Mass spectrometry of N-substituted amino acids and their derivatives: Correlation of the abundances of the M+. and selected fragment ions of metamers

The mass spectral fragmentations of nineteen new metameric N-(E)-stilbenyloxyalkylcarbonyl- [or (E)-(4′-chlorostilbenyloxyalkylcarbonyl)]-substituted amino acids and their metameric methyl esters and hydrazides were investigated. Fragmentation pathways are proposed on the basis of accurate mass and metastable transition measurements. The correlation between the intensities of M^+. and the selected fragment ions of these compounds is discussed. The data obtained create the basis for distinguishing metamers.     

Determination of (E)-3,5,4′-Trimethoxystilbene in Rat Plasma by LC with ESI-MS

(E)-3,5,4′-trimethoxystilbene (BTM-0512) is a resveratrol analog with a variety of pharmacological action, including anti-cancer properties, anti-allergic activity, estrogenic activity, antiangiogenic activity, and vascular-targeting activity against microtubule-destabilization. There is, however, no validated analytical method for quantification of (E)-3,5,4′-trimethoxystilbene in biological matrices, so pharmacokinetic data and suitable methods for determination of the compound in plasma are currently lacking. A rapid and sensitive liquid chromatographic–mass spectrometric method for determination of (E)-3,5,4′-trimethoxystilbene in rat plasma, using carbamazepine as internal standard, has been developed and validated. Plasma samples were treated with acetonitrile to precipitate proteins. Samples were then analyzed by HPLC on a 250mm × 4.6 mm i.d., 5-μm particle, C₁₈ column with methanol–water, 80:20 (v/v), containing 10 mm ammonium acetate and 0.2% formic acid (pH 3.0), as mobile phase, delivered at 0.85 mL min⁻¹. A single-quadrupole mass spectrometer with an electrospray interface operated in selected-ion monitoring mode was used to detect [M + H]⁺ ions at m/z 271.3 for (E)-3,5,4′-trimethoxystilbene and m/z 237.5 for the internal standard. (E)-3,5,4′-trimethoxystilbene and the internal standard eluted as sharp, symmetrical peaks with retention times of 8.9 and 4 min, respectively. Calibration plots for (E)-3,5,4′-trimethoxystilbene in rat plasma at concentrations ranging from 0.01 to 5.0 μg mL⁻¹ were highly linear. Intra-day and inter-day precision, as RSD, was <12.9%, and accuracy was in the range 94.8–104.7%. The limit of detection in plasma was 0.005 μg mL⁻¹. The method was successfully used to determine the concentration of (E)-3,5,4′-trimethoxystilbene after oral administration of 86 mg kg⁻¹ of the drug to Sprague–Dawley rats and can be used to investigate the pharmacokinetics of the compound.     

Preparation and Structure of (E)-1-(3′-Hydroxy-2-Furanyl)-3-(3″-Hydroxy-4″-Methoxyphenyl)-2-Propen-1-One

Abstract

A facile procedure is presented for the synthesis of (E)-1-(3′-hydroxy-2′-furanyl)-3-(3″-hydroxy-4″-methoxyphenyl)-2- propen-1-one (6). Galactosylisomaltol (1) was condensed with isovanillin (2) under strong alkaline conditions at 25 [ddot]C to form (E)-1-(3′-O-β-D-galactopyranosyloxy-2′-furanyl)-3-(3″- hydroxy-4″-methoxyphenyl)-2-propen-1-one (4). (E)-1-(3′-hydroxy-2′-furanyl)-3-(3″-hydroxy-4″-methoxyphenyl)-2-propen-1-one (6) was obtained by acid hydrolysis of 4 in a 53.9% yield. This hetero-cyclic 2-propen-1-one was characterized on the basis of spectral data (IR and ¹H NMR), physicochemical properties, and conversion to a mono-O-acetyl derivative.     

Studies on the Stereochemistry of 2-(Nitromethylidene)-Heterocycles

The ¹H-NMR spectra of 2-(nitromethylidene)pyrrolidine ( 7 ), 1-methyl-2-(nitromethylidene)imidazolidind ( 10 ) and 3-(nitromethylidene)tetrahydrothiazine ( 11 ) in CDCl₃ and (CD₃)₂SO indicate that these compounds have the intramolecularly H-bonded structures (Z)- 7 , (E)- 10 and (Z)- 11 while the N-methyl derivative 8 of 7 is (E)-configurated in both solvents. 1-Benzylamino-1-(methyltio)-2-nitroehtylene ( 13 ), an acylic model, has the H-bonded configuration (E)- 13 in CDCl₃ and in (CD₃)₂SO. 2-(Nitromethylidene)thiazolidine ( 3 ) has the (E)-configuration in CDCl₃ but exists in (CD₃)₂SO as a mixture of (Z)- and (E)-isomers with the former predominating. Both species are detected to varying proportions in a mixture of the two solvents. ¹⁵N-NMR spectroscopy of 3 ruled out unambiguously the nitronic acid structure 6 and the nitromethyleimine structure 5 . The N-methyl derivative 4 of 3 is (Z)-configurated in (CD₃)₂SO. Comparison of the olefinic proton shifts of (Z)- 3 and (Z)- 4 with those of analogues and also of 1,1-bis(methylti)-2-nitroethylene ( 12 ) shows decreased conjugation of the lone pair of electrons of the ring N-atom in (Z)- 3 and (Z)- 4 . This is also supported by ¹³C-NMR studies. Plausible explanations for the phenomenon are offered by postulating that the ring N-atoms are pyramidal in (Z)- 3 and (Z)- 4 and planar in other cases or, alternatively, that the conjugated nitroenamine system gets twisted due to steric interaction between the NO₂-group and the ring S-atom. Single-crystal X-ray studies of 3 and 8 show that the former exists in the (Z)-configuration and the latter in (E)-configuration; the ring N-atom in the former has slightly more pyramidal character than in the latter.     

Calorimetric and theoretical studies on the system of {(R)-(+)-limonene+(S)-(-)-limonene}

In order to reveal the origin of chiral discrimination, excess molar heat capacities (C_P ^E) of ((R)-(+)-limonene+(S)-(−)-limonene) were determined by using a differential scanning calorimeter at temperatures between T=293.15 and 303.15 K. All C_P ^E curves show S-shape. It was inferred that randomness appears in the (S)-(-)-limonene-rich region, and that non-randomness appears in the (R)-(+)-limonene-rich region. To clarify the differences in homochiral interactions and heterochiral interactions, molecular orbital calculations were carried out.     

Crystal structure and quantum chemical calculations of (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one

The known Schiff base compound, (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one, was prepared as before by reacting 1-benzyl-5-methylindoline-2,3-dione with 4-methoxyaniline. The product was unambiguously characterized using elemental analysis, ¹H and ¹³C-NMR spectroscopy, and its new single-crystal X-ray structural analysis. Molecular orbital calculations were conducted in order to investigate the structures and relative stabilities of the (E) and (Z) isomers of 1-benzyl-3-([4 methoxyphenyl]-imino)-5-methylindolin-2-one. Specific attention was paid to the (E) isomer. The available crystallographic experimental data for the latter ensured also validation of the model structures computationally derived at the theoretical B3LYP/6-31G(d,p) level.     

The Isotopomeric (Z)- and (E)-2,3-Dimethyl(1,1,1,4,4,4-2H6)but-2-enes: Mechanistic Probes for Stereospecific Epoxidation

By unambiguous methods, (Z)- and (E)-2, 3-dimethyl(1, 1, 1, 4, 4, 4-²H₆)but-2-enes ( 3 ) were synthesized and transformed to the epoxides 4 with 3-chloroperbenzoic acids. Both the isotopomeric olefins and the epoxides are detected separately by ¹H-NMR at 400 MHz. Epoxidation of (Z)- 3 with [Rh^ICl(PPh₃)₃]/cumene hydroperoxide resulted in a 1: 1 mixture of (Z)- and (E)- 4 , while reaction of (Z)- 3 with [Fe^III(tpp)]Cl/PhIO gave only (Z)- 4 (tpp = tetraphenylporphyrin).     

Electrospray-Ionization Mass Spectrometry. Part III. Acid-Catalyzed Isomerization of N,N′-Bis[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines by the Zip Reaction

The electrospray tandem mass spectra (ESI-MS/MS) of the three N,N′-bis[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines 1–3 displayed the same fragment-ion signals. These isomers could not be differentiated by ESI-MS/MS, since their fragmentation patterns are similar. (E,E)-N-(3-[¹⁵N]Aminopropyl)-3,3′-bis(4- hydroxyphenyl)-N,N′-(butane-1,4-diyl)bis[prop-2-enamide] ([¹⁵N(1)])-( 1 ) was synthesized in order to get further information about the fragmentation mechanisms. The comparison of the ESI-MS/MS of 1 and [¹⁵N(1)]- 1 revealed a transamidation, the Zip reaction, under mass-spectral conditions of the [ 1 + H]⁺ ions. Because of this reaction, the three isomers 1–3 could not be distinguished.     

Photochemical Reactions 151st Communication. Photo-oxygenation of (E)- and (Z)-7-Methyl-β-ionone

Photo-oxygenation of (E)-7-methyl-β-ionone ((E)? 1 ) and (E)-8-methyl-β-ionone ((E)? 2 ) gave rise to the formation of the hydroperoxy-enones (E)? 10 and (E)? 15 , respectively, which, in part, underwent intramolecular epoxidation to the hydroxy-epoxy-ketones 11 and 16 , respectively, The product distribution of the photo-oxidation of (Z)? 1 shows a marked influence of the skewed ground-state conformation of the dienone chromophore. Thus, singlet oxygen (¹O₂) was added to C(γ) of the dienone chromophore leading to the spirocyclic peroxy-hemiacetal 12 and to the endoperoxide 13 . In addition, the tricyclic peroxide 14 was formed as a new type of product via primary addition of ¹O₂ to C(γ) of the dienone chromophore. The structure of 14 was established by X-ray crystal-structure analysis of the hemiacetal 22 .     

New isomeric N-substituted hydrazones of 2-, 3-and 4-pyridinecarboxaldehydes

Eighteen compounds unknown in the literature, N-(E)-stilbenyloxyalkylcarbonyl- and N-(E)-stilbenyloxyalkylcarbonylaminoalkylcarbonyl-substituted hydrazones of 2-, 3- and 4-pyridinecarboxaldehydes have been prepared. The stereochemical behavior of these compounds in dimethyl-d₆ sulfoxide solution has been studied by ¹H-nmr technique. The E geometrical isomers and cisltrans amide conformers have been found for N-substituted-hydrazones 1–16 .     

Synthesis and Structural Studies of 2-(hydroxyimino)-1-methylpropylideneamino-phenyliminobutan-2-one Oxime, Ligand and its Complexes with Cu(II) and Ni(II)

A new ligand incorporating a dioxime moiety, (2E,3E)-3-[(2-{[(1E,2E)-2-(hydroxyimino)-1-methylpropylidene]amino}phenyl)imino]butan-2-one oxime, (H₂Phmdo) (3) has been prepared by reacting 2,3-butanedionemono-{O-[4-(1-methyl-2-oxo-propylideneaminooxy)-2,3-bis-(1-methyl-2-oxo-propylideneaminooxy-methyl)-but-2-enyl]-oxime} (2) with 1,2-phenylenediamine. Mono-, di- and trinuclear copper(II) and/or nickel(II) complexes of H₂Phmdo were characterized by elemental analyses, magnetic moments, ¹H-n.m.r. and ¹³C-n.m.r., i.r. and mass spectral studies. The mononuclear copper(II) and nickel(II) complexes of H₂Phmdo were found to have a 1:1 metal:ligand ratio. Elemental analyses, stoichiometric and spectroscopic data of the metal complexes indicated that the metal ions are coordinated to the oxime and imine nitrogen atoms (C=N). In the dinuclear complexes, in which the first Cu^(II) or Ni^(II) ion was complexed with nitrogen atoms of the oxime and imine groups, the second Cu^(II) ion is ligated with dianionic oxygen atoms of the oxime groups and are linked to the 1,10-phenanthroline nitrogen atoms. The data support the proposed structure of H₂Phmdo and its complexes.     

New synthesis of ( E )-3,7-dimethyl-2,7-octadienylpropionate and ( E )-3,7-dimethyl-2-octen-1,8-diol, pheromone components of San Jose scaleinsect Quadraspidiotus pernicious and african monarch butterfly Danaus chrysippus

6-Methyl-6-hepten-2-one (3) on reaction with ethyl α-dimethylphosphonate/NaH gives a mixture of (E)-and (Z)-conjugated esters. The major (E)-isomer, (E)-ethyl-3,7-dimethyl-2,7-octadienoate (4), on reduction with LiAlH₄ at room temperature furnishes (E)-3,7-dimethyl-2,7-octadien-l-ol (5) which on propionylation affords (E)-3,7-dimethyl-2,7-octadienyl propionate (1). Carbinol (5) is converted into its silyl ether (E)-2,6-dimethyl-8-t-butyldimethylsilyloxy-l,6-octadiene (6) witht-Bu(Me)₂SiCl in CH₂Cl₂, which on hydroboronation-oxidation with 9-BBN/NaOH-H₂O₂ followed by disilylalion with (n-Bu)₄N⁺ F⁻ at room temperature, gives (E)-3,7-dimethyl-2-octen-l,8-diol (2).     

Isolation by HPLC. and Identification by NMR. Spectroscopy of 11 mono-, di- and tri-cis isomers of an aromatic analogue of retinoic acid,ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6, 8-tetraenoate

Photoisomerization of an aromatic analogue of retinoic acid, ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6, 8-tetraenoate 1 in dilute solutions of hexane, benzene, and ethanol yielded multi-component mixtures of cis isomers which were separated by HPLC. FT-¹H-NMR. at 270 MHz and, in some cases, homonuclear decoupling and Overhauser experiments as well as ¹³C-NMR. were applied to establish the structures of 4 mono-cis, 4 (of 6 possible) di-cis, and 3 (of 4 possible) tri-cis isomers. The structures of 3 isomeric esters, namely (2Z, 4E, 6E, 8E) 6 , (2Z, 4Z, 6E, 8E) 9 , and (2Z, 4Z, 6Z, 8E) 7 were independently confirmed by direct syntheses. The ¹H-NMR. data of all these compounds and the ¹³C-NMR. data of the all-trans and of 6 cis isomers available in sufficiently large quantities are discussed.     

Spectral characterization and biocidal activity of organotin(IV) (E)-3-[(2′,6′-dichlorophenylamido)]propenoates

Biocidal and spectroscopic aspects of organotin(IV) complexes with (E)-3-[(2′,6′-dichlorophenylamido)]propenoic acid are described with support of elemental analysis. IR, ¹H, ¹³C, ¹¹⁹Sn NMR and mass spectral data suggest that the ligand is bidentate, coordinating through oxygen atoms and that diorganotin(IV) complexes are six-coordinate. Triorganotin(IV) carboxylates exist as pentacoordinated trigonal bipyramidal complexes in the solid state and tetrahedral ones in solution. The complexes have been screened against bacteria, fungi and brine-shrimp larvae to assess their biological activity.     

(E)-, (Z)-Interconversion in 3-aroylmethyl-5-arylmethylene-2,4-dioxo-1,3-thiazolidines

Summary The (E)-, (Z)-interconversion in 3-aroylmethyl-5-arylmethylene-2,4-dioxo-1,3-thiazolidines is simply achieved upon treating with phenylhydrazine in acetic acid solutions. Configurational assignments are based on¹H-NMR spectral data.

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(E)-, (Z)-Interkonversion von 3-Aroylmethyl-5-arylmethylen-2,4-dioxo-1,3-thiazolidinen

Zusammenfassung Die (E)-, (Z)-Interkonversion in 3-Aroylmethyl-5-arylmethylen-2,4-dioxo-1,3-thiazolidinen wird durch Behandlung mit Phenylhydrazin in essigsaurer Lösung erreicht. Die Zuordnung von Konfigurationen basiert auf¹H-NMR-Daten.

     

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles

Abstract  

An efficient synthesis method for the preparation of a series of new (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles was developed. The reaction of (Z)- and (E)-3-styrylchromones with hydrazine hydrate afforded the corresponding (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles, except for nitro derivatives, where both (Z)- and (E)-4′-nitro-3-styrylchromones afforded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations is discussed and the stereochemistries of all products were established by NMR experiments.     

Conformational Properties of (Z,Z)-, (E,Z)-, and (E,E)-Cycloocta-1,4-dienes

Summary.  Ab initio calculations at the HF/6-31G^* level of theory for geometry optimization and the MP2/6-31G^*//HF/6-31G^* level for a single point total energy calculation are reported for (Z,Z)-, (E,Z)-, and (E,E)-cycloocta-1,4-dienes. The C ₂-symmetric twist-boat conformation of (Z,Z)-cycloocta-1,4-diene was calculated to be by 3.6 kJ·mol⁻¹ more stable than the C _S-symmetric boat-chair form; the calculated energy barrier for ring inversion of the twist-boat conformation via the C _S-symmetric boat-boat geometry is 19.1 kJ·mol⁻¹. Interconversion between twist-boat and boat-chair conformations takes place via a half-chair (C ₁) transition state which is 43.5 kJ·mol⁻¹ above the twist-boat form. The unsymmetrical twist-boat-chair conformation of (E,Z)-cycloocta-1,4-diene was calculated to be by 18.7 kJ·mol⁻¹ more stable than the unsymmetrical boat-chair form. The calculated energy barrier for the interconversion of twist-boat-chair and boat-chair is 69.5 kJ·mol⁻¹, whereas the barrier for swiveling of the trans-double bond through the bridge is 172.6 kJ·mol⁻¹. The C _S symmetric crown conformation of the parallel family of (E,E)-cycloocta-1,4-diene was calculated to be by 16.5 kJ·mol⁻¹ more stable than the C _S-symmetric boat-chair form. Interconversion of crown and boat-chair takes place via a chair (C _S) transition state which is 37.2 kJ·mol⁻¹ above the crown conformation. The axial- symmetrical twist geometry of the crossed family of (E,E)-cycloocta-1,4-diene is 5.9 kJ·mol⁻¹ less stable than the crown conformation. Corresponding author. E-mail: isayavar@yahoo.com Received March 25, 2002; accepted April 3, 2002     

Photochemical reactions, 136th communication. Photochemistry of conjugated epoxyenones and dienes of the ionone series: Influence of a neighboring spiro-oxirane function

The preparation and photolyses of the diepoxyenones (E)- 8 and (E)- 9 as well as the diepoxydiene (E)- 10 are described. On ¹π,π^*-excitation (λ = 254 nm), the diastereoisomeric diepoxyenones (E)- 8 and (E)- 9 undergo isomerization via the ylide intermediate f and the carbene intermediate g leading to the primary photoproducts 17A and 18–21 (Scheme 8). On ¹n, π^*-excitation (λ > 347 nm), (E)- 8 shows behaviour typical of epoxyenones undergoing C(γ), O-bond cleavage of the oxirane and isomerization to compounds 22 , (E/Z)- 23 and (E)- 24 (Scheme 10). On singlet excitation, the diepoxydiene (E)- 10 , is cleaved to the carbonyl ylide j and the carbenes 1 and m (Scheme 11). The carbonyl ylide j fragments via the dipolar intermediate k to the acetylenic dienone (E)- 31 . The carbene 1 , showing behaviour typical of vinyl carbenes, furnishes the cyclopropene 30 . The alternative carbene m , however, undergoes an insertion reaction into the neighboring oxirane C,C-bond leading to the proposed but not isolated oxetene 43 , which is further transformed to the products 33A _ B by an intramolecular cycloaddition.     

Electron impact mass spectrometry of 2-(2-pyridyl)-2,3-dihydroxy-5-phenyl-4-pentene

The mass spectrometric behaviour of 2-(2-pyridyl)-2,3-dihydroxy-5-phenyl-4-pentene has been studied with the aid of B/E, B²/E linked scans, exact mass measurements, collisionally activated dissociation mass-analysed ion kinetic energy spectra, and labelling experiments. The primary loss of water is proved to involve both hydroxylic hydrogens, thus suggesting the formation of an epoxidic radical ion and the presence of extensive skeletal rearrangements.     

Synthesis and structural studies of (2E,3E)-3-[(6-{[(1E,2E)-2-(hydroxyimino)-1-methylpropylidene]amino}pyridin-2-yl)imino]butan-2-one oxime, ligand and its mono-, di- and trinuclear copper(II) complexes

A new dioxime ligand, (2E,3E)-3-[(6-{[(1E,2E)-2-(hydroxyimino)-1-methylpropylidene]amino}-pyridin-2-yl)imino]butan-2-one oxime, (H₂Pymdo) (3) has been synthesized in H₂O by reacting 2,3-butenedione monoxime (2) with 2,6-diaminopyridine. Mono-, di- and tri-nuclear copper(II) complexes of the dioxime ligand (H₂Pymdo) and/or 1,10-phenanthroline have been prepared. The dioxime ligand (H₂Pymdo) and its copper(II) complexes were characterized by ¹H-n.m.r., ¹³C-n.m.r. and elemental analyses, magnetic moments, i.r. and mass spectral studies. The mononuclear copper(II) complex of H₂Pymdo was found to have a 1:1 metal:ligand ratio. Elemental analyses, stoichiometric and spectroscopic data of the metal complexes indicated that the metal ions are coordinated to the oxime and imine nitrogen atoms (C=N). In the dinuclear complexes, in which the first Cu(II) ion was complexed with nitrogen atoms of the oxime and imine groups, the second Cu(II) ion is ligated with dianionic oxygen atoms of the oxime groups and are linked to the 1,10-phenanthroline nitrogen atoms. The trinuclear copper(II) complex (6) was formed by coordination of the third Cu(II) ion with dianionic oxygen atoms of each of two molecules of the mononuclear copper(II) complexes. The data support the proposed structure of H₂Pymdo and its Cu(II) complexes.