Direct Comparison of Solution and Gas-Phase Reactions of the Three Distonic Isomers of the Pyridine Radical Cation with Methanol

To directly compare the reactivity of positively charged carbon-centered aromatic σ-radicals toward methanol in solution and in the gas phase, the 2-, 3-, and 4-dehydropyridinium cations (distonic isomers of the pyridine radical cation) were generated by ultraviolet photolysis of the corresponding iodo precursors in a mixture of water and methanol at varying pH. The reaction mixtures were analyzed by using liquid chromatography/mass spectrometry. Hydrogen atom abstraction was the only reaction observed for the 3- and 4-dehydropyridinium cations (and pyridines) in solution. This also was the major reaction observed earlier in the gas phase. Depending on the pH, the hydrogen atom can be abstracted from different molecules (i.e., methanol or water) and from different sites (in methanol) by the 3- and 4-dehydropyridinium cations/pyridines in solution. In the pH range 1–4, the methyl group of methanol is the main hydrogen atom donor site for both 3- and 4-dehydropyridinium cations (just like in the gas phase). At higher pH, the hydroxyl groups of water and methanol also act as hydrogen atom donors. This finding is rationalized by a greater abundance of the unprotonated radicals that preferentially abstract hydrogen atoms from the polar hydroxyl groups. The percentage yield of hydrogen atom abstraction by these radicals was found to increase with lowering the pH in the pH range 1.0–3.2. This pH effect is rationalized by polar effects: the lower the pH, the greater the fraction of protonated (more polar) radicals in the solution. This finding is consistent with previous results obtained in the gas phase and suggests that gas-phase studies can be used to predict solution reactivity, but only as long as the same reactive species is studied in both experiments. This was found not to be the case for the 2-iodopyridinium cation. Photolysis of this precursor in solution resulted in the formation of two major addition products, 2-hydroxy- and 2-methoxypyridinium cations, in addition to the hydrogen atom abstraction product. These addition products were not observed in the earlier gas-phase studies on 2-dehydropyridinium cation. Their observation in solution is explained by the formation of another reactive intermediate, the 2-pyridyl cation, upon photolysis of 2-iodopyridinium cation (and 2-iodopyridine). The same intermediate was observed in the gas phase but it was removed before examining the reactions of the desired radical, 2-dehydropyridinium cation (which cannot be done in solution)

Reactivity of a σ,σ,σ,σ-Tetraradical: The 2,4,6-Tridehydropyridine Radical Cation

The 2,4,6-tridehydropyridine radical cation, an analogue of the elusive 1,2,3,5-tetradehydrobenzene, was generated in the gas phase and its reactivity examined. Surprisingly, the tetraradical was found not to undergo radical reactions. This behavior is rationalized by resonance structures hindering fast radical reactions. This makes the cation highly electrophilic, and it rapidly reacts with many nucleophiles by quenching the N–C <i>ortho</i>-benzyne moiety, thereby generating a relatively unreactive <i>meta</i>-benzyne analogue

Substituent Effects on the Nonradical Reactivity of 4-Dehydropyridinium Cation

Recent studies have shown that the reactivity of the 4-dehydropyridinium cation significantly differs from the reactivities of its isomers toward tetrahydrofuran. While only hydrogen atom abstraction was observed for the 2- and 3-dehydropyridinium cations, nonradical reactions were observed for the 4-isomer. In order to learn more about these reactions, the gas-phase reactivities of the 4-dehydropyridinium cation and several of its derivatives toward tetrahydrofuran were investigated in a Fourier transform ion electron resonance mass spectrometer. Both radical and nonradical reactions were observed for most of these positively charged radicals. The major parameter determining whether nonradical reactions occur was found to be the electron affinity of the radicalsonly those with relatively high electron affinities underwent nonradical reactions. The reactivities of the monoradicals are also affected by hydrogen bonding and steric effects

Identification of <i>N</i>‑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 <i>in vivo</i> oxidation of sulfur and nitrogen atoms in many drugs into sulfoxide and <i>N</i>-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 <i>N-</i>oxide and sulfoxide functionalities in protonated polyfunctional drug metabolites. Only ions with <i>N</i>-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 <i>N-</i>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 <i>two</i> DMA molecules instead of just one. This provides information on the environment of the <i>N</i>-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

(−)ESI/CAD MS^<i>n</i> Procedure for Sequencing Lignin Oligomers Based on a Study of Synthetic Model Compounds with β‑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 β-O-4 linkages, and three synthesized S-lignin model compounds (a dimer, trimer, and tetramer) with β-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 β-O-4 linkages, or both 5-5 and β-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 β-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