Differentiation of the Aziridine Functionality from Related Functional Groups in Protonated Analytes by Using Selective Ion-Molecule Reactions Followed by Collision-Activated Dissociation in a Linear Quadrupole Ion Trap Mass Spectrometer.

Aziridines are commonly used as reagents for the synthesis of drug substances although they are potentially mutagenic and genotoxic. Therefore, their unambiguous detection is critically important. Unfortunately, tandem mass spectrometry (MS2) based on collision-activated dissociation (CAD), a powerful method used for the identification of many unknown compounds in complex mixtures, does not provide diagnostic fragmentation patterns for ionized aziridines. Therefore, a different mass spectrometry approach based on MS3 experiments is presented here for the identification of the aziridine functionalities. This approach is based on selective gas-phase ion-molecule reactions of protonated analytes with tris(dimethylamino)borane (TDMAB) followed by diagnostic CAD reactions in a modified linear quadrupole ion trap (LQIT) mass spectrometer. TDMAB reacts with protonated aziridines by forming adduct ions that have lost a dimethylamine (DMA) molecule ([M + H + TDMAB - HN(CH3)2]+). CAD on these product ions generated diagnostic fragment ions with m/z-values 25- and 43-units lower than those of the ion-molecule reaction product ions. None of the ion-molecule reaction product ions formed from other, structurally related, protonated analytes produced related fragment ions. Quantum chemical calculations were employed to explore the mechanisms of the observed reactions.

Differentiation of Protonated Sulfonate Esters from Isomeric Sulfite Esters and Sulfones by Gas-Phase Ion-Molecule Reactions Followed by Diagnostic Collision-Activated Dissociation in Tandem Mass Spectrometry Experiments.

Sulfonate esters, a class of potentially mutagenic drug impurities, are strictly regulated in pharmaceuticals. On the other hand, sulfite esters and sulfones, analogs of sulfonate esters, have limited safety concerns. However, previously developed analytical methods for sulfonate ester identification cannot be used to differentiate sulfonate esters from the isomeric sulfite esters and sulfones. A tandem mass spectrometric method is introduced here for the differentiation of these compounds. Diisopropoxymethylborane (DIMB) reacts with protonated sulfonate esters, sulfite esters, and sulfones (and many other compounds) in the gas phase to form the product ion [M + H + DIMB - CH3CH(OH)CH3]+. Upon collision-activated dissociation (CAD), these product ions generate diagnostic fragment ions that enable the differentiation of sulfonate esters, sulfite esters, and sulfones from each other. For example, SO2 elimination enabled the unambiguous identification of sulfite esters. On the other hand, elimination of CH3B═O followed by elimination of (CH3)2C═O was only observed for sulfonate esters. Neither type of diagnostic fragment ions was detected for the products of sulfones. However, the product ions formed for sulfones with an additional hydroxyl substituent underwent the elimination of another CH3CH(OH)CH3 molecule, which enabled their identification. Finally, ion-molecule reactions of DIMB with various other functionalities were also examined. Some of them yielded the product ions [M + H + DIMB - CH3CH(OH)CH3]+ but none of these product ions underwent the diagnostic CAD reactions discussed above. Quantum chemical calculations were employed to explore the mechanisms of the reactions. The limits of detection for the diagnostic ion-molecule reaction product ions in high-performance liquid chromatography (HPLC)/mass spectrometry (MS2) experiments were found to range from 0.075 to 1.25 nmol.

A Diagnostic Nitrosamine Detection Approach for Pharmaceuticals by Using Tandem Mass Spectrometry Based on Diagnostic Gas-Phase Ion-Molecule Reactions.

N-Nitrosamines are strictly regulated in pharmaceutical products due to their carcinogenic nature. Therefore, the ability to rapidly and reliably identify the N-nitroso functionality is urgently needed. Unfortunately, not all ionized N-nitroso compounds produce diagnostic fragment ions and hence tandem mass spectrometry based on collision-activated dissociation (CAD) cannot be used to consistently identify the N-nitroso functionality. Therefore, a more reliable method was developed based on diagnostic functional-group selective ion-molecule reactions in a linear quadrupole ion trap mass spectrometer. 2-Methoxypropene (MOP) was identified as a reagent that reacts with protonated N-nitrosamines in a diagnostic manner by forming an adduct followed by the elimination of 2-propenol (CH3C(OH)═CH2]). From 18 protonated N-nitrosamine model compounds studied, 15 formed the diagnostic product ion. The lack of the diagnostic reaction for three of the N-nitrosamine model compounds was rationalized based on the presence of a pyridine ring that gets preferentially protonated instead of the N-nitroso functionality. These N-nitrosamines can be identified by subjecting a stable adduct formed upon ion-molecule reactions with MOP to CAD. Further, the ability to use ion-molecule reactions followed by CAD to differentiate protonated O-nitroso compounds with a pyridine ring from analogous N-nitrosamines was demonstrated This methodology is considered to be robust for the identification of the N-nitroso functionality in unknown analytes. Lastly, HPLC/MS2 experiments were performed to determine the detection limit for five FDA regulated N-nitrosamines.

Characterization of ionized lignin model compounds with α-O-4 linkages by positive- and negative-ion mode electrospray ionization tandem mass spectrometry based on collision-activated dissociation.

RATIONALE: The biggest obstacle in the rational conversion of biomass into aromatic chemicals is the identification of unknown compounds in lignin degradation mixtures that are highly complex. As opposed to lignin degradation products with ß-O-4 linkages, very little is known about the mass spectrometric analysis of lignin degradation products with α-O-4 linkages. METHODS: Lignin model compounds with an α-O-4 and another linkage, as well as lignin model compounds with only ß-O-4 linkages, were ionized by attachment of lithium or sodium cations under positive-ion mode electrospray ionization (ESI) or by deprotonation in negative-ion mode ESI in a linear quadrupole ion trap mass spectrometer. The ions were subjected to collision-activated dissociation in multiple-stage tandem mass spectrometry experiments to characterize their fragmentation patterns. RESULTS: All studied compounds formed abundant sodium and lithium cation adducts in positive-ion mode ESI with no fragmentation. Model compounds with ß-O-4 linkages displayed stable [M - H]- ions in negative-ion mode ESI whereas compounds with α-O-4 linkages only showed fragment ions. CAD of the lithiated α-O-4 compounds provided more structural information than CAD of sodiated compounds. However, both sodiated and lithiated compounds with α-O-4 linkages showed losses of monomer units at the MS2 stage, which is useful for sequencing of lignins with this type of linkage. CONCLUSIONS: An ionization and sequencing method has been developed for lignin model compounds with α-O-4 linkages that spontaneously fragment upon ionization via (-)ESI.

Studies of the Fragmentation Mechanisms of Deprotonated Lignin Model Compounds in Tandem Mass Spectrometry.

Unlabeled and deuterium-labeled dimeric lignin model compounds with ß-O-4 linkages were evaporated and ionized using negative ion mode electrospray ionization, transferred into a linear quadrupole ion trap, isolated, and subjected to collision-activated dissociation (CAD; MS2 experiments). The elemental compositions of the fragment ions were determined by using a high-resolution Orbitrap mass analyzer, and their structures were examined using further CAD experiments (MSn experiments wherein n = 2-5). Data analysis was facilitated by determining the fragmentation pathways for several deprotonated model compounds. The structures of the key fragment ions of several pathways were determined by comparison of the CAD mass spectra measured for undeuterated and deuterated analogues and for deprotonated authentic compounds. Some of the proposed reaction mechanisms were tested by examining additional deprotonated synthetic model compounds. Quantum chemical calculations were used to delineate the most likely reaction pathways and reaction mechanisms. This work provides basic information needed for the design of tandem mass spectrometry-based CAD sequencing strategies for mixtures of lignin degradation products.

Differentiation of Deprotonated Acyl-, N-, and O-Glucuronide Drug Metabolites by Using Tandem Mass Spectrometry Based on Gas-Phase Ion-Molecule Reactions Followed by Collision-Activated Dissociation.

Glucuronidation, a common phase II biotransformation reaction, is one of the major in vitro and in vivo metabolism pathways of xenobiotics. In this process, glucuronic acid is conjugated to a drug or a drug metabolite via a carboxylic acid, a hydroxy, or an amino group to form acyl-, O-, and/or N-glucuronide metabolites, respectively. This process is traditionally thought to be a detoxification pathway. However, some acyl-glucuronides react with biomolecules in vivo, which may result in immune-mediated idiosyncratic drug toxicity (IDT). In order to avoid this, one may attempt in early drug discovery to modify the lead compounds in such a manner that they then have a lower probability of forming reactive acyl-glucuronide metabolites. Because most drugs or drug candidates bear multiple functionalities, e.g., hydroxy, amino, and carboxylic acid groups, glucuronidation can occur at any of those. However, differentiation of isomeric acyl-, N-, and O-glucuronide derivatives of drugs is challenging. In this study, gas-phase ion-molecule reactions between deprotonated glucuronide metabolites and BF3 followed by collision-activated dissociation (CAD) in a linear quadrupole ion trap mass spectrometer were demonstrated to enable the differentiation of acyl-, N-, and O-glucuronides. Only deprotonated N-glucuronides and deprotonated, migrated acyl-glucuronides form the two diagnostic product ions: a BF3 adduct that has lost two HF molecules, [M - H + BF3 - 2HF]-, and an adduct formed with two BF3 molecules that has lost three HF molecules, [M - H + 2BF3 - 3HF]-. These product ions were not observed for deprotonated O-glucuronides and unmigrated, deprotonated acyl-glucuronides. Upon CAD of the [M - H + 2BF3 - 3HF]- product ion, a diagnostic fragment ion is formed via the loss of 2-fluoro-1,3,2-dioxaborale (MW of 88 Da) only in the case of deprotonated, migrated acyl-glucuronides. Therefore, this method can be used to unambiguously differentiate acyl-, N-, and O-glucuronides. Further, coupling this methodology with HPLC enables the differentiation of unmigrated 1-ß-acyl-glucuronides from the isomeric acyl-glucuronides formed upon acyl migration. Quantum chemical calculations at the M06-2X/6-311++G(d,p) level of theory were employed to probe the mechanisms of the reactions of interest.

Differentiating Isomeric Deprotonated Glucuronide Drug Metabolites via Ion/Molecule Reactions in Tandem Mass Spectrometry.

Isomeric O- and N-glucuronides are common drug metabolites produced in phase II of drug metabolism. Distinguishing these isomers by using common analytical techniques has proven challenging. A tandem mass spectrometric method based on gas-phase ion/molecule reactions of deprotonated glucuronide drug metabolites with trichlorosilane (HSiCl3) in a linear quadrupole ion trap mass spectrometer is reported here to readily enable differentiation of the O- and N-isomers. The major product ion observed upon reactions of HSiCl3 with deprotonated N-glucuronides is a diagnostic HSiCl3 adduct that has lost two HCl molecules ([M - H + HSiCl3 - 2HCl]-). This product ion was not observed for deprotonated O-glucuronides. Reaction mechanisms were explored with quantum chemical calculations at the M06-2X/6-311++G(d,p) level of theory.

Polar Effects Control the Gas-Phase Reactivity of para-Benzyne Analogs.

We report herein a gas-phase reactivity study on a para-benzyne cation and its three cyano-substituted, isomeric derivatives performed using a dual-linear quadrupole ion trap mass spectrometer. All four biradicals were found to undergo primary and secondary radical reactions analogous to those observed for the related monoradicals, indicating the presence of two reactive radical sites. The reactivity of all biradicals is substantially lower than that of the related monoradicals, as expected based on the singlet ground states of the biradicals. The cyano-substituted biradicals show substantially greater reactivity than the analogous unsubstituted biradical. The greater reactivity is rationalized by the substantially greater (calculated) electron affinity of the radical sites of the cyano-substituted biradicals, which results in stabilization of their transition states through polar effects. This finding is in contrast to the long-standing thinking that the magnitude of the singlet-triplet splitting controls the reactivity of para-benzynes.

Substituent Effects on the Reactivity of the 2,4,6-Tridehydropyridinium Cation, an Aromatic σ,σ,σ-Triradical.

2,4,6-Tridehydropyridinium cation (7) undergoes three consecutive atom or atom group abstractions from reagent molecules in the gas phase. By placing a π-electron-donating hydroxyl group between two radical sites, their reactivity can be quenched by enhancing their through-space coupling via a favorable resonance structure. Indeed, 3-hydroxy-2,4,6-tridehydropyridinium cation (8) abstracts only one atom or group of atoms from reagents. On the other hand, an electron-withdrawing cyano group between two of the radical sites (9) destabilizes the analogous resonance structure and diminishes through-space coupling between the radical sites, resulting in abstraction of three atoms, just like 7. However, the cyano-substituent also increases acidity to the point that 9 reacts pre-dominantly via proton transfer instead of undergoing radical reactions. Therefore, acidic triradicals may undergo nonradical, barrierless proton transfer reactions faster than radical reactions, which are usually accompanied by barriers. Examination of the analogous cyano-substituted mono-and biradicals revealed behavior similar to that of the corresponding unsubstituted species, with the exception of substantially greater reactivities due to their greater (calculated) vertical electron affinities. Finally, the 3-cyano-2,6-didehydropyridinium cation with a singlet ground state (S-T splitting: -11.9 kcal mol-1) was found to react exclusively from the lowest-energy triplet state by fast proton transfer reactions.

Identification of Protonated Sulfone and Aromatic Carboxylic Acid Functionalities in Organic Molecules by Using Ion-Molecule Reactions Followed by Collisionally Activated Dissociation in a Linear Quadrupole Ion Trap Mass Spectrometer.

Gas-phase reactivity of protonated model compounds with different functional groups toward trimethoxymethylsilane (TMMS) was studied to explore the utility of this reagent in mass spectrometric identification of specific functionalities for potentially rapid characterization of drug metabolites. Only protonated analytes with a carboxylic acid, a sulfone, or a sulfonamide functionality formed diagnostic adducts that had lost a methanol molecule upon reactions with TMMS. Collisionally activated dissociation (CAD) of these methanol-eliminated adduct ions (MS3 experiments) produced characteristic fragment ions of m/z 75, 105, and 123 for sulfones, while an additional methanol elimination was observed for carboxylic acids and sulfonamides. CAD of latter products (MS4 experiments) resulted in elimination of diagnostic neutral molecules CO2 (44 Da) and C2H6O2Si (90 Da) for aromatic carboxylic acids. Both aliphatic carboxylic acids and sulfonamides yield several fragment ions in these MS4 experiments that are different from those observed for sulfones or aromatic carboxylic acids. Potential energy surfaces were calculated (at the M06-2X/6-311++G(d,p) level of theory) to explore the mechanisms of various reactions. In summary, sulfones and aromatic carboxylic acids can be differentiated from each other and also from sulfonamides and aliphatic carboxylic acids based on reactions with TMMS and one or two CAD experiments. Aliphatic carboxylic acids and sulfonamides could not be differentiated from each other.

(-)ESI/CAD MSn Procedure for Sequencing Lignin Oligomers Based on a Study of Synthetic Model Compounds with ß-O-4 and 5-5 Linkages.

Seven synthesized G-lignin oligomer model compounds (ranging in size from dimers to an octamer) with 5-5 and/or ß-O-4 linkages, and three synthesized S-lignin model compounds (a dimer, trimer, and tetramer) with ß-O-4 linkages, were evaporated and deprotonated using negative-ion mode ESI in a linear quadrupole ion trap/Fourier transform ion cyclotron resonance mass spectrometer. The collision-activated dissociation (CAD) fragmentation patterns (obtained in MS2 and MS3 experiments, respectively) for the negative ions were studied to develop a procedure for sequencing unknown lignin oligomers. On the basis of the observed fragmentation patterns, the measured elemental compositions of the most abundant fragment ions, and quantum chemical calculations, the most important reaction pathways and likely mechanisms were delineated. Many of these reactions occur via charge-remote fragmentation mechanisms. Deprotonated compounds with only ß-O-4 linkages, or both 5-5 and ß-O-4 linkages, showed major 1,2-eliminations of neutral compounds containing one, two, or three aromatic rings. The most likely mechanisms for these reactions are charge-remote Maccoll and retro-ene eliminations resulting in the cleavage of a ß-O-4 linkage. Facile losses of H2O and CH2O were also observed for all deprotonated model compounds, which involve a previously published charge-driven mechanism. Characteristic "ion groups" and "key ions" were identified that, when combined with their CAD products (MS3 experiments), can be used to sequence unknown oligomers.

Unusual (+/-)-electrospray ionization induced fragmentation: Structural elucidation of an in-process synthetic intermediate of doravirine (MK-1439) using liquid chromatography/high-resolution tandem mass spectrometry and two-dimensional nuclear magnetic resonance.

RATIONALE: During the development of a novel synthetic route to doravirine (1), a human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI), an unanticipated reaction intermediate, methyl (Z)-2-(3-chloro-5-cyanophenoxy)-5-(3-(3-chloro-5-cyanophenoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-ethoxy-3-(trifluoromethyl)pent-2-enoate (2), was isolated. Moreover, an unusual electrospray ionization (ESI)-induced fragmentation was observed for 2. Hence, efforts were made towards the understanding of the structure of 2, which was crucial for the understanding of the reaction mechanism. METHODS: The isolated impurity was fully characterized by liquid chromatography coupled with high-resolution tandem mass spectrometry (LC/HRMS/MS), hydrogen/deuterium (H/D) exchange, and an ensemble of two-dimensional nuclear magnetic resonance (2D-NMR) techniques. Density functional theory (DFT) calculations were also conducted. RESULTS: An unusual ESI-induced fragmentation was observed for intermediate 2, giving an ion for half of the molecule in the positive ion mode, with the other half of the molecule affording an ion in the negative ion mode. CONCLUSIONS: To the best of our knowledge, this unique ESI-induced fragmentation has not been previously reported in the literature. The underlying mechanism was explored and is supported by DFT calculations, which could greatly help the structural characterization of unknown impurities with similar structural features using ESI-MS in the future. Copyright © 2017 John Wiley & Sons, Ltd.

Oxyfunctionalization of the Remote C-H Bonds of Aliphatic Amines by Decatungstate Photocatalysis.

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H2 O2 or O2 as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value-added ketone products. Lastly, NMR spectroscopy using in situ LED-irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.

Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,ß-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation.

A highly active and enantioselective phosphine-nickel catalyst for the asymmetric hydrogenation of α,ß-unsaturated esters has been discovered. The coordination chemistry and catalytic behavior of nickel halide, acetate, and mixed halide-acetate with chiral bidentate phosphines have been explored and deuterium labeling studies, the method of continuous variation, nonlinear studies, and kinetic measurements have provided mechanistic understanding. Activation of molecular hydrogen by a trimeric (Me-DuPhos)3Ni3(OAc)5I complex was established as turnover limiting followed by rapid conjugate addition of a nickel hydride and nonselective protonation to release the substrate. In addition to reaction discovery and optimization, the previously unreported utility high-throughput experimentation for mechanistic elucidation is also described.

Antenna Biphenols: Development of Extended Wavelength Chiroptical Reporters.

Molecular hosts capable of chiroptical sensing of complexed guest molecules offer an attractive alternative to conventional methods for the analysis of the absolute configuration and enantiopurity. Sensors based on the Pfeiffer effect rely on complexation-driven asymmetric transformation of the first kind and can produce a chiroptical signal against an otherwise null background. To be most effective, the wavelength of the induced chiroptical sensor readout should be free and clear of interfering signals coming from the sample under investigation. In this study, we report the introduction of stereodynamic zinc complexes of antenna biphenols, a new class of sensors bearing antenna-like appendages that can extend the wavelength of the chiroptical signal while also improving enantioselective guest recognition.

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.

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 © 2016 John Wiley & Sons, Ltd.

Gas-phase ion-molecule reactions for the identification of the sulfone functionality in protonated analytes in a linear quadrupole ion trap mass spectrometer.

RATIONALE: The oxidation of sulfur atoms is an important biotransformation pathway for many sulfur-containing drugs. In order to rapidly identify the sulfone functionality in drug metabolites, a tandem mass spectrometric method based on ion-molecule reactions was developed. METHODS: A phosphorus-containing reagent, trimethyl phosphite (TMP), was allowed to react with protonated analytes with various functionalities in a linear quadrupole ion trap mass spectrometer. The reaction products and reaction efficiencies were measured. RESULTS: Only protonated sulfone model compounds were found to react with TMP to form a characteristic [TMP adduct-MeOH] product ion. All other protonated compounds investigated, with functionalities such as sulfoxide, N-oxide, hydroxylamino, keto, carboxylic acid, and aliphatic and aromatic amino, only react with TMP via proton transfer and/or addition. The specificity of the reaction was further demonstrated by using a sulfoxide-containing anti-inflammatory drug, sulindac, as well as its metabolite sulindac sulfone. CONCLUSIONS: A method based on functional group-selective ion-molecule reactions in a linear quadrupole ion trap mass spectrometer has been demonstrated for the identification of the sulfone functionality in protonated analytes. A characteristic [TMP adduct-MeOH] product ion was only formed for the protonated sulfone analytes. The applicability of the TMP reagent in identifying sulfone functionalities in drug metabolites was also demonstrated. Copyright © 2016 John Wiley & Sons, Ltd.

Alkali Cation Chelation in Cold ß-O-4 Tetralignol Complexes.

We employ cold ion spectroscopy (UV action and IR-UV double resonance) in the gas phase to unravel the qualitative structural elements of G-type alkali metal cationized (X = Li(+), Na(+), K(+)) tetralignol complexes connected by ß-O-4 linkages. The conformation-specific spectroscopy reveals a variety of conformers, each containing distinct infrared spectra in the OH stretching region, building on recent studies of the neutral and alkali metal cationized ß-O-4 dimers. The alkali metal ion is discovered to bind in penta-coordinate pockets to ether and OH groups involving at least two of the three ß-O-4 linkages. Different binding sites are distinguished from one another by the number of M(+)···OH···O interactions present in the binding pocket, leading to characteristic IR transitions appearing below 3550 cm(-1). This interaction is mitigated in the major conformer of the K(+) adduct, demonstrating a clear impact of the size of the charge center on the three-dimensional structure of the tetramer.

Fast pyrolysis of 13C-labeled cellobioses: gaining insights into the mechanisms of fast pyrolysis of carbohydrates.

A fast-pyrolysis probe/tandem mass spectrometer combination was utilized to determine the initial fast-pyrolysis products for four different selectively (13)C-labeled cellobiose molecules. Several products are shown to result entirely from fragmentation of the reducing end of cellobiose, leaving the nonreducing end intact in these products. These findings are in disagreement with mechanisms proposed previously. Quantum chemical calculations were used to identify feasible low-energy pathways for several products. These results provide insights into the mechanisms of fast pyrolysis of cellulose.