Understanding collision-induced dissociation of dofetilide: a case study in the application of density functional theory as an aid to mass spectral interpretation

Abstract

Fragmentation of molecules under collision-induced dissociation (CID) conditions is not well-understood. This may make interpretation of MSMS spectra difficult and limit the effectiveness of software tools intended to aid mass spectral interpretation. Density Functional Theory (DFT) has been successfully applied to explain the thermodynamics of fragmentation in the gas phase by the modelling the effect that protonation has on the bond lengths (and hence bond strengths). In this study, dofetilide and four methylated analogues were used to investigate further the potential for using DFT to understand and predict the CID fragmentation routes. The products ions present in the CID spectra of all five compounds were consistent with charge-directed fragmentation, with protonation adjacent to the cleavage site being required to initiate fragmentation. Protonation at the dissociative site may have occurred either directly or via proton migration. A correlation was observed between protonation-induced bond lengthening and the bonds which were observed to break in the CID spectra. This correlation was quantitative in that the bonds calculated to elongate to the greatest extent gave rise to the most abundant of the major product ions. Thus such quantum calculations may offer the potential for contributing to a predictive tool for aiding the accuracy and speed mass spectral interpretation by generating numerical data in the form of bond length increases to act as descriptors flagging potential bond cleavages.

Predicting collision-induced dissociation spectra: Semi-empirical calculations as a rapid and effective tool in software-aided mass spectral interpretation

“…This was observed to be true of all 15 compounds in that their product ions were derived from several protonated precursors, and further exemplified by the data for 1‐methyl‐2‐pyrrolidinol shown in Table . This is consistent with previous studies which highlighted that the precursor ions appear to be a mixture of ions which are protonated on a number of different basic sites across the molecule . Other groups have also reported that precursor ions appear to be a mixture of ions protonated at different positions.…”

“…There are commercial software packages available to aid spectral interpretation but, in general, these have the limitation that they over‐predict the number of product ions formed. For example, four major (>5%) product ions were observed in the product ion spectrum of protonated dofetilide, but the Waters' Mass Fragment software (Waters Corporation, Manchester, UK) predicted 20 possible product ions on the basis of the accurate mass data and over 100 possible product ions for the nominal mass values . The reason for this over‐prediction is that many of the software packages lack any insight into the specific chemical structure of a given compound, so that they may predict product ions structures which are not chemically feasible.…”

“…The authors have used DFT in previous studies with the pharmaceutical compounds fluconazole, maraviroc and dofetilide to rationalise CID product ion spectra in terms of bond weakening resulting from conformational changes . In general, with a few exceptions, lengthening a bond will cause it to weaken and render it more susceptible to cleavage .…”

Non-targeted screening approaches for contaminants and adulterants in food using liquid chromatography hyphenated to high resolution mass spectrometry

“…For example, the number of predicted compounds from a database search can be reduced by excluding compounds with predicted MS/MS spectra that do not match the observed [94]. Advancements in predictive fragmentation are being developed [95][96][97][98][99][100][101] and have been reviewed previously [76]. Examples of MS/MS fragmentation prediction tools include, but are not limited to, ACD/MS Fragmenter [102], MolFind [94], MetFrag [101], MIDAS (Metabolite Identification via Database Searching) [103] and SmartMass [91].…”

Examination of small molecule losses in 5‐methylpyranopelargonidin MS/MS CID spectra by DFT calculations

“…Among others, infrared multiphoton dissociation spectroscopy (IRMPD) and collision‐induced dissociation (CID) investigation together with DFT calculations were employed for evaluation of the fragmentation behaviour of p‐aminophenol; this simple model reveals differences between thermodynamically driven (IRMPD) and kinetically driven (CID) fragmentations . DFT methods were also used for prediction of fragmentation of dofetilide and its derivatives; it was found that protonation of the analyte is an important factor causing elongation of the bonds making them more susceptible to subsequent break . Another interesting use of computational chemistry in the tandem mass spectrometry (MS/MS) analysis of isomers was shown by Galezowska et al These authors observed good agreement between experimental abundances of fragments in MS/MS spectra of selected quinazoline derivatives and Boltzmann distribution of these fragments based on a calculation of their protonation enthalpies .…”