX, X = F, Cl, Br). Copyright © 2014 John Wiley & Sons, Ltd.
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    Full-text · Article · Apr 2013
  • [Show abstract] [Hide abstract] ABSTRACT: This paper reports here Nazarov cyclization and oxo-Diels–Alder reaction induced by the naked silver cation in the collisional activation of silver(I)/chalcone complexes, which lead to the final elimination of AgOH and AgH, respectively. Deuterium labeling experiments, DFT calculations, and the substituent effect were utilized to confirm the reaction mechanisms.
    Article · May 2013
  • [Show abstract] [Hide abstract] ABSTRACT: In collisional activation of argentinated N-arylmethyl-pyridin-2-ylmethanimine, a neutral molecule of AgNH2 is eliminated, carrying one hydrogen from the methylene and the other one from the ortho position (relative to the ipso carbon) of the aryl ring. Taking argentinated N-benzyl-pyridin-2-ylmethanimine for example, the proposition that the AgNH2 loss results from intramolecular arylmethyl transfer combined with cyclodeamination is rationalized by deuterium labeling experiments, blocking experiments, and theoretical calculations. The structure of the final product ion from loss of AgNH2 was confirmed further by multistage mass spectrometry. Figure ᅟ
    Article · Dec 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Rationale: Experiments were performed to probe the creation of apparent even-electron, [M-H](+) ions by CID of Ag-cationized peptides with N-terminal imine groups (Schiff bases). Methods: Imine-modified peptides were prepared using condensation reactions with aldehydes. Ag(+) -cationized precursors were generated by electrospray ionization (ESI). Tandem mass spectrometry (MS(n) ) and collision-induced dissociation (CID) were performed using a linear ion trap mass spectrometer. Results: Loss of AgH from peptide [M + Ag](+) ions, at the MS/MS stage, creates closed-shell [M-H](+) ions from imine-modified peptides. Isotope labeling unambiguously identifies the imine C-H group as the source of H eliminated in AgH. Subsequent CID of the [M-H](+) ions generated sequence ions that are analogous to those produced from [M + H](+) ions of the imine-modified peptides. Conclusions: Experiments show (a) formation of novel even-electron peptide cations by CID and (b) the extent to which sequence ions (conventional b, a and y ions) are generated from peptides with fixed charge site and thus lacking a conventional mobile proton. Copyright © 2015 John Wiley & Sons, Ltd.
    Article · Jan 2016