James S. Riedeman

Identification of the sulfone functionality in protonated analytes via ion/molecule reactions in a linear quadrupole ion trap mass spectrometer.

A tandem mass spectrometric method is presented for the rapid identification of drug metabolites that contain the sulfone functional group. This method is based on a gas-phase ion/molecule reaction of protonated sulfone analytes with trimethyl borate (TMB) that yields a diagnostic product ion, adduct-Me2O, at high reaction efficiency. A variety of compounds with different functional groups, such as sulfoxides, hydroxylamines, N-oxides, anilines, phenol, an aliphatic amine, and an aliphatic alcohol, were examined to probe the selectivity of this reaction. Except for protonated sulfones, most of the protonated compounds react very slowly or not at all with TMB. Most importantly, none of them give the adduct-Me2O product. A mechanism that explains the observed selectivity is proposed for the diagnostic reaction and is supported by quantum chemical calculations. The reaction was tested with the anti-inflammatory drug sulindac and its metabolite, sulindac sulfone, which were readily distinguished. The presence of other functionalities in addition to sulfone was found not to influence the diagnostic reactivity.

Multiported pulsed valve interface for a linear quadrupole ion trap mass spectrometer to enable rapid screening of multiple functional-group selective ion-molecule reactions.

Ion-molecule reactions provide a powerful tool for structural elucidation of ionized pharmaceutical analytes in tandem mass spectrometry. However, all previous interfaces for the introduction of reagents for ion-molecule reactions have utilized a single reagent approach. In this study, a multiported pulsed valve system was designed and characterized for rapid introduction of three neutral reagents into a linear quadrupole ion trap. Additionally, automatic triggering was used to allow for the introduction of the reagents on a chromatographic time scale. This system enables automatic, high throughput screening of complex mixtures by using at least three different ion-molecule reactions. Further, rapid testing of new neutral reagents is also possible.

Characterization of aromatic organosulfur model compounds relevant to fossil fuels by using atmospheric pressure chemical ionization with CS2 and high‐resolution tandem mass spectrometry

RATIONALE The chemistry of desulfurization involved in processing crude oil is greatly dependent on the forms of sulfur in the oil. Sulfur exists in different chemical bonding environments in fossil fuels, including those in thiophenes and benzothiophenes, thiols, sulfides, and disulfides. In this study, the fragmentation behavior of the molecular ions of 17 aromatic organosulfur compounds with various functionalities was systematically investigated by using high-resolution tandem mass spectrometry. METHODS Multiple-stage tandem mass spectrometric experiments were carried out using a linear quadrupole ion trap (LQIT) equipped with an atmospheric pressure chemical ionization (APCI) source. (+)APCI/CS2 was used to generate stable dominant molecular ions for all the compounds studied except for three sulfides that also showed abundant fragment ions. The LQIT coupled with an orbitrap mass spectrometer was used for elemental composition analysis, which facilitated the identification of the neutral molecules lost during fragmentation. RESULTS The characteristic fragment ions generated in MS(2) and MS(3) experiments provide clues for the chemical bonding environment of sulfur atoms in the examined compounds. Upon collision-induced dissociation (CID), the molecular ions can lose the sulfur atom in a variety of ways, including as S (32 Da), HS(•) (33 Da), H2 S (34 Da), CS (44 Da), (•) CHS (45 Da) and CH2 S (46 Da). These neutral fragments are not only indicative of the presence of sulfur, but also of the type of sulfur present in the compound. Generally, losses of HS(•) and H2 S were found to be associated with compounds containing saturated sulfur functionalities, while losses of S, CS and (•) CHS were more common for heteroaromatic sulfur compounds. CONCLUSIONS High-resolution tandem mass spectrometry with APCI/CS2 ionization is a viable approach to determining the types of organosulfur compounds. It can potentially be applied to analysis of complex mixtures, which is beneficial to improving the desulfurization process of fossil fuels. Copyright

Identification of N-Oxide and Sulfoxide Functionalities in Protonated Drug Metabolites by Using Ion–Molecule Reactions Followed by Collisionally Activated Dissociation in a Linear Quadrupole Ion Trap Mass Spectrometer

The in vivo oxidation of sulfur and nitrogen atoms in many drugs into sulfoxide and N-oxide functionalities is a common biotransformation process. Unfortunately, the unambiguous identification of these metabolites can be challenging. In the present study, ion-molecule reactions of tris(dimethylamino)borane followed by collisionally activated dissociation (CAD) in an ion trap mass spectrometer are demonstrated to allow the identification of N-oxide and sulfoxide functionalities in protonated polyfunctional drug metabolites. Only ions with N-oxide or sulfoxide functionality formed diagnostic adducts that had lost dimethyl amine (DMA). This was demonstrated even for an analyte that contains a substantially more basic functionality than the functional group of interest. CAD of the diagnostic product ions (M) resulted mainly in type A (M - DMA) and B fragment ions (M - HO-B(N(CH3)2)2) for N-oxides, but sulfoxides also formed diagnostic C ions (M - O═BN(CH3)2), thus allowing differentiation of the functionalities. Some protonated analytes yielded abundant TDMAB adducts that had lost two DMA molecules instead of just one. This provides information on the environment of the N-oxide and sulfoxide functionalities. Quantum chemical calculations were performed to explore the mechanisms of the above-mentioned reactions. The method can be implemented on HPLC for real drug analysis.

Laser-Induced Acoustic Desorption/Electron Ionization of Amino Acids and Small Peptides

AbstractLaser-induced acoustic desorption (LIAD) allows for desorption of neutral nonvolatile compounds independent of their volatility or thermal stability. Many different ionization methods have been coupled with LIAD. Hence, this setup provides a better control over the types of ions formed than other mass spectrometry evaporation/ionization methods commonly used to characterize biomolecules, such as ESI or MALDI. In this study, the utility of LIAD coupled with electron ionization (EI) was tested for the analysis of common amino acids with no derivatization. The results compared favorably with previously reported EI mass spectra obtained using thermal desorption/EI. Further, LIAD/EI mass spectra collected for hydrochloride salts of two amino acids were found to be similar to those measured for the neutral amino acids with the exception of the appearance of an HCl+● ion. However, the hydrochloride salt of arginine showed a distinctly different LIAD/EI mass spectrum than the previously published literature EI mass spectrum, likely due to its highly basic side chain that makes a specific zwitterionic form particularly favorable. Finally, EI mass spectra were measured for seven small peptides, including di-, tri-, and tetrapeptides. These mass spectra show a variety of ion types. However, an type ions are prevalent. Also, electron-induced dissociation (EID) of protonated peptides has been reported to form primarily an type ions. In addition, the loss of small neutral molecules and side-chain cleavages were observed that are reminiscent of other high-energy fragmentation methods, such as EID. Finally, the isomeric dipeptides LG and IG were found to produce drastically different EI mass spectra, thus allowing differentiation of the leucine and isoleucine amino acids in these dipeptides. Graphical Abstractᅟ

Mass spectrometric studies of fast pyrolysis of cellulose.

A fast pyrolysis probe/linear quadrupole ion trap mass spectrometer combination was used to study the primary fast pyrolysis products (those that first leave the hot pyrolysis surface) of cellulose, cellobiose, cellotriose, cellotetraose, cellopentaose, and cellohexaose, as well as of cellobiosan, cellotriosan, and cellopentosan, at 600°C. Similar products with different branching ratios were found for the oligosaccharides and cellulose, as reported previously. However, identical products (with the exception of two) with similar branching ratios were measured for cellotriosan (and cellopentosan) and cellulose. This result demonstrates that cellotriosan is an excellent small-molecule surrogate for studies of the fast pyrolysis of cellulose and also that most fast pyrolysis products of cellulose do not originate from the reducing end. Based on several observations, the fast pyrolysis of cellulose is suggested to initiate predominantly via two competing processes: the formation of anhydro-oligosaccharides, such as cellobiosan, cellotriosan, and cellopentosan (major route), and the elimination of glycolaldehyde (or isomeric) units from the reducing end of oligosaccharides formed from cellulose during fast pyrolysis.