Chiral discrimination of drugs by DNA tetranucleotides under electrospray ionisation conditions

The DNA tetranucleotides, extended versions of GCA at the 3'-end or 5'-end, were used as chiral selectors for the chiral discrimination of atenolol, DOPA, tamsulosin, valacyclovir and zolmitriptan. Chiral discrimination was achieved by investigating the collision-induced dissociation spectra of the [X+Y-2H](2-) ion generated by electrospraying a solution mixture of tetranucleotide (X) and R- or S-analyte drug (Y). The relative abundances of the precursor ion and the product ion, resulting from the loss of drug, were considered for measuring the degree of chiral discrimination. Among all the tetranucleotides studied, AGCA showed the highest chiral discrimination. The present study emphasised the position of an adenine base in the tetranucleotide in chiral discrimination. The suitability of the method for the measurement of optical purity was also demonstrated in the case of zolmitriptan.     

Letter: on the retrosynthetic process of some 2-pyridinecarboxamides in electrospray ionisation conditions

The occurrence of retrosynthetic processes, usually observed in electron ionization conditions, can be considered of interest, giving information of on possible new synthetic routes. Generally, retrosynthesis is typical of odd electron ion species, but in the present case it has been observed for electrospray (ESI) generated [MH]+ species of 2-pyridinecarboxamides. In fact, either in the ESI spectrum or in the MS/MS spectrum of [MH]+ species, a primary water loss is observed, giving rise to the molecular ion of the corresponding imidazolines, employed as synthons for the title compounds. The breakdown curves related to this water loss has been determined, indicating that this process is more favoured for the bromine-containing molecules.     

Generation and ion-molecule reactions of ethyl diazoacetate anion radical (EtO2CCHN2XXX)

Thermal electron attachment to EtO₂CCHN₂ produced the parent anion radical EtO₂CCHN₂-(m/z 114). The ion-molecule reactions of m/z 114 with 30 neutral substrates were examined. Using the bracketing method, PA(EtO₂CCHN₂^XXX) = 355±4 kcal mol^-1 was determined. The reaction of m/z 4 with CH₃SH produced H₂CS^XXX, the product of β-elimination of H⁺₂ from the thiol. From a series of bracketing studies and determination of the equilibrium constant for the electron transfer (ET) process CH₃C(O)C(O)CH₃^-+EtO₂CCHN₂ = CH₃C(O)C(O)CH₃+EtO₂CCHN₂^XXX EA(EtO₂CCHN₂) = 19.7 kcal mol^-1 was derived. Both associative and dissociative ET were observed in the reactions of m/z 114 with certain perhalomethanes (depending on their EA) as well as halogen-atom abstraction from BrCCl³. While no reaction was observed between m/z 114 with CH₃CHO or (CH₃)₂CO, m/z 114 reacted with certain other ketones and esters (CF₃CO₂R) mainly to yield enolate anions of the β-keto esters, EtO₂CCHC(O^-)R. These enolate anions are believed to be formed by nucleophilic addition of C_α of m/z 114 to the carbonyl group of the neutral substrate followed by loss of N₂ and radical β-fragmentation.     

A bifurcated pathway of oxygen atom transfer reactions from a monooxo molybdenum(VI) complex under electrospray ionisation mass spectrometric conditions

A stable molybdenum(V) complex, LMoOCl2(where L is hydrotris(3,5-dimethylpyrazolyl)borate), has been oxidized under mass spectrometric conditions. The oxidized species reacts with tertiary phosphines and the products have been detected by mass spectrometry. The product distribution has been followed by isotope labeling experiments, and energy dependent electrospray mass spectrometry. These experiments reveal not only oxygen atom transfer but also loss of a chlorine atom from the resulting species.     

Gas-phase ion-molecule reactions of small nitroalkanes and their deprotonated anions

Gas-phase reactions of nitromethane (1), nitroethane (2), 2-nitropropane (3), 2-methyl-2-nitropropane (4) and nitrocyclopropane (5) were studied at 300 K using the flowing afterglow technique. These nitroalkanes react with gas-phase bases HO(-), CH(3)O(-) and HOO(-) very rapidly with rate coefficients of (2.5-4.3) x 10(-9) cm(3) s(-1) and reaction efficiencies of 60-100%, for example, k = 3.2 x 10(-9) cm(3) s(-1) (86%) for 5 reacting with hydroperoxide anion. Proton transfer (PT) is the only reaction observed for 1 while elimination (E2) is the exclusive pathway for 4 yielding isobutene and NO(2)(-). Both PT and E2 reactions are observed for 2, 3 and 5, the former being the major pathway. Deprotonated anions of 1, 2, 3 and 5 were subjected to reactivity studies with CH(3)I, CO(2), CS(2) and SO(2). Nucleophilic substitution (S(N)2) reaction occurs with CH(3)I while characteristic products CS(2)O(-) and SO(3)(-) are formed from CS(2) and SO(2), respectively, along with competing adduct formation. The SN(2) rate is greater, whereas the reactivities with the triatomic reagents are smaller for deprotonated nitrocyclopropane than for the other acyclic anions. These observations strongly suggest that the reactions of nitroalkane [M - H](-) anions occur through initial attack from the terminal oxygen; the nitrocyclopropane carbanion is more strained and, thus, less stabilized by resonance [R(2)C(-) - NO2 <--> R(2)=NO(2)(-)] resulting in the greater basicity/nucleophilicy and the less negative charge on the oxygen site.     

Generation of alkoxide anions from a series of aliphatic diols and alcohols and their ion-molecule reactions with carbon dioxide in the gas phase

Alkoxide anions, [M-H](-) from a series of aliphatic diols and alcohols are generated in the source under negative ion electrospray ionisation conditions by cone-voltage fragmentation of the corresponding [M + F](-) ions. The collision-induced dissociation (CID) spectra of [M-H](-) ions consist of [M-H-2H](-) ions, in addition to the other characteristic fragment ions, and the relative abundance of [M-H-2H(-) ions among the series of diols varies as a function of chain length that could be explained based on their stabilities through intramolecular hydrogen bonding. The reactivity of alkoxide anions is studied through ion-molecule reactions with CO(2) in the collision cell of a triple quadrupole mass spectrometer. All the alkoxide anions reacted with CO(2) and formed corresponding carbonate anions, [M-H + CO(2)](-) ions. The reactivity of alkoxide anions within the series of diols also reflected the stability of their [M-H](-) ions.     

Peptide polarity and the position of arginine as sources of selectivity during positive electrospray ionisation mass spectrometry

Electrospray ionisation (ESI) is a selective process and, for similar sized analytes, the intrinsic properties of the molecules affect the ionisation process and their response. This research sets out to determine the effect of some of these properties in peptides: peptide polarity and the presence of arginine at positions 1 and 4 in the amino acid sequence on the ESI response. Six peptides; molecular mass ranges 1.3-1.6 kDa; substance P (SP) and glutamate fibrinopeptide (GFP) and 3.2-3.7 kDa; calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), glucagon-like peptide 1 (GLP1) and defensin human neutropeptide 2 (DHNP2), were investigated. We have demonstrated that in positive ESI, for similar sized peptides and the same charge state, the responsiveness is in the order: Peptides with N or C terminal arginine > most non-polar peptides > least non-polar peptides. Therefore, arginine at the terminal position is a source of selectivity. Data from matrix-assisted laser desorption ionisation (MALDI) analysis supports that of the ESI experiments: Peptides with a terminal arginine residue generated higher signal intensities. Our observations extend our understanding of the ESI process and provide a rational approach to optimising sensitivity of electrospray conditions where a narrow mass range of peptides are poorly chromatographically resolved. This information will provide for a more effective method development process, especially during label-free quantitative determination of peptides extracted in solution.     

Characterisation of nicotine and related compounds using electrospray ionisation with ion trap mass spectrometry and with quadrupole time-of-flight mass spectrometry and their detection by liquid chromatography/electrospray ionisation mass spectrometry

Electrospray ionisation ion trap mass spectrometry (ESI-MS(n)) has been used to study the fragmentation patterns of nicotine and nine of its related compounds. From this study certain characteristic fragmentations are apparent with generally the pyrrolidine or piperidine ring being subject to chemical modifications. The structures of the product ions proposed for the ESI-MS(n) study have been supported by results from electrospray ionisation quadrupole time-of-flight mass spectrometry (ESI-QTOF-MS). Compounds with pyrrolidine and piperidine rings that possess an unsubstituted N atom have been shown to lose NH(3) at the MS(2) stage. Those compounds with N-methyl groups lose CH(3)NH(2) at the MS(2) stage. The loss of NH(3) or CH(3)NH(2) leaves the corresponding rings opened and this is followed by ring closure at the pyridine-2 carbon atom. Mono-N-oxides fragment in a similar way but the di-N-oxide can also fragment by cleavage of the bond between the pyridine and pyrrolidine rings. Cotinine also can undergo cleavage of this bond between the rings.This data therefore provides useful information on how substituents and the nature of the non-pyridine ring can affect the fragmentation patterns of nicotine and its related compounds. This information can be used in the characterisation of these compounds by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) which results in the separation of nicotine and its related compounds with limits of detection (LODs) ranging from 15 to 105 ng/mL. The use of LC/ESI-MS to study nicotine-containing samples resulted in the simultaneous and unambiguous identification of seven of the compounds discussed in this paper: cotinine identified at retention time 12.5 min (with its [M+H](+) ion at m/z 177), nornicotine 16.0 min (m/z 149), anatabine 18.0 min (m/z 161), myosmine 18.5 min (m/z 147), anabasine 20.4 min (m/z 163), nicotine 22.2 min (m/z 163), and nicotyrine 31.4 min (m/z 159). For quality control of nicotine replacement therapy products, these nicotine impurities can be readily identified and determined at levels up to 0.3% for single impurities and up to 1.0% for total impurities.     

Differential interactions of isomeric amino sugars with insulin studied under electrospray ionisation mass spectrometry

Protein-ligand interactions were studied for bovine insulin-amino sugar systems under electrospray ionisation mass spectrometry conditions. The isomeric amino sugars showed differences in the relative abundance of 1:1 protein-ligand complex formation. The electrospray ionisation and tandem mass spectrometry results of the complex clearly demonstrated that the differences in the interaction of isomeric sugars with insulin are mainly due to the differences in their gas-phase basicity. The same phenomenon is replicated in the formation of complexes between insulin and other ligands, such as amino acids, as well as in the binding of the amino sugars with amyloid β 1-40 peptide.     

Evidence that gas-phase ion-molecule reactions are responsible for the behaviour of crown ethers under fast atom bombardment conditions

The fast atom bombardment mass spectrometry of some crown ethers shows the formation of both [M + H]⁺ and [M ? H]⁺ ions, paralleling behaviour already observed using electron impact ionization. The study of these oily samples with and without a glycerol matrix, trifluoroacetic acid or alkali metal salts, suggests that the ionization process does not occur in the condensed phase, but in the selvedge region by gas-phase ion-molecule reactions in accordance with the ‘gas-phase explosion model’. Positive-ion chemical ionization experiments support this proposal.     

The characterisation of selected antidepressant drugs using electrospray ionisation with ion trap mass spectrometry and with quadrupole time-of-flight mass spectrometry and their determination by high-performance liquid chromatography/electrospray ionisation tandem mass spectrometry

The electrospray ionisation ion trap tandem mass spectrometry (ESI-MS(n)) of selected antidepressant drugs, i.e., citalopram, fluoxetine, mirtazapine, paroxetine, sertraline, and venlafaxine, has been investigated. Sequential product ion fragmentation experiments (MS(n)) have been performed in order to elucidate the degradation pathways for the [M+H](+) ions and their predominant product ions. These MS(n) experiments show certain characteristic fragmentations in that functional groups are generally cleaved from the ring systems as molecules such as H(2)O, amines and phenols. When an aromatic entity is present in a drug molecule together with a nitrogen-containing saturated ring structure as with mirtazapine, fragmentation initially occurs at the latter ring with the former being predictably resistant to fragmentation. Also, when an amine-containing drug molecule such as fluoxetine also contains a functional group, which liberates a phenol with a significantly lower DeltaH(f) (0) value than that of the corresponding amine, the phenol is preferentially liberated. The structures of product ions proposed for ESI-MS(n) can be supported by electrospray ionisation quadrupole-time-of-flight tandem mass spectrometry (ESI-QToF-MS/MS). These molecules can be identified and determined in mixtures at low ng/mL concentrations by the application of high-performance liquid chromatography/electrospray ionisation tandem mass spectrometry (HPLC/ESI-MS(2)), which can also be used for their analysis in hair samples.     

Cyclopalladated complexes of 2-phenylaniline and their catalytic activity in Suzuki and Heck reactions under mild conditions

A series of palladium complexes bearing monodentate and bidentate ligands were applied in the Suzuki reaction of aryl halides and the Heck reaction of styrene with phenylboronic acid. The complexes were found to be effective catalysts for these reactions affording the cross-coupled products in moderate to excellent yields.     

Determination of fluoroquinolones in chicken tissues by LC-coupled electrospray ionisation and atmospheric pressure chemical ionisation

The aim of this work was to develop a method for determining seven quinolones (ciprofloxacin, danofloxacin, enrofloxacin, sarafloxacin, difloxacin, oxolinic acid and flumequine) in chicken muscle by LC coupled to MS. Two ionisation techniques, ESI and atmospheric pressure chemical ionisation (APCI) were compared using standard solutions. LOD and LOQwere determined under the optimised conditions for the two sources. The ESI was found the best for the purpose. The optimised method (LC-ESI-MS) was validated for the simultaneous analysis of the quinolones regulated by European Community in spiked chicken tissues, using norfloxacin as internal standard. Recoveries obtained varied in the range 60-109%. This method was compared with LC-UV method established previously.     

Copper-catalyzed tandem reactions of 2-halobenzenamines with isothiocyanates under ligand- and base-free conditions

A ligand-free copper-catalyzed reaction of 2-halobenzenamines with isothiocyanates has been developed for the synthesis of 2-aminobenzothiazoles. In the presence of CuBr and TBAB (tetra-n-butyl ammonium bromide, additive), a variety of 2-halobenzenamines underwent the reaction with isothiocyanates at 40 °C, affording 2-aminobenzothiazoles in moderate to excellent yields. It is noteworthy that the reaction is conducted under mild, relatively low catalyst loading, and ligand- and base-free conditions.     

Coupling desorption electrospray ionisation and neutral desorption/extractive electrospray ionisation with a travelling-wave based ion mobility mass spectrometer for the analysis of drugs

Desorption electrospray ionisation (DESI) and neutral desorption/extractive electrospray ionisation (EESI) have been coupled to a hybrid quadrupole travelling-wave (T-Wave)-based ion mobility time-of-flight mass spectrometer for the direct accurate mass analysis of active ingredients formulated into pharmaceutical samples. The collision cross-section measurements of polyethylene glycol (PEG) excipients detected in one formulation were estimated and compared with published data. These estimated collision cross-sections of the PEG species showed good agreement with published data.     

Reduction of CO2 and SO2 with low valent nickel compounds under mild conditions

The reaction of [(dippe)Ni(μ-H)](2) (A) (dippe = 1,2-bis(diisopropyl-phosphinoethane) with CO(2) in toluene afforded the carbonyl nickel(0) compounds of the type {(dippe)Ni(CO)](2)(μ-dippe)}(1) and (dippe)Ni(CO)(dippe==O)] (2), which were characterized by standard spectroscopic methods; complex (1) was also characterized by single crystal X-ray diffraction. Reaction of (A) with SO(2) yields the thiosulfate nickel(II) compound [Ni(dippe)(S(2)O(3))] (5), which was fully characterized by standard spectroscopic methods and X-ray crystallography. In both cases, a reduction reaction of CO(2) to CO and SO(2) to S(2)O(3)(2-) with (A) took place under mild conditions.     

Ring contraction reactions of 2,3-dihydro-4H-1,3-oxazin-4-ones under electrospray ionization conditions

The mass spectral behavior of 2,3-dihydro-4H-1,3-oxazin-4-ones has been investigated using electrospray ionization multi-stage mass spectrometry (ESI-MS(n)). All compounds showed a predominant retro-Diels-Alder (RDA) fragmentation pathway, and a novel ring contraction reaction by loss of isocynates was also found. The fragmentation mechanisms proposed for 4H-1,3-oxazin-4-ones are supported by ESI-MS/MS/MS spectra.