Collision-induced Dissociation Research Articles

Differential Mobility Spectrometry-Tandem Mass Spectrometry with Multiple Ion Monitoring Coupled with in Source-Collision Induced Dissociation: A New Strategy for the Quantitative Analysis of Pharmaceutical Polymer Excipients in Rat Plasma.

Polylactic acids (PLAs) are synthetic polymers composed of repeating lactic acid subunits. For their good biocompatibility, PLAs have been approved and widely applied as pharmaceutical excipients and scaffold materials. Liquid chromatography-tandem mass spectrometry is a powerful analytical tool not only for pharmaceutical ingredients but also for pharmaceutical excipients. However, the characterization of PLAs presents particular problems for mass spectrometry techniques. In addition to their high molecular weights and wide polydispersity, multiple charging and various adductions are intrinsic features of electrospray ionization. In the present study, a strategy combining of differential mobility spectrometry (DMS), multiple ion monitoring (MIM) and in-source collision-induced dissociation (in source-CID) has been developed and applied to the characterization and quantitation of PLAs in rat plasma. First, PLAs will be fragmented into characteristic fragment ions under high declustering potential in the ionization source. The specific fragment ions are then screened twice by quadrupoles to ensure a high signal intensity and low interference for mass spectrometry detection. Subsequently, DMS technique has been applied to further reduce the background noise. The appropriately chosen surrogate specific precursor ions could be utilized for the qualitative and quantitative analysis of PLAs, which provided results with the advantages of low endogenous interference, sufficient sensitivity and selectivity for bioassay. The linearity of the method was evaluated over the concentration range 3-100 μg/mL (r2 = 0.996) for PLA 20,000. The LC-DMS-MIM coupled with in source-CID strategy may contribute to the pharmaceutical studies of PLAs and the possible prospects of other pharmaceutical excipients.

Formation and Tandem Mass Spectrometry of Doubly Charged Lipid-Metal Ion Complexes.

Phospholipids are major components of most eukaryotic cell membranes. Changes in metabolic states are often accompanied by phospholipid structure variations. The structural changes of phospholipids are the hallmark of disease states, or specific lipid structures have been associated with distinct organisms. Prime examples are microorganisms that synthesize phospholipids with, for example, different branched chain fatty acids. Assignment and relative quantitation of structural isomers of phospholipids that arise from attachment of different fatty acids to the glycerophospholipid backbone are difficult with routine tandem mass spectrometry or with liquid chromatography without authentic standards. In this work, we report on the observation that all investigated phospholipid classes form doubly charged lipid-metal ion complexes during electrospray ionization (ESI) and show that these complexes can be used to assign lipid classes and fatty acid moieties, distinguish isomers of branched chain fatty acids, and relatively quantify these isomers in positive-ion mode. Use of water free methanol and addition of divalent metal salts (100 mol %) to ESI spray solutions afford highly abundant doubly charged lipid-metal ion complexes (up to 70 times of protonated compounds). Higher-energy collisional dissociation and collision-induced dissociation of doubly charged complexes yield a diverse set of lipid class-dependent fragment ions. In common for all lipid classes is the liberation of fatty acid-metal adducts that yield fragment ions from the fatty acid hydrocarbon chain upon activation. This ability is used to pinpoint sites of branching in saturated fatty acids and is showcased for free fatty acids as well as glycerophospholipids. The analytical utility of doubly charged phospholipid-metal ion complexes is demonstrated by distinguishing fatty acid branching-site isomers in phospholipid mixtures and relatively quantifying the corresponding isomeric compounds.

Collision-Induced Fission of Oblate Gold Superatom in [Au9(PPh3)8]3+: Deformation-Mediated Mechanism.

Collision-induced dissociation (CID) patterns of the phosphine-protected Au-based clusters [PdAu8(PPh3)8]2+ (PdAu8) and [Au9(PPh3)8]3+ (Au9), featuring crown-shaped M@Au8 (M = Pd, Au) cores, were investigated. For PdAu8, ordinary sequential PPh3 losses (PdAu8 → [PdAu8(PPh3)m]2+ + (8 - m)PPh3 (m = 7, 6, 5)) were observed. In contrast, Au9 underwent cluster-core fission (Au9 → [Au6(PPh3)6]2+ (Au6) + [Au3(PPh3)2]+ (Au3)) upon sufficiently high energy collision, associated with splitting the number of valence electrons in the superatomic orbitals from 6e (Au9) into 4e (Au6) and 2e (Au3). Density functional theory calculations revealed oblate and prolate cores of Au9 and Au6 with semiclosed superatomic electron configurations of (1S)2(1Px)2(1Py)2 and (1S)2(1Pz)2, respectively. This result indicated a significant deformation of the cluster-core motif during the CID process. We attribute the clear difference between PdAu8 and Au9 to the softer Au-Au bond in Au9 and propose that the collision-induced structural deformation plays a critical role in the fission.

Chemical Transformations Can Occur during DMS Separations: Lessons Learned from Beer's Bittering Compounds.

While developing a DMS-based separation method for beer's bittering compounds, we observed that the argentinated forms of humulone tautomers (i.e., [Hum + Ag]+) were partially resolvable in a N2 environment seeded with 1.5 mol % of isopropyl alcohol (IPA). Attempting to improve the separation by introducing resolving gas unexpectedly caused the peaks for the cis-keto and trans-keto tautomers of [Hum + Ag]+ to coalesce. To understand why resolution loss occurred, we first confirmed that each of the tautomeric forms (i.e., dienol, cis-keto, and trans-keto) responsible for the three peaks in the [Hum + Ag]+ ionogram were assigned to the correct species by employing collision-induced dissociation, UV photodissociation spectroscopy, and hydrogen-deuterium exchange (HDX). The observation of HDX indicated that proton transfer was stimulated by dynamic clustering processes between IPA and [Hum + Ag]+ during DMS transit. Because IPA accretion preferentially occurs at Ag+, which can form pseudocovalent bonds with a suitable electron donor, solvent clustering also facilitated the formation of exceptionally stable microsolvated ions. The exceptional stability of these microsolvated configurations disproportionately impacted the compensation voltage (CV) required to elute each tautomer when the temperature within the DMS cell was varied. The disparity in CV response caused the peaks for the cis- and trans-keto species to merge when a temperature gradient was induced by the resolving gas. Moreover, simulations showed that microsolvation with IPA mediates dienol to trans-keto tautomerization during DMS transit, which, to the best of our knowledge, is the first observation of keto/enol tautomerization occurring within an ion-mobility device.

A Dual-Gated Structures for Lossless Ion Manipulations-Ion Mobility Orbitrap Mass Spectrometry Platform for Combined Ultra-High-Resolution Molecular Analysis.

High-resolution ion mobility spectrometry-mass spectrometry (HR-IMS-MS) instruments have enormously advanced the ability to characterize complex biological mixtures. Unfortunately, HR-IMS and HR-MS measurements are typically performed independently due to mismatches in analysis time scales. Here, we overcome this limitation by using a dual-gated ion injection approach to couple an 11 m path length structures for lossless ion manipulations (SLIM) module to a Q-Exactive Plus Orbitrap MS platform. The dual-gate setup was implemented by placing one ion gate before the SLIM module and a second ion gate after the module. The dual-gated ion injection approach allowed the new SLIM-Orbitrap platform to simultaneously perform an 11 m SLIM separation, Orbitrap mass analysis using the highest selectable mass resolution setting (up to 140 k), and high-energy collision-induced dissociation (HCD) in ∼25 min over an m/z range of ∼1500 amu. The SLIM-Orbitrap platform was initially characterized using a mixture of standard phosphazene cations and demonstrated an average SLIM CCS resolving power (RpCCS) of ∼218 and an SLIM peak capacity of ∼156, while simultaneously obtaining high mass resolutions. SLIM-Orbitrap analysis with fragmentation was then performed on mixtures of standard peptides and two reverse peptides (SDGRG1+, GRGDS1+, and RpCCS = 305) to demonstrate the utility of combined HR-IMS-MS/MS measurements for peptide identification. Our new HR-IMS-MS/MS capability was further demonstrated by analyzing a complex lipid mixture and showcasing SLIM separations on isobaric lipids. This new SLIM-Orbitrap platform demonstrates a critical new capability for proteomics and lipidomics applications, and the high-resolution multimodal data obtained using this system establish the foundation for reference-free identification of unknown ion structures.

Influence of 2'-Modifications (O-Methylation, Fluorination, and Stereochemical Inversion) on the Base Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities of i-Motif Structures.

Naturally occurring and chemically engineered modifications are among the most powerful strategies explored for fine-tuning the conformational characteristics and intrinsic stability of nucleic acids topologies. Modifications at the 2'-position of the ribose or 2'-deoxyribose moieties differentiate nucleic acid structures and have a significant impact on their electronic properties and base-pairing interactions. 2'-O-Methylation, a common post-transcriptional modification of tRNA, is directly involved in modulating specific anticodon-codon base-pairing interactions. 2'-Fluorinated and arabino nucleosides possess novel and beneficial medicinal properties and find use as therapeutics for treating viral diseases and cancer. However, the potential to deploy 2'-modified cytidine chemistries for tuning i-motif stability is largely unknown. To address this knowledge gap, the effects of 2'-modifications including O-methylation, fluorination, and stereochemical inversion on the base-pairing interactions of protonated cytidine nucleoside analogue base pairs, the core stabilizing interactions of i-motif structures, are examined using complementary threshold collision-induced dissociation techniques and computational methods. The 2'-modified cytidine nucleoside analogues investigated here include 2'-O-methylcytidine, 2'-fluoro-2'-deoxycytidine, arabinofuranosylcytosine, 2'-fluoro-arabinofuranosylcytosine, and 2',2'-difluoro-2'-deoxycytidine. All five 2'-modifications examined here are found to enhance the base-pairing interactions relative to the canonical DNA and RNA cytidine nucleosides with the greatest enhancements arising from 2'-O-methylation and 2',2'-difluorination, suggesting that these modifications should well be tolerated in the narrow grooves of i-motif conformations.

Protonated and Sodiated Cyclophosphamide Fragmentation Pathways Evaluation by Infrared Multiple Photon Dissociation Spectroscopy.

Cyclophosphamide (CP or CTX) is a widely used antineoplastic agent, and the evaluation of its efficacy and its impacts on the environment are dependent on tandem mass spectrometry (MSn) techniques. Because there is no dedicated experimental study to characterize the actual molecular nature of the CP fragments upon collision-induced dissociation, this work evaluated the chemical structure of the fragments of protonated and sodiated CP and CP protonation sites by infrared multiple photon dissociation spectroscopy supported by density functional theory calculations. This study allowed us to propose a new fragment structure and confirm the nature of multiple fragments, including those relevant for transitions used for CP quantitative and qualitative analyses. Our results also show that there is no spectroscopic evidence that can rule out the existence of aziridinium fragments, making it clear that further studies on the nature of iminium/aziridinium fragments in the gas phase are necessary.

Unimolecular Reactivity of [Cu(R)(CF3 )3 ]- Complexes (R=Organyl): Stepwise versus Concerted Mechanism in Copper-Mediated Trifluoromethylation.

The cuprate complexes [Cu(R)(CF3 )3 ]- (R=organyl) offer an efficient synthetic access to valuable trifluoromethylation products RCF3 . Here, electrospray-ionization mass spectrometry is used to analyze the formation of these intermediates in solution and probe their fragmentation pathways in the gas phase. Furthermore, the potential energy surfaces of these systems are explored by quantum chemical calculations. Upon collisional activation, the [Cu(R)(CF3 )3 ]- complexes (R=Me, Et, Bu, s Bu, allyl) afford the product ions [Cu(CF3 )3 ]⋅- and [Cu(CF3 )2 ]- . The former obviously results from an R⋅ loss, whereas the latter originates either from the stepwise release of R⋅ and CF3 ⋅ radicals or a concerted reductive elimination of RCF3 . The gas-phase fragmentation experiments as well as the quantum chemical calculations indicate that the preference for the stepwise reaction toward [Cu(CF3 )2 ]- increases with the stability of the formed organyl radical R⋅. This finding suggests that the recombination of R⋅ and CF3 ⋅ radicals may possibly contribute to the formation of RCF3 from [Cu(R)(CF3 )3 ]- in synthetic applications. In contrast, the [Cu(R)(CF3 )3 ]- complexes (R=aryl) only yield [Cu(CF3 )2 ]- when subjected to collision-induced dissociation. These species exclusively undergo a concerted reductive elimination because the competing stepwise pathway is disfavored by the low stability of aryl radicals.

Separation of Isobaric Lipids in Imaging Mass Spectrometry Using Gas-Phase Charge Inversion Ion/Ion Reactions.

The diverse array of chemical compounds present in tissue samples results in many isobaric (i.e., same nominal mass) compounds in imaging mass spectrometry experiments. Adequate separation and differentiation of these compounds is necessary to ensure accurate analyte identification and avoid composite images comprising multiple compounds. High-resolution accurate mass (HRAM) measurements are able to resolve these compounds in some instances, but HRAM measurements are not always feasible depending on the instrument platform and the desired experimental time scale. Alternatively, tandem mass spectrometry (MS/MS) can be used to perform gas-phase transformations that improve molecular specificity. While conventional MS/MS methods employ collision induced dissociation (CID) to fragment compounds of interest and then analyze the product masses, gas-phase ion/ion reactions can be used to instead selectively react with desired classes of analytes. Herein, we have used gas-phase charge inversion ion/ion reactions to selectively resolve phosphatidylcholines (PCs) in isobaric lipid mixtures. A 1,4-phenylenedipropionic acid (PDPA) reagent dianion readily reacts with [M + H]+, [M + Na]+, and [M + K]+ ion types to produce demethylated product anions for each PC, [PC - CH3]-. These product anions are no longer isobaric and now differ in mass by 22 Da (protonated versus sodiated) and 16 Da (sodiated versus potassiated), respectively. This reaction has been used to differentiate isobaric lipids in the imaging mass spectrometry analysis of rat brain tissue.

Prediction of Fragmentation Pathway of Azilsartan Protonated Ion Using High Resolution Mass Spectrometry (HR-MS/MS) with Q-TOF Analyzer- A Perspective Study

Introduction: UPLC coupled with a high-resolution mass analyzer i.e, Q-TOF analyzer with electrospray ionization (ESI) source using collision-induced dissociation (CID) method was applied to study the characteristic product ions of azilsartan protonated ion. Method: The experimental results of high-resolution mass spectra explained the elemental compositions of product ions accurately and reasonable fragmentation pathways were proposed for azilsartan protonated ions. Calculated mass error in parts per million (ppm) for molecular ions and product ions and results of mass error found from this study from 0.2 ppm to 3.5 ppm. Result: The characteristic fragmentation pathways were helpful to analyze and interpret the stability and possible degradation pathway of the parent ion. Conclusion: The present study explains the significant role of high-resolution mass spectrometry in the structural analysis of the protonated ion of azilsartan.

Cover Feature: Electrospray Ionization Tandem Mass Spectrometry With Collision Induced Dissociation of Uranyl Peroxide Nanoclusters Containing Various Uranyl Bridging Ligands (Chem. Eur. J. 39/2023)

Detecting the presence of uranyl peroxide nanoclusters (UPCs) in solution is difficult, so this study used tandem mass spectrometry with collision-induced dissociation to probe bridging ions surrounding the uranyl ion and to determine fragmentation fingerprints of UPCs. The image shows an abstract artistic representation of the nanocluster U24Pp12, [(UO2)24(O2)24(P2O7)12]48–, and its movement through a quadrupole mass analyzer with subsequent fragmentation. More information can be found in the Research Article by V. G. Rodriguez and P. C. Burns (DOI: 10.1002/chem.202300794). Image designed by V.G.R.

High throughput LC/ESI-MS/MS method for simultaneous analysis of 20 oral molecular-targeted anticancer drugs and the active metabolite of sunitinib in human plasma

Many types of oral molecular-targeted anticancer drugs are clinically used in cancer genomic medicine. Combinations of multiple molecular-targeted anticancer drugs are also being investigated, expecting to prolong the survival of patients with cancer. Therapeutic drug monitoring of oral molecular-targeted drugs is important to ensure efficacy and safety. A liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) has been used for simultaneous determination of these drugs in human plasma. However, the sensitivity of mass spectrometers and differences in the therapeutic range of drugs have rendered the development of simultaneous LC/ESI-MS/MS methods difficult. In this study, a simultaneous quantitative method for 20 oral molecular-targeted anticancer drugs and the active metabolite of sunitinib was developed based on the results of linear range shifts of the calibration curves using four ion abundance adjustment techniques (collision energy defects, in-source collision-induced dissociation, secondary product ion selected reaction monitoring, and isotopologue selected reaction monitoring). The saturation of the detector for the seven analytes was resolved by incorporating optimal ion abundance adjustment techniques. Furthermore, the reproducibility of this method was confirmed in validation tests, and plasma from patients was measured by this method to demonstrate its usefulness in actual clinical practice. This analytical method is expected to make a substantial contribution to the promotion of personalized medicine in the future.

Noncovalent Modulation of Chemoselectivity in the Gas Phase Leads to a Switchover in Reaction Type from Heterolytic to Homolytic to Electrocyclic Cleavage.

Inthe gas phase, thermal activation of supramolecular assemblies such as host-guest complexes leads commonly to noncovalent dissociation into the individual components. Chemical reactions, for example of encapsulated guest molecules, are only found in exceptional cases. As observed by mass spectrometry, when 1-amino-methyl-2,3-diazabicyclo[2.2.2]oct-2-ene (DBOA) is complexed by the macrocycleb-cyclodextrin, its protonated complex undergoes collision-induced dissociation into its components, the conventional reaction pathway. Inside the macrocyclic cavity of cucurbit[7]uril (CB7), a competitive chemical reaction of monoprotonated DBOA takes place upon thermal activation, namely a stepwise homolytic covalent bond cleavage with the elimination of N2, while the doubly protonated CB7•DBOA complex undergoes an inner-phase elimination of ethylene, a concerted, electrocyclic ring-opening reaction. These chemical reaction pathways stand in contrast to the gas-phase chemistry of uncomplexed monoprotonated DBOA, for which an elimination of NH3predominates upon collision-induced activation, as a heterolytic bond cleavage reaction. The combined results, which can be rationalized in terms of organic-chemical reaction mechanisms and density-function theoretical calculations, demonstrate that chemical reactions in the gas phase can be steered chemoselectively through noncovalent interactions.

On the Gas-Phase Interactions of Alkyl and Phenyl Formates with Water: Ion-Molecule Reactions with Proton-Bound Water Clusters.

Ion-molecule reactions between the neutral ethyl- (EF), isopropyl- (IF), t-butyl- (TF) and phenyl formate (PF) and proton-bound water clusters W2H+ and W3H+ (W = H2O) showed that the major reaction product is water loss from the initial encounter complex, followed ultimately by the formation of the protonated formate. Collision-induced dissociation breakdown curves of the formate-water complexes were obtained as a function of collision energy and modeled to extract relative activation energies for the observed channels. Density functional theory calculations (B3LYP/6-311+G(d,p)) of the water loss reactions were consistent with reactions having no reverse energy barrier in each case. Overall, the results indicate that the interaction of formates with atmospheric water can form stable encounter complexes that will dissociate by sequential water loss to form protonated formates.

Argentination: A Silver Bullet for Cannabinoid Separation by Differential Mobility Spectrometry.

As the legality of cannabis continues to evolve globally, there is a growing demand for methods that can accurately quantitate cannabinoids found in commercial products. However, the isobaric nature of many cannabinoids, along with variations in extraction methods and product formulations, makes cannabinoid quantitation by mass spectrometry (MS) challenging. Here, we demonstrate that differential mobility spectrometry (DMS) and tandem-MS can distinguish a set of seven cannabinoids, five of which are isobaric: Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-THC, exo-THC, cannabidiol, cannabichromene, cannabinol, and cannabigerol. Analytes were detected as argentinated species ([M + Ag]+), which, when subjected to collision-induced dissociation, led to the unexpected discovery that argentination promotes distinct fragmentation patterns for each cannabinoid. The unique fragment ions formed were rationalized by discerning fragmentation mechanisms that follow each cannabinoid's MS3 behavior. The differing fragmentation behaviors between species suggest that argentination can distinguish cannabinoids by tandem-MS, although not quantitatively as some cannabinoids produce small amounts of a fragment ion that is isobaric with the major fragment generated by another cannabinoid. By adding DMS to the tandem-MS workflow, it becomes possible to resolve each cannabinoid in a pure N2 environment by deconvoluting the contribution of each cannabinoid to a specific fragmentation channel. To this end, we used DMS in conjunction with a multiple reaction monitoring workflow to assess cannabinoid levels in two cannabis extracts. Our methodology exhibited excellent accuracy, limits of detection (10-20 ppb depending on the cannabinoid), and linearity during quantitation by standard addition (R2 > 0.99).

Kendrick mass defect analysis - a tool for high-resolution Orbitrap mass spectrometry of native lignin.

Lignin is the second most abundant biopolymer in nature and a promising renewable feedstock for the production of aromatic compounds, composite materials, sorbents, etc. Being a complex mixture of oligomeric molecules with anirregular structure, natural lignin is an extremely difficult object to study. Its molecular level characterization requires advanced analytical techniques among which atmospheric pressure photoionization Orbitrap mass spectrometry holds a promising place. In the present study, Kendrick mass defect (KMD) analysis was proposed to facilitate the visualization and interpretation of Orbitrap mass spectra of the biopolymer on an example of Siberian pine dioxane lignin preparation. The use of the typical guaiacylpropane structure C10H12O4 as a Kendrick base unit made it possible to effectively identify oligomer series with different polymerization degrees and structurally related compounds, as well as to reliably determine the elemental compositions and structures of oligomers with high molecular weights (> 1kDa). For the first time, KMD analysis was applied to the interpretation of the complex tandem mass spectra of lignin oligomers, rapid discrimination of the product ion series, and the establishment of the main collision-induced dissociation pathways. It was demonstrated that especially promising was the use of KMD filtering in the study of broadband fragmentation tandem mass spectra, which allows for the structural characterization of all oligomers with a particular degree of polymerization.

Dissociation Kinetics in Quadrupole Ion Traps: Effective Temperatures under Dipolar DC Collisional Activation Conditions.

Ions stored in an electrodynamic ion trap can be forced from the center of the ion trap to regions of higher radio frequency (RF) electric fields by exposing them to a dipolar DC (DDC) potential applied across opposing electrodes. Such ions absorb power from the trapping RF field, resulting in increased ripple motion at the frequency of the trapping RF. When a bath gas is present, ions undergo energetic collisions that result in "RF-heating" sufficient to induce fragmentation. DDC is therefore a broad-band (i.e., mass-to-charge-independent) means for collisional activation in ion traps with added bath gas. Under appropriate conditions, the internal energy distribution of an ion population undergoing dissociation can be approximated with an effective temperature, Teff. In such cases, it is possible to determine thermal activation parameters, such as Arrhenius activation energies and A-factors, by measuring dissociation kinetics. In this work, the well-studied thermometer ion, protonated leucine enkephalin, was subjected to DDC activation under rapid energy exchange conditions and in two separate bath gases, N2 and Ar, to measure Teff as a function of the ratio of DDC and RF voltages. As a result, an empirically derived calibration was generated to link experimental conditions to Teff. It was also possible to quantitatively evaluate a model described by Tolmachev et al. that can be used to predict Teff. It was found that the model, which was derived under the assumption of an atomic bath gas, accurately predicts Teff when Ar was used as the bath gas but overestimates Teff when N2 was the bath gas. Adjustment of the Tolmachev et al. model for a diatomic gas resulted in an underestimate of Teff. Thus, use of an atomic gas can provide accurate activation parameters, while an empirical correction factor should be used to generate activation parameters using N2.

Electrospray ionization tandem mass spectrometry with collision induced dissociation of uranyl peroxide nanoclusters containing various uranyl bridging ligands.

We utilized electrospray ionization tandem mass spectrometry with collision-induced dissociation (ESI-MS/MS) to study the gas phase fragmentation of uranyl peroxide nanoclusters with hydroxo, peroxo, oxalate, and pyrophosphate bridging ligands. These nanoclusters fragment into uranium monomers and dimers with mass-to-charge (m/z) ratios in the 280-380 region. The gas phase fragmentation of each cluster studied yields a distinct UO6- anion attributed to the cleavage of a uranyl ion bound to 2 peroxide groups, along with other anions that can be attributed to the initial composition of the nanoclusters.

Synthesis, experimental and molecular dynamics simulation of the ESI-CID spectrum of the nerve agent Novichok analog O-2-methoxyethyl N- [bis(dimethylamino)methylidene]-P-methylphosphonamidate

The comprehensive and accurate analysis of mass spectral data is critical for the unequivocal identification of environmental samples containing compounds short-listed by the Chemical Weapons Convention (CWC). In particular, experiments with nerve agents are limited by the high risks involved in their handling. Therefore, the possibility of studying fragmentation pathways by a theoretical approach is especially welcome. In this work, for the first time, O-2-methoxyethyl N- [bis(dimethylamino)methylidene]-P-methylphosphonamidate, an analog of the Novichok nerve agent A-242, was synthesized employing a one-pot microscale synthesis. Electron ionization (EI) and electrospray ionization (ESI) mass spectra (MS) were measured to provide data for CWC verification purposes. Considering that ESI-MS/MS is a powerful method for analyzing non-volatile, highly polar, and very water-soluble compounds, such as degradation products of nerve agents, we extensively investigated for the first time the ESI-(collision-induced dissociation) CID fragmentation pathways of the selected molecule. For this purpose, molecular dynamics simulations using the Quantum Chemical Mass Spectrometry (QCxMS) method employing the semiempirical electronic structure method GFN2-xTB were compared with Triple Quadrupole electrospray ionization (ESI) experimental spectra in positive ion mode. The base peak of the EI spectrum for this molecule was found to be m/z 151, which strongly suggests a McLafferty +1 (ML+1) rearrangement involving the 2-methoxyethyl moiety. The formation of ion the m/z 106 in the ESI-CID spectrum, according to the simulations, results from the rearrangement involving a transfer of one dimethylamino group to the phosphorus atom, a mechanism that would be difficult to identify without employing theoretical methods.

Probing Intermediates of Ion/Molecule Reactions by their Independent Gas‐Phase Synthesis and Fragmentation – The Thiomethoxymethyl Complexes [(bipy)M(CH2SCH3)]+ (M=Pt, Pd, Ni)

AbstractIn the ion/molecule reaction (IMR) of “rollover”‐cyclometalated [(bipy−H)Pt]+ with (CH3)2S, the loss of C2H4 from the encounter complex was observed as the main process some years ago. The cationic complex [(bipy)Pt(CH2SCH3)]+ was identified as a crucial intermediate by DFT calculations. In order to prove its key role experimentally, the cation has now been generated independently and studied by collision‐induced dissociation (CID). The main process is C2H4 loss, which proves [(bipy)Pt(CH2SCH3)]+ to be an intermediate also in the IMR of [(bipy−H)Pt]+ with (CH3)2S. Based on DFT calculations, the thiomethoxymethyl complexes [(bipy)M(CH2SCH3)]+ (M=Pd and Ni) would also serve as intermediates in the IMRs of [(bipy−H)M]+. While these IMRs cannot be studied explicitly, because the parent ions cannot be generated, the potential intermediate [(bipy)M(CH2SCH3)]+ has been subjected to CID. The main fragmentation channels for both metals corresponds to C2H4 loss. The CID experiments thus provide insights into the hypothetical IMRs of [(bipy−H)M]+ with (CH3)2S. The comparison of the DFT calculations for all three metals Ni, Pd, and Pt with the experimental findings uncovers subtle aspects of the underlying reaction mechanisms. This work highlights the suitability of CID experiments of potential reaction intermediates for the elucidation of reaction mechanisms of IMRs as well as the limitations of this approach.