Yunfeng Chai

Hydride transfer reactions via ion–neutral complex: fragmentation of protonated N‐benzylpiperidines and protonated N‐benzylpiperazines in mass spectrometry

An ion-neutral complex (INC)-mediated hydride transfer reaction was observed in the fragmentation of protonated N-benzylpiperidines and protonated N-benzylpiperazines in electrospray ionization mass spectrometry. Upon protonation at the nitrogen atom, these compounds initially dissociated to an INC consisting of [RC(6)H(4)CH(2)](+) (R = substituent) and piperidine or piperazine. Although this INC was unstable, it did exist and was supported by both experiments and density functional theory (DFT) calculations. In the subsequent fragmentation, hydride transfer from the neutral partner to the cation species competed with the direct separation. The distribution of the two corresponding product ions was found to depend on the stabilization energy of this INC, and it was also approved by the study of substituent effects. For monosubstituted N-benzylpiperidines, strong electron-donating substituents favored the formation of [RC(6)H(4)CH(2)](+), whereas strong electron-withdrawing substituents favored the competing hydride transfer reaction leading to a loss of toluene. The logarithmic values of the abundance ratios of the two ions were well correlated with the nature of the substituents, or rather, the stabilization energy of this INC.

Gas-Phase Chemistry of Benzyl Cations in Dissociation of N-Benzylammonium and N-Benzyliminium Ions Studied by Mass Spectrometry

In this study, the fragmentation reactions of various N-benzylammonium and N-benzyliminium ions were investigated by electrospray ionization mass spectrometry. In general, the dissociation of N-benzylated cations generates benzyl cations easily. Formation of ion/neutral complex intermediates consisting of the benzyl cations and the neutral fragments was observed. The intra-complex reactions included electrophilic aromatic substitution, hydride transfer, electron transfer, proton transfer, and nucleophilic aromatic substitution. These five types of reactions almost covered all the potential reactivities of benzyl cations in chemical reactions. Benzyl cations are well-known as Lewis acid and electrophile in reactions, but the present study showed that the gas-phase reactivities of some suitably ring-substituted benzyl cations were far richer. The 4-methylbenzyl cation was found to react as a Brønsted acid, benzyl cations bearing a strong electron-withdrawing group were found to react as electron acceptors, and para-halogen-substituted benzyl cations could react as substrates for nucleophilic attack at the phenyl ring. The reactions of benzyl cations were also related to the neutral counterparts. For example, in electron transfer reaction, the neutral counterpart should have low ionization energy and in nucleophilic aromatic substitution reaction, the neutral counterpart should be piperazine or analogues. This study provided a panoramic view of the reactions of benzyl cations with neutral N-containing species in the gas phase.

Gas‐Phase Nucleophilic Aromatic Substitution between Piperazine and Halobenzyl Cations: Reactivity of the Methylene Arenium Form of Benzyl Cations

Nucleophilic aromatic substitution (SNAr) [1] is one of the most fundamental reactions in organic chemistry. The most popular mechanism for SNAr reactions is an addition–elimination process involving a s complex (Meisenheimer complex) intermediate. Although SNAr reactions in solution have been well documented, there are only a few reports on their gas-phase chemistry. Studying chemical reactions in the gas phase allows to determine the intrinsic features of reactions and to characterize the short-lived intermediates in isolation from solvent, counterion, catalyst interference and aggregation effects. The key stage in a SNAr reaction is the formation of the s complex, which has become a subject of special concern. The typical anionic s complexes formed between anionic nucleophiles and aromatic substrates bearing strong electron-withdrawing groups are found to be relatively stable. In recent years there has been a breakthrough in studies on the gas-phase anionic SNAr reactions [2] and anionic s complexes alone. Although several s complextype structures in the cationic state, such as HC6H6, H + C6H5F and C6H6NH3 + , had been observed in the gas phase by spectroscopy, they showed no aromatic substitution reactivity due to their poor leaving group. Cationic s-complex-mediated SNAr reactions in the gas phase are still rare. Among the few studies performed, the substrate is merely ionized halobenzenes and the nucleophile is ammonia or methyl isocyanide. In this study, we report the gas-phase SNAr reactions between piperazine (nucleophile) and halogen-substituted benzyl cations (substrate) using electrospray ionization mass spectrometry (ESI-MS). Benzyl cations are highly reactive intermediates in various chemical and biochemical reactions. It has been demonstrated that two major resonance forms (A and B), as shown in Scheme 1, contribute significantly to the total structure of the benzyl cation. However the “methylene arenium” form (B) has little contribution in reactions, because the reaction of benzyl cation with electron-rich reagents nearly always occurs at the benzylic methylene group both in solution and in the gas phase due to its maintenance of the aromaticity of the product. One exception in the gas phase was observed in the fragmentation reaction of Fr chet dendrons. In that example, steric constraints force the intramolecular reaction to occur at the phenyl ring of the benzyl cation but not at the benzylic position. To our knowledge, the reaction of halobenzyl cations with piperazine reported here is the first non-restricted case in which the methylene arenium exhibits nucleophilic substitution reactivity at the phenyl ring. Because of the advantages of being solventand counterion-free, mass spectrometry can be exploited to synthesize ions and study gas-phase organic reactions. In the present study, the reactants of piperazine and halobenzyl cations were simultaneously in-situ-generated by collision-induced dissociation (CID) of protonated N-(halobenzyl)piperazines using an ESI ion trap mass spectrometer (Scheme 2). The two nascent reactants with a suitable amount of internal energy are consequently trapped in an ion/neutral complex through electrostatic interactions. The two components of the ion/neutral complex are able to rotate with respect to one another, and therefore they show reactivities similar to those expected for the isolated species. Under CID conditions, the inverse process, in which piperazine attacks the benzylic position of the halobenzyl cation, is prevented; hence, other reactions between the reactants are quite likely to take place. It should be added that the rear-

N-Centered Odd-Electron Ions Formation from Collision-Induced Dissociation of Electrospray Ionization Generated Even-Electron Ions: Single Electron Transfer via Ion/Neutral Complex in the Fragmentation of Protonated N,N′-Dibenzylpiperazines and Protonated N-Benzylpiperazines

Single electron transfer (SET) via ion/neutral complex (INC) was proposed and confirmed to be the key step in the formation of N-centered odd-electron ions from fragmentation of protonated even-electron ions in the present study. Upon collisional activation, the model compounds, protonated N,N′-dibenzylpiperazine and protonated N-benzylpiperazines initially dissociated to form intermediate INCs consisting of N-benzylpiperazine (or piperazine) and benzyl cation. In these ion/neutral complexes, SET reaction and direct separation as well as other reactions were observed and characterized experimentally and theoretically. Density functional theory calculations demonstrated that the energy requirement for homolysis of the precursor ion was so large that it could not be achieved, whereas the heterolytic dissociation followed by electron transfer via INC was energetically preferred. The SET process occurred only when the radical products were more stable than the separation products. The energy barrier for SET in the compounds studied was roughly estimated by comparison with other competing reactions. When the INC contained electron donor with lower ionization energy and electron acceptor with higher electron affinity, the SET reaction was more efficient.

Dissociative Benzyl Cation Transfer versus Proton Transfer: Loss of Benzene from Protonated N-Benzylaniline

In collisional activation of protonated N-benzylaniline, the benzene loss from the benzyl moiety is actually not the result of dissociative proton transfer (PT). In fact, benzyl cation transfer (BCT) from the nitrogen to the anilinic ring (ortho or para position) is the key step for benzene loss. Such dissociation occurs only after the benzyl group migrating from the site with the highest benzylation nucleophilicity (nitrogen) to a different one (aromatic ring carbon), which is described as dissociative benzyl cation transfer.

Kinetic and Thermodynamic Control of Protonation in Atmospheric Pressure Chemical Ionization

AbstractFor p-(dimethylamino)chalcone (p-DMAC), the N atom is the most basic site in the liquid phase, whereas the O atom possesses the highest proton affinity in the gas phase. A novel and interesting observation is reported that the N- and O-protonated p-DMAC can be competitively produced in atmospheric pressure chemical ionization (APCI) with the change of solvents and ionization conditions. In neat methanol or acetonitrile, the protonation is always under thermodynamic control to form the O-protonated ion. When methanol/water or acetonitrile/water was used as the solvent, the protonation is kinetically controlled to form the N-protonated ion under conditions of relatively high infusion rate and high concentration of water in the mixed solvent. The regioselectivity of protonation of p-DMAC in APCI is probably attributed to the bulky solvent cluster reagent ions (SnH+) and the analyte having different preferred protonation sites in the liquid phase and gas phase. Figureᅟ

Gas Phase Chemistry of Li+ with Amides: the Observation of LiOH Loss in Mass Spectrometry

Collision-induced dissociation (CID) of Li+ adducts of three sets of compounds that contains an amide bond, including 2-(4, 6-dimethoxypyrimidin-2-ylsulfanyl)-N-phenylbenzamide, its derivatives and simpler structures was investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Observed fragment ions include those that reflect loss of LiOH. Other product ions result from the Smiles rearrangement and direct C–S bond cleavage. MS/MS of H/D exchange products demonstrated occurrence of a 1,3-H shift from the amide nitrogen atom to the phenyl ring of these compounds. The LiOH loss from Li+ adducts of amides was further examined by CID of [M + Li]+ ions of N-phenylbenzamide and N-phenylcinnamide. Loss of LiOH was essentially the sole fragmentation reaction observed for the former. For the latter, both losses of LiOH and H2O were discovered. The presence of electron-donating substituents of the phenyl ring of these compounds was found to facilitate elimination of LiOH, while that loss was retarded by electron-withdrawing substituents. Proposed fragment ion structures were supported by elemental compositions deduced from ultrahigh resolution Fourier transform ion cyclotron resonance tandem mass spectrometry (FTICR-MS/MS) m/z value determinations. Density functional theory-based (DFT) calculations were performed to evaluate potential mechanisms for these reactions.

Formation of [M + 15]+ ions from aromatic aldehydes by use of methanol: in-source aldolization reaction in electrospray ionization mass spectrometry†

Unexpected [M + 15](+) ions were formed during the analysis of aromatic aldehydes by use of methanol in positive-ion electrospray ionization mass spectrometry. Aromatic aldehydes with electron-withdrawing groups or electron-donating groups were all tested to make sure the universality. All the aromatic aldehydes studied with methanol as the solvent could generate [M + 15](+) ion, and for most of them, the [M + 15](+) ion was more intense than the [M + H](+) ion. Deuterium-labeling experiment, high-performance liquid chromatography-MS experiment, collision-induced dissociation experiment, and theoretical calculations were performed to identify the formation of [M + 15](+) ion. The proposed reaction mechanism is a gas-phase aldol reaction between protonated aromatic aldehydes and methanol occurring in electrospray source. Understanding and using this unique gas-phase ion/molecule reaction can indeed offer a novel and fast approach for the direct identification of aromatic aldehydes.

Qualitative and quantitative analysis of enantiomers by mass spectrometry: Application of a simple chiral chloride probe via rapid in-situ reaction

A tandem mass spectrometry method for high-sensitivity qualitative and quantitative discrimination of chiral amino compounds is conducted. The method is based on a chemical derivation process that uses a simple reagent, L-1-(phenylsulfonyl)pyrrolidine-carbonyl chloride, as the probe. The method is applicable in both organic solutions and biological conditions. Twenty-one pairs of enantiomer containing amino acids, amino alcohols, and amines are used to produce diastereomers using the probe via in situ reaction for 20 s at room temperature. The resulting diastereomers are successfully recognized based on the relative peak intensities of their fragments in positive mode, with the chiral recognition ability values ranging from 0.35 to 3.83. The L/D ratio of Pro spiked at different concentrations (enantiomeric excess) in both acetonitrile and dog plasma is determined by establishing calibration curves. This method achieves a lower limit of quantification of 50 pmol in analyzing amino acids using an extract ion chromatograph. The relative standard deviation for both qualitative and quantitative results is <5%. Thus, the present method is demonstrated as a new and practical technique of rapidly and sensitively determining enantiomers of amino compounds.

Gas phase retro‐Michael reaction resulting from dissociative protonation: fragmentation of protonated warfarin in mass spectrometry

A mass spectrometric study of protonated warfarin and its derivatives (compounds 1 to 5) has been performed. Losses of a substituted benzylideneacetone and a 4-hydroxycoumarin have been observed as a result of retro-Michael reaction. The added proton is initially localized between the two carbonyl oxygens through hydrogen bonding in the most thermodynamically favorable tautomer. Upon collisional activation, the added proton migrates to the C-3 of 4-hydroxycoumarin, which is called the dissociative protonation site, leading to the formation of the intermediate ion-neutral complex (INC). Within the INC, further proton transfer gives rise to a proton-bound complex. The cleavage of one hydrogen bond of the proton-bound complex produces the protonated 4-hydroxycoumarin, while the separation of the other hydrogen bond gives rise to the protonated benzylideneacetone. Theoretical calculations indicate that the 1, 5-proton transfer pathway is most thermodynamically favorable and support the existence of the INC. Both substituent effect and the kinetic method were utilized for explaining the relative abundances of protonated 4-hydroxycoumarin and protonated benzylideneacetone derivative. For monosubstituted warfarins, the electron-donating substituents favor the generation of protonated substituted benzylideneacetone, whereas the electron-withdrawing groups favor the formation of protonated 4-hydroxycoumarin.