Electrospray ionization mass spectrometric characterization of key Te(IV) cationic intermediates for the addition of TeCl4 to alkynes

Tellurium tetrachloride adds to alkynes via two pathways: a concerted syn-addition that yields Z-tri- and -tetrasubstituted alkenes or an anti-addition that yields E-alkenes. The mechanistic aspects of these divergent pathways for TeCl4 addition to alkynes have been investigated by on-line electrospray ionization (tandem) mass spectrometry (ESI-MS(/MS)). Via ESI-MS(/MS), we have been able to intercept and characterize the active electrophile TeCl3+ in tetrahydrofuran (THF) solutions of TeCl4, as well as its THF complex and several TeClx(OH)y+ derivatives. For the first time, also, key Te(IV) cationic intermediates of the electrophilic addition of TeCl4 to alkynes were captured for gas-phase MS investigation. The detailed structural data of cyclic tellurane intermediates intercepted herein seems to provide insights into the coordinative behavior of the Te(IV) atom and its mode of action towards biological targets.     

The mechanism of Tröger's base formation probed by electrospray ionization mass spectrometry

Using direct infusion electrospray ionization mass and tandem mass spectrometric experiments [ESI-MS(/MS)], we have performed on-line monitoring of some reactions used to form Tr?ger's bases. Key intermediates, either as cationic species or as protonated forms of neutral species, have been intercepted and characterized. The role of urotropine as the methylene source in these reactions has also been accessed. Reaction pathways shown by ESI-MS(/MS) have been probed by gas-phase ion/molecule reactions, and an expanded mechanism for Tr?ger's base formation based on the mass spectrometric data has been elaborated.     

Studies on CH3CN-assisted decomposition of 1st Grubbs catalyst by electrospray ionization tandem mass spectrometry

The CH(3)CN-assisted decomposition reaction of the 1(st) Grubbs catalyst (1) was studied using electrospray ionization tandem mass spectrometry (ESI-MS/MS). We detected a series of Ru-intermediates and decomposition products by off-line and on-line ESI-MS(/MS) monitoring of the decomposition process. In particular, an on-line microreactor method was applied with ESI-MS/MS to profile the change and relationship of various Ru-intermediates by controlling the reaction within the first 30 s of its time scale. The main fast decomposition mechanism of Ru-catalyst 1 in the presence of CH(3)CN was similar to that proposed by Grubbs, and this was confirmed by detecting the (PhCH(2)PCy(3))(+) ion at m/z 371 as the major decomposition products with ESI-MS. We also studied the time evolution of the transient reactive Ru-intermediate ions step by step with ESI-MS/MS and detected the C-H bond activation products of toluene--dehydrogenated PCy(3), such as P(Cy)(2)(C(6)H(9)), P(Cy)(2)Ph--by analyzing the decomposition reaction solution by gas chromatography (GC)/MS. The mechanism of another minor decomposition pathway involving the phosphine activation of catalyst 1 was proposed on the basis of the ESI-MS(/MS) interception and characterization of the transient reactive Ru-species in the decomposition reaction solution. Finally the coordination effect of the CH(3)CN in assisting the decomposition and stabilizing the transient Ru-complexes is discussed.     

Investigation of reaction mechanisms by electrospray ionization mass spectrometry: characterization of intermediates in the degradation of phenol by a novel iron/magnetite/hydrogen peroxide heterogeneous oxidation system

Electrospray ionization (ESI) mass spectrometry (MS) and tandem mass spectrometry (MS/MS) were used to monitor the oxidation of phenol by a novel heterogeneous Fenton system based on a Fe(0)/Fe(3)O(4) composite and H(2)O(2). On-line ESI-MS(/MS) shows that this heterogeneous system promotes prompt oxidation of phenol to hydroquinone, which is subsequently oxidized to quinone, other cyclic poly-hydroxylated intermediates and an acyclic carboxylic acid. A peroxide-type intermediate, probably formed via an electrophilic attack of HOO(.) on the phenol ring, was also intercepted and characterized. ESI-MS(/MS) monitoring of the oxidation of two other model aromatic compounds, benzene and chlorobenzene, indicates the participation of analogous intermediates. These results suggest that oxidation by the heterogeneous system is promoted by highly reactive HO(.) and HOO(.) radicals generated from H(2)O(2) on the surface of the Fe(0)/Fe(3)O(4) composite via a classical Fenton-like mechanism.     

Chelation-controlled radical chain reactions studied by electrospray ionization mass spectrometry

Electrospray ionization mass spectrometry (ESI-MS) is a novel tool for the investigation of chemical reactions in solution and for the direct detection and identification of reactive intermediates. The tributyltin hydride mediated addition of tert-butyl iodide to dimethyl 2-cyclohexyl-4-methyleneglutarate (2) in the presence of Lewis acids was investigated by ESI-MS using a microreactor coupled on-line to an ESI mass spectrometer. For the first time we have been able to show that transient radicals in radical chain reactions can be detected unambiguously under steady-state conditions in the reaction solution and can be characterized by ESI-MS/MS and accurate mass determination. The detection of different heterodimer radical complexes by ESI-MS/MS has provided new insights into the mechanism of Lewis acid controlled radical chain reactions. Dimeric chelate complexes of glutarates, such as 2 and 3, and Lewis acids, like Sc(OTf)3, MgBr2OEt2 and LiClO4, were observed as well as higher aggregates with additional equivalents of Lewis acid. Evidence for a dynamic equilibrium of the complexes in solution was found by NMR spectroscopy. The ESI-MS investigation of the chelation of glutarate 2 with various Lewis acids has led to the conclusion that the tendency for Lewis acids to form dimeric chelate complexes and higher aggregates has an important effect on the stereoselective outcome of the radical reactions.     

The mechanism of the Stille reaction investigated by electrospray ionization mass spectrometry

On-line monitoring of Stille reactions was performed via direct infusion electrospray ionization mass spectrometry (ESI-MS) and its tandem version (ESI-MS/MS). When operated in the positive ion mode, ESI(+)-MS was able to transfer, directly from solution to the gas phase, the species involved in all main steps of a Stille reaction, that is, the catalytically active palladium species Pd(PPh3)2, in its molecular ion form as well as the key cationic Pd(II) intermediates, including cyclic IPd-(CH2CH)Sn species. When searching for anionic species, ESI(-)-MS monitoring showed I- as the only anion detectable in the reaction medium. A detailed catalytic cycle for a Stille reaction was elaborated in which reaction intermediates and the previously elusive catalytically active Pd(0) species are shown in association with the respective ionic species intercepted by ESI-MS and further characterized by ESI-MS/MS.     

Electrospray ionization mass spectrometry: a major tool to investigate reaction mechanisms in both solution and the gas phase

Electrospray ionization mass spectrometry (ESI-MS), in conjunction with its tandem version ESI-MS/MS, is now established as a major tool to study reaction mechanisms in solution. This suitability results mainly from the ability of ESI to "fish" ions directly from solution to the gas phase environment of mass spectrometers. In this review, we summarize recent studies from our laboratory on the use of on-line monitoring by ESI-MS ion fishing of several types of reactions that permitted us to follow how these reactions progress as a function of both time and conditions using the ultra-high sensitivity and speed of ESI-MS to detect and even characterize transient reaction intermediates. We also show that the intrinsic reactivity of each key gaseous species fished by ESI can be further investigated via ESI-tandem mass spectrometry experiments, searching for the most active species via gas-phase ion/molecule reactions. In the gas-phase, solvent and counter-ion effects are absent. These studies often permit a detailed overview of major steps via the interception, characterization and reactivity investigation of key reaction players.     

Study of the Transient Reactive Pd(IV) Intermediate in the Pd(OAc)2‐Catalyzed Oxidative Coupling Reaction System by Electrospray Ionization Tandem Mass Spectrometry

Pd‐catalyzed oxidative coupling reaction was of great importance in the aromatic C? H activation and the formation of new C? O and C? C bonds. Sanford has pioneered practical, directed C? H activation reactions employing Pd(OAc)₂ as catalyst since 2004. However, until now, the speculated reactive Pd(IV) transient intermediates in these reactions have not been isolated or directly detected from reaction solution. Electrospray ionization tandem mass spectrometry (ESI‐MS/MS) was used to intercept and characterize the reactive Pd(IV) transient intermediates in the solutions of Pd(OAc)₂‐catalyzed oxidative coupling reactions. In this study, the Pd(IV) transient intermediates were detected from the solution of Pd(OAc)₂‐catalyzed oxidative coupling reactions by ESI‐MS and the MS/MS of the intercepted Pd(IV) transient intermediate in reaction system was the same with the synthesized authentic Pd(IV) complex. Our ESI‐MS(/MS) studies confirmed the presence of Pd(IV) reaction transient intermediates. Most interestingly, the MS/MS of Pd(IV) transient intermediates showed the reductive elimination reactivity to Pd(II) complexes with new C? O bond formation into product in gas phase, which was consistent with the proposed reactivity of the Pd(IV) transient intermediates in solution.     

Investigation of radical cation in electrophilic fluorination by ESI-MS

Reaction solutions of selectfluor (1) with triphenylethylene (4a) and tetraphenylethylene (4b) were monitored by ESI-MS and ESI-MS/MS. Detection and characterization of the key radical cationic intermediates 5a.+ and 5b.+) fully supports the SET mechanism in electrophilic fluorination as depicted above. [reaction: see text]     

ESI-MS detection of proposed reaction intermediates in the air-promoted and ligand-modulated oxidative Heck reaction

Electrospray ionization mass spectrometry (ESI-MS) and subsequent MS/MS analyses were used to directly detect palladium-containing cationic reaction intermediates in a ligand controlled palladium(II)-catalyzed oxidative Heck arylation. All potential intermediates were observed as dmphen-ligated palladium(II) species, suggesting that the dmphen bidentate ligand is attached to the metal center during the entire catalytic cycle. The study supports previous mechanistic propositions and provides new information regarding the composition of aryl-containing Pd(II) complexes in an ongoing oxidative Heck reaction. In addition, sodium acetate was found to be a useful base alternative to previously used tertiary amines.     

Brønsted Acid Catalyzed Morita–Baylis–Hillman Reaction: A New Mechanistic View for Thioureas Revealed by ESI‐MS(/MS) Monitoring and DFT Calculations

A Morita–Baylis–Hillman (MBH) reaction catalyzed by thiourea was monitored by ESI‐MS(/MS) and key intermediates were intercepted and characterized. These intermediates suggest that thiourea acts as an organocatalyst in all steps of the MBH reaction cycle, including the rate‐limiting proton‐transfer step. DFT calculations, performed for a model MBH reaction between formaldehyde and acrolein with trimethylamine as base and in the presence or the absence of thiourea, suggest that thiourea accelerates MBH reactions by decreasing the transition‐state (TS) energies through bidentate hydrogen bonding throughout the whole catalytic cycle. In the rate‐limiting proton‐transfer step, the thiourea acts not as a proton shuttle, but as a Brønsted acid stabilizing the basic oxygen center that is formed in the TS.     

Analysis of synthetic chemical drugs in adulterated Chinese medicines by capillary electrophoresis/electrospray ionization mass spectrometry

Sixteen synthetic chemical drugs, often found in adulterated Chinese medicines, were studied by capillary electrophoresis/UV absorbance (CE/UV) and capillary electrophoresis/electrospray ionization mass spectrometry (CE/ESI-MS). Only nine peaks were detected with CZE/UV, but on-line CZE/MS provided clear identification for most compounds. For a real sample of a Chinese medicinal preparation, a few adulterants were identified by their migration times and protonated molecular ions. For coeluting compounds, more reliable identification was achieved by MS/MS in selected reaction monitoring mode. Micellar electrokinetic chromatography (MEKC) using sodium dodecyl sulfate (SDS) provided better separation than capillary zone electrophoresis (CZE), and, under optimal conditions, fourteen peaks were detected using UV detection. In ESI, the interference of SDS was less severe in positive ion mode than in negative ion mode. Up to 20 mM SDS could be used in direct coupling of MEKC with ESI-MS if the mass spectrometer was operated in positive ion mode. Because of better resolution in MEKC, adulterants can be identified without the use of MS/MS.     

ESI-MS study on the aldol reaction catalyzed by L-proline

The aldol reaction catalyzed by L-proline has been monitored and the accepted mechanism confirmed by intercepting and characterizing, for the first time, all the proposed intermediates by ESI-MS/MS.     

Investigating the reaction mechanism and organocatalytic synthesis of α,α'-dihydroxy ketones

A biomimetic TK one-pot reaction using hydroxypyruvate and aldehydes to generate α,α'-dihydroxy ketones in water has recently been described. To investigate this tertiary-amine mediated reaction mechanism two approaches were used. Firstly, (13)C labelled lithium hydroxypyruvate was synthesised and used to establish where hydroxypyruvate is incorporated in the product. In separate experiments reaction intermediates were also successfully intercepted and structurally identified using ESI-MS with tandem mass spectrometry ESI-MS/MS. These studies indicated that two mechanisms appear to be operating, one involving the addition of the tertiary amine catalyst to hydroxypyruvate, the other an aldol-based mechanism. Since the first mechanism may enable facial stereodifferentiation in the addition of intermediates to the aldehyde, a preliminary study on the use of chiral catalysts was performed and the first asymmetric organocatalytic synthesis of α,α'-dihydroxy ketones in aqueous media achieved, in up to 50% ee, using a quinine ether catalyst.     

Relative binding affinities of molecular capsules investigated by ESI-mass spectrometry

ESI-MS(/MS) has been used as a method which allows the fast, unambiguous and sensitive simultaneous detection and relative stability approximation of supramolecular assemblies in mixtures. In spite of the obvious fundamental differences between solution and gas phase, ESI-MS in the case of self-assembled molecular capsules has been shown to produce very similar results to single binding experiments monitored by NMR titrations as well as conformational searches performed by Monte-Carlo simulations. MS/MS experiments reveal the same relative order of gas phase stabilities as previously found in solution. Moreover, proton transfer reactions which lead to new molecular capsules, are not detectable in the time-averaged NMR spectrum. However, the newly produced species are found in the complex mixtures by ESI-MS and can be conveniently characterized by subsequent MS/MS experiments: in a collision-induced dissociation the single half-spheres are easily discovered and structurally assigned. Thus, ESI-MS has worked as a valuable tool for the rapid screening of complex supramolecular mixtures and in combination with MS/MS experiments elucidated both the path of unexpected side reactions as well as the thermodynamic gas-phase stabilities of all components in the mixture.     

Characterization of gingerol-related compounds in ginger rhizome (Zingiber officinale Rosc.) by high-performance liquid chromatography/electrospray ionization mass spectrometry

This study sought to determine the utility of liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) coupled with diode array detection in identifying gingerol-related compounds from crude extracts of ginger rhizome. The fragmentation behaviors of compounds in both (-)- and (+)ESI-MS/MS were used to infer and confirm the chemical structures of several groups of compounds, including the gingerols, methylgingerols, gingerol acetates, shogaols, paradols, gingerdiols, mono- and diacetyl gingerdiols, and dehydrogingerdiones. Diode array detection at different wavelengths was used to confirm MS/MS-based identification. In total, 31 gingerol-related compounds were identified from the methanolic crude extracts of fresh ginger rhizome in this study. Three of these compounds were found to be new compounds. This study demonstrated that LC/ESI-MS/MS is a powerful on-line tool for identification of gingerol-related compounds, especially for thermally labile compounds that cannot be readily detected by GC/MS analysis.     

Probing the mechanism of direct Mannich-type alpha-methylenation of ketoesters via electrospray ionization mass spectrometry

Reactions promoting direct Mannich-type alpha-methylenation of alpha, beta and gamma-ketoesters have been monitored via electrospray ionization mass and tandem mass spectrometric experiments. Key intermediates of the catalytical cycle of this synthetically useful reaction have been intercepted and characterized. The mechanistic information provided by electrospray ionization mass spectrometry/mass spectrometry (ESI-MS/MS) guided the optimization of reaction conditions, allowing alpha-methyleneketoesters to be prepared in high yields (80-95%) and in high-enough purity for immediate further manipulation.     

Real-time, on-line monitoring of organic chemical reactions using extractive electrospray ionization tandem mass spectrometry

Extractive electrospray ionization mass spectrometry (EESI-MS) for real-time monitoring of organic chemical reactions was demonstrated for a well-established pharmaceutical process reaction and a widely used acetylation reaction in the presence of a nucleophilic catalyst, 4-dimethylaminopyridine (4-DMAP). EESI-MS provides real-time information that allows us to determine the optimum time for terminating the reaction based on the relative intensities of the precursors and products. In addition, tandem mass spectrometric (MS/MS) analysis via EESI-MS permits on-line validation of proposed reaction intermediates. The simplicity and rapid response of EESI-MS make it a valuable technique for on-line characterization and full control of chemical and pharmaceutical reactions, resulting in maximized product yield and minimized environmental costs. Copyright (c) 2008 John Wiley & Sons, Ltd.     

A rapid ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometric method for the qualitative and quantitative analysis of the constituents of the flower of Trollius ledibouri Reichb

A rapid ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometric (UPLC–ESI-MS/MS) method was developed for the qualitative and quantitative determination of the constituents of the flower of Trollius ledibouri Reichb. The analysis was performed on an AcQuity UPLC™ BEH C₁₈ column using gradient elution with a mobile phase of 0.1% acetic acid and acetonitrile over 20 min. A tandem quadrupole spectrometer operating in either full scan mode or in MS/MS mode for multiple reaction monitoring (MRM) was used for the qualitative and quantitative analysis of the constituents, respectively. According to the mass spectrometric fragmentation mechanism and UPLC–ESI-MS/MS data, the chemical structures of 15 constituents of the flower of T. ledibouri Reichb. were identified on-line without time-consuming isolation and four of them, 2″-O-β-l-galactopyranosylorientin, 2″-O-β-arabinopyranosylorientin, orientin and vitexin, were quantified. The limits of quantification of these four flavonoids were 540, 321, 515 and 220 μg g⁻¹ plant material, respectively. Four commercial samples from different sources were analyzed. The UPLC–ESI-MS/MS method for analyzing the constituents can be used to evaluate the quality of the flower of T. ledibouri Reichb.     

Rapid protein identification using a disposable on-line clean-up/concentrating device and electrospray ionization mass spectrometry

A simple, low-cost, expedient method has been developed for identification of proteins isolated from two-dimensional (2D) gels. The method described uses a disposable on-line clean-up device, a syringe infusion pump and electrospray ionization mass spectrometry (ESI-MS). The on-line clean-up and concentrating device is a tapered capillary column filled with 1.5 cm of 5 microm C18 particles. The short column was easily prepared and was connected directly to the ESI source through a low-flow ESI sprayer. Peptides resulting from enzymatic digestion of proteins were eluted from the short column isocratically using a syringe infusion pump and analyzed by ESI-MS. This simple set-up was found useful in the analysis of proteins isolated from 2D gels. Compared to the more conventional micro-liquid chromatography/tandem mass spectrometry (microLC/MS/MS), this method can identify proteins rapidly without the need for an HPLC pump and removes the problem of cross-contamination caused by system carryover. These advantages make the method described competitive with conventional LC/MS even though the latter method gives slightly expanded sequence coverage.