S N H reactions of pyrazine N-oxides and 1,2,4-triazine 4-oxides with CH-active compounds

Nucleophilic substitution of hydrogen in pyrazine N-oxides under the action of CH-active compounds requires activation with acylating agents. This activation facilitates aromatization of intermediate ^H adducts via elimination of the acid residue to form substituted pyrazines. More electrophilic 1,2,4-triazine 4-oxides react with carbanions derived from CH-active compounds without additional activation according to a scheme, which has previously been unknown for azine N-oxides. This scheme involves aromatization of ^H adducts through elimination of water by the E1cb mechanism. The reaction products occur in DMSO-d₆ solutions predominantly as 6-methylene-1,6-dihydropyrazines and 5-methylene-4,5-dihydro-1,2,4-triazines.     

Natural abundance 17O NMR spectroscopy of heterocyclic N-oxides and Di N-oxides. Structural effects

The ¹⁷O chemical shift data for a series of azine N-oxides, diazine N-oxides and di-N-oxides at natural abundance are reported. Isomeric methyl substituted quinoline N-oxides exhibited chemical shifts which are interpreted in terms of electronic and compressional effects. The ¹⁷O chemical shift for 8-methylquinoline N-oxide (370 ppm) is deshielded by 25 ppm more than predicted, based upon electronic considerations. The ¹⁷O chemical shift for the N-oxide of 8-hydroxyquinoline (289 ppm) is substantially shielded as a result of intramolecular hydrogen bonding. The relative ¹⁷O chemical shifts for diazine N-oxides of pyrazine, pyridazine and pyrimidine follow predictions based on back donation considerations. Because of solubility limitations, spectra of only two N,N′-dioxides were obtained. The chemical shift of benzopyrazine di N-oxide in acetonitrile was shielded by 18 ppm compared to that of its mono N-oxide.     

Direct arylation of azine N-oxides with aryl triflates

Palladium catalyzed direct arylation of azine N-oxides using aryl triflates to afford the corresponding 2-aryl azine N-oxides is described. The reaction is carried out with a range of both N-oxides and aryl triflates. The arylation can be carried out in sequence to yield differentially diarylated products. The regioselectivity and scope of 3-substituted azine N-oxides are investigated. The method is applied to the synthesis of a compound that exhibits antimalarial and antimicrobial activities.     

Localization of N-oxide groups by means of nitrogen chemical shifts

The applicability of nitrogen chemical shifts to the localization of N-oxide groups in azine ring systems is exemplified by 1,2,4-triazine systems. The average excitation energy approximation in the theory of magnetic shielding gives a good linear correlation with the nitrogen shieldings in azine N-oxides.     

Investigation of Symphytum cordatum alkaloids by liquid-liquid partitioning, thin-layer chromatography and liquid chromatography-ion-trap mass spectrometry

From the alkalised crude extract of Symphytum cordatum (L.) W.K. roots, pyrrolizidine alkaloids (PAs) were extracted as free tertiary bases and polar N-oxides in a merely one-step liquid-liquid partitioning (LLP) in separation funnel and subsequently pre-fractionated by preparative multiple-development (MD) thin-layer chromatography (TLC) on silica gel plates. In this way three alkaloid fractions of different polarities and retention on silica gel plates were obtained as: the most polar N-oxides of the highest retention, the tertiary bases of medium retention, and diesterified N-oxides of the lowest retention. The former fraction was reduced into free bases by sodium hydrosulfite and purified by LLP on Extrelut-NT3 cartridge. It was further analysed together with the two other fractions by high-performance liquid chromatography (HPLC)-ion-trap mass spectrometry with atmospheric pressure chemical ionization (APCI) interface on XTerra C₁₈ column using a gradient elution. Based on MSⁿ spectra, 18 various alkaloids have been tentatively determined for the first time in this plant as the following types of structure: echimidine-N-oxide (three diasteroisomers), 7-sarracinyl-9-viridiflorylretronecine (two diasteroisomers), echimidine (two diasteroisomers), lycopsamine (two diasteroisomers), dihydroechinatine-N-oxide, dihydroheliospathuline-N-oxide, lycopsamine-N-oxide (three diasteroisomers), 7-acetyllycopsamine-N-oxide, symphytine-N-oxide (two diasteroisomers) and 2″,3″-epoxyechiumine-N-oxide.     

Characterization of Titania/Silica Gel by Means of Low-Pressure Nitrogen Adsorption

Adsorbents synthesized by grafting of titania onto mesoporous silica gel surfaces at different temperatures were studied by means of nitrogen adsorption–desorption and water desorption. The pore size distribution f(R_p) of titania/silica gel depends on the titania concentration (C_TiO2) and the temperature of titania synthesis. Nonuniformity of TiO₂ phase is maximal at a low C_TiO2 value (3.2 wt.% anatase deposited at 473 K), and two peaks of the fractal dimension distribution f(D) are observed at such a concentration of titania, but at larger C_TiO2 values, only one f(D) peak is seen. More ordered filling of pores and adsorption sites by nitrogen, reflecting in the shape of adsorption energy distributions f(E) at different pressures of adsorbate, is observed for adsorbent with titania (rutile+anatase) grafted on silica gel at a higher temperature (673 K).     

Interaction of divalent cations Zn,Cd and Hg on surface of silica gelwith aminoethanethiol as evaluated by calorimetric titration

Calorimetric titration was applied to study the interaction of zinc, cadmium and mercury on surface of silica gel modified with 2-aminoethanethiol, using 3-chloropropyltrimetoxysilane as precursor silylating agent. The anchored Sil–SNH₂ surface gave 0.70 mmol g^–1 of molecules covalently bonded per gram of silica. This surface displayed a chelating moiety containing sulfur and nitrogen basic centers, which are potentially capable of extracting cations from aqueous solutions, such as MCl₂ (M=Zn, Cd, Hg). This process of extraction was carried out by the batch method when similar chemisorption isotherms were observed for all cations. The data were adjusted to modified Langmuir equation. The sequence of the maximum retention capacity was Hg>Cd>Zn. The processes of cation interactions showed exothermic enthalpies. The calculated ΔG values are in agreement with the spontaneity of the proposed reactions and conformed to the values found by using Langmuir model applied to these systems. The endothermic entropic values, as expected, indicated that the reactions are favorable.     

Tandem mass spectrometry of peptides: Mechanistic aspects and structural information based on neutral losses. II—Tri- and larger peptides

The neutral products arising during the collisionally activated dissociation of protonated oligopeptides (MH⁺) are post-ionized by collision and detected in neutral fragment-reionization (⁺N_fR⁺) mass spectra. For the isomeric tripeptides Ala-Gly-Gly, Gly-Ala-Gly and Gly-Gly-Ala, the amino acid and dipeptide losses from the C-terminus and the diketopiperazine losses from the N-terminus allow for differentiation. These neutral fragments are identified in the corresponding ⁺N_fR⁺ spectra by comparison to reference collision-induced dissociative ionization (CIDI) mass spectra of individual amino acids, dipeptides and diketopiperazines. Peptides with distinct C-termini but otherwise identical sequences are found to yield ⁺N_fR⁺ products that are characteristic of the respective C-terminal amino acid. This is demonstrated for several peptide pairs, including leucine- and methionine-enkephalin. In general, ⁺N_fR⁺ spectra are dominated by the heavier neutral losses; further, ⁺N_fR⁺ and CIDI cause extensive dissociation, indicating that the collisional ionization process imparts high average internal energies.     

Experimental verification of diverging mechanisms in the binding of ether,thioether, and sulfone ligands to a dirhodium tetracarboxylate

Complexation of the oxygen atom in 2‐butylphenylethers and sulfur in 2‐butylphenylthioethers to a rhodium atom in dirhodium tetracarboxylate Rh^(II)₂[(R)‐(+)‐MTPA]₄ is compared. Oxygen atoms complex via electrostatic attraction exclusively leading to an increase in α effects on C‐2 complexation shifts in the sequence OCH₃ > F > Br > NO₂. However, that trend is opposite in thioethers. This can be rationalized by an additional highest occupied molecular orbital (HOMO)–LUMO interaction and the response of this interaction upon complex formation shifts. Thereby, an experimental evidence was found for the existence of the HOMO–LUMO binding mechanism which has been proposed previously based on theoretical considerations and indirect spectroscopic evidence. Sulfones hardly bind to Rh^(II)₂[(R)‐(+)‐MTPA]₄. Diastereomeric dispersion effects at ¹³C and ¹H signals can be observed for all compounds indicating that enantiodifferentiation is easy in all classes of functionalities. Copyright © 2010 John Wiley & Sons, Ltd.     

Coupling protocol for thin layer chromatography/matrix-assisted laser desorption ionization

Summary This paper reports the investigation and optimization of the thin layer chromatography/matrix-assisted laser desorption/ionization (TLC-MALDI) coupling protocol. The fundamental coupling parameters which influence sensitivity and lateral analyte spreading are extraction solvent selection, extraction time, and pressure. Selection of the solvent is dependent upon its extraction efficiency, which has been correlated with extraction solventR _f value. Maximum extraction efficiency occurs after two minutes for the analyte/solvent system studied. High extraction efficiency solvents cause significant lateral spreading of analyte; up to a three-fold increase in initial analyte spot size. Analyte recovery was found to be limited by the silica gel inter-partice porosity and the solvent extraction efficiency. For maintaining chromatographic resolution and maximizing signal intensity, extraction solvents withR _f values between 0.4 to 0.6 are optimal. The upper analyte recovery limit, using extraction solvents within thisR _f range, is estimated at 22%. Dedicated to Professor Werner Haerdi on the occasion of his 70^th birthday.     

A new bis(azine) tetradentate ligand and its transition metal complexes: Synthesis,characterisation, and extraction properties

A new bis(bidentate) azine ligand was prepared by linking (1Z,1′Z)-1,1′-{butane-1,4-diylbis[oxybenzene-4,1-diyl(1Z)ethyl-1-ylidene]}dihydrazine to salicylaldehyde. Two kinds of binuclear copper(II) and nickel(II) complexes with different stoichiometries were prepared. Reaction of bis(azine) ligand with Cu(II) and Ni(II) acetate at a 1: 1 mole ratio gave double-stranded binuclear bis(azine) complexes with stoichiometry [M(L)(H₂O)₂]₂ containing [M(II)N₂O₂] centres while at a 2: 1 mole ratio, reaction of Cu(II) and Ni(II) chloride with bis(azine) resulted in dinuclear metal complexes with the general stoichiometry [M₂(L)Cl₂(H₂O)₂]. Structures of the bis(azine) ligand and its complexes were identified by elemental analysis, IR and UV-VIS spectra, magnetic susceptibility measurements, TGA, and powder XRD. Extraction properties of the bis(azine) ligand towards some transition metal cations and dichromate anions were also reported. It was found that the bis(azine) ligand does not extract cations but it has high extraction ability towards dichromate anions.     

Intermittent compression of N-alkyl-N,N-dimethylamine N-oxides encapsulated in a container with bis[2]catenane topology

Abstract

We report the encapsulation of a homologous series of N-alkyl-N,N-dimethylamine N-oxides in a molecular container with bis[2]catenane topology. N-oxides with short alkyl chains are co-encapsulated with one solvent molecule. Elongation of the alkyl chain from R = methyl to pentyl produced the progressive compression of the guest. The hexyl N-oxide reduces its compression by being singly encapsulated. Longer N-oxides (R = octyl to decyl) had to fold to adapt to the capsule’s dimensions and also experience a progressive compression. The mechanically interlocked nature of the container and the polar functionalisation of its cavity are responsible for the assembly of encapsulation complexes in solution displaying high packing coefficients (0.65–0.70). The high energy conformations adopted by the alkyl chains of the bound N-oxides are deduced from NMR experiments and molecular modelling studies.     

Direct determination of pKa values of cationic acids conjugated to heterocyclic amine N-oxides in polar aprotic and amphiprotic solvents

The applicability of the direct method of pK_a determination in the case of protonated heterocyclic amine N-oxides in a series of polar non-aqueous (aprotic and amphiprotic) solvents has been tested. The method is based on the pH determination of the non-aqueous solution of complex salt (the semiperchlorate in this case) formed by the N-oxides studied. The direct method not only provides for quick (one data point per each pK_a determined), but also relatively accurate estimates of acidic dissociation constants. It has been experimentally shown on the example of substituted pyridine N-oxides that this method is precise enough in all studied non-aqueous solvents when applied to compounds of not too low basicity (the pK_a being of the order of 5 or higher). To prove this, the pK_a values of protonated monocyclic N-oxides obtained by the direct method have been compared with those resulting from the potentiometric titration curve. The agreement between the results found by using both methods is very good in most cases, the differences being within standard deviations. Based upon this observation it can be inferred that the pK_a values of protonated bicyclic N-oxides in solvents studied determined by using the direct method can be also considered reliable, especially in the case of polar aprotic solvents.     

Co(III) N,N′-diarylformamidine dithiocarbamate complexes: Synthesis,characterization, crystal structures and biological studies

Three symmetric N,N-diarylformamidine dithiocarbamates, N,N′-bis(2,6-dimethylphenyl)formamidine dithiocarbamate (DTL1), N,N′-bis(2,6-disopropylphenyl)formamidine dithiocarbamate (DTL2) and N,N′-dimesitylformamidine dithiocarbamate (DTL3), and three unsymmetric ones, N′-(2,6-dichlorophenyl-N-(2,6-dimethylphenyl)formamidine dithiocarbamate (DTL4), N′-(2,6-dichlorophenyl)-N-(2,6-diisopropylphenyl)formamidine dithiocarbamate (DTL5) and N′-(2,6-dichlorophenyl)-N-mesitylformamidine dithiocarbamate (DLT6), were reacted with chloridocobalt(III) in water to give Co-(DTL1)₃ ( 1 ), Co-(DTL2)₃ ( 2 ), Co-(DTL3)₃ ( 3 ), Co-(DTL4)₃ ( 4 ), Co-(DTL5)₃ ( 5 ) and Co-(DTL6)₃ ( 6 ). All the dithiocarbamates and complexes were characterized using ¹H NMR, ¹³C NMR, Fourier transform infrared, UV–visible and mass spectra and the purity confirmed by elemental analysis. In addition, crystal structures of complexes 1 , 2 , 4 and 5 were determined, confirming the formation of mononuclear species in which the Co(III) centers coordinated to six sulfur atoms from three dithiocarbamate ligands resulting in distorted octahedral geometries. All complexes showed moderate to good antibacterial activities against Gram-negative bacteria Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae and Pseudomonas aeruginosa even at low concentrations. None of the six were active against Gram-positive bacterium methicillin-resistant Staphylococcus aureus and only active against S. aureus at high concentrations. Complexes 5 and 6 were found to be more active than ciprofloxacin against S. typhimurium, E. coli, P. aeruginosa and K. pneumoniae and complexes with chloro-substituted ligands generally had enhanced activities. Antioxidant activities of the dithiocarbamate salts and their Co(III) complexes were also investigated using DPPH assay and the complexes were found to be more efficient. Complex 2 with an IC₅₀ value of 2.84 × 10⁻⁴ mM displayed the highest activity of all compounds tested, even outdoing ascorbic acid. The radical scavenging ability of the complexes followed the order 2 > 1 > ascorbic acid > 3 > 4 > 6 > 5 .     

Simultaneous determination of levofloxacin hemihydrate and ambroxol hydrochloride in tablets by thin-layer chromatography combined with densitometry

This paper describes the application of thin-layer chromatography (TLC) combined with densitometry to simultaneous determination of levofloxacin hemihydrate (LEV) and ambroxol hydrochloride (AMB) in bulk and tablets. The separation was achieved on aluminum sheet of silica gel 60 F ₂₅₄ using chloroform: methanol: toluene: ammonia (10: 6: 3: 0.8 v/v/v/v) as mobile phase. Quantification was carried out densitometrically at 245 nm. This system was found to give compact spots for LEV (R _f value of 0.4) and AMB (R _f value of 0.7). The calibration curves for LEV and AMB was found to be linear between 9960–16600 ng/spot (r ² = 0.999) and 600–1000 ng/spot (r ² = 0.999), respectively. The mean percentage recoveries from tablets for LEV and AMB were 99.45% and 99.58%, respectively. The TLC-densitometry method has many advantages, such as simplicity, reasonable sensitivity, rapidity, and low cost, and it can be successfully used in routine analysis of both these drugs in tablet formulations.     

Beitr?ge zur Papierchromatographie organischer Substanzen

Zusammenfassung Ungesättigte Verbindungen, hauptsächlich Olefine C₂–C₁₂, werden als Quecksilber(II)-salze mit Hilfe der Papierchromatographie und Dünnschichtchromatographie aufgetrennt. Geeignete Lösungsmittelgemische werden angegeben und die Zusammenhänge mit Fleckengröße und R_f-Werten graphisch dargestellt.

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Summary Unsaturated compounds, mainly olefines C₂–C₁₂, are separated in form of their mercuric salts by help of chromatography on paper or on thin layers of silica gel. Suitable solvent mixtures are given and their relations to spot sizes and R_f-values are represented in graphs.

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IV. Mitteilung: Kabil, A., u. V. Prey: Mh. Chem. 89, 497 (1958).     

15N-NMR. Studies of Aminopyridines,Aminopyrimidines and of Some Diazine N-Oxides

¹⁵N-NMR. spectra of mono- and diaminopyridines, and mono-, di- and triaminopyrimidines including trimethoprim and other dihydrofolate reductase inhibitors have been studied in neutral and acidic media. Complete chemical shift assignments are given. Ring-nitrogen shifts are discussed in terms of β-, χ- and δ-substituent effects of amino and alkyl groups. Protonation states in TFA- and FSO₃H-solution and protonation increments for the ¹⁵N-shifts of ring and amino N-atoms are determined. A linear correlation is observed between amino substituent effects (Δδ(¹⁵N)) on the ring N-atom in aminopyridines and corresponding Δδ (¹³C) values in aminobenzenes and, similarly, between Δδ(¹⁵N) values in aminopyrimidines and Δδ(¹³C) values in aminopyridines. Assignment of the ¹⁵N-NMR. spectra of pyrimidine N-oxides, pyrazine N-oxides and pyridazine N-oxides is achieved by comparison with ¹⁴N-NMR. data and with the aid of Yb(fod)₃-induced shifts. One-bond ¹⁵N, ¹H-coupling constants are reported for aminopyridines and aminopyrimidines and discussed in terms of conjugative interaction between NH₂-group and ring system.     

Fluorination of perfluoroalkylsulfenyl chlorides,perfluorodialkyl disulfides and perfluorodialkyl sulfides with chlorine monofluoride

In reactions with perfluoroalkylsulfenyl chlorides (R_fSCl; R_f = F₃, C₂F₅, n-C₃F₇, n-C₄F₉) and perfluoroalkyl disulfides (R_fSSR_f′; R_f = R_f′ = CF₃, R_f = CF₃, R_f′ = C₂F₅) at 25°, chlorine monofluoride acts primarily as a chlorinating and fluorinating reagent to give the corresponding perfluoroalkylsulfur chloride tetrafluorides, R_fSF₄Cl, in good yields. However, small amounts of perfluoroalkylsulfur pentafluorides, R_fSF₅, are also obtained. A mixture of the cis and trans isomers of bis(trifluoromethyl)sulfur tetrafluoride and of trifluoromethyl pentafluoroethylsulfur tetrafluoride has been formed by the reaction of the corresponding bis(perfluoroalkyl) sulfides and chlorine monofluoride. The new perfluoroalkylsulfur chloride tetrafluorides are colorless, unpleasant smelling liquids. The infrared, mass and ¹⁹F NMR spectral data, as well as thermodynamic and elementary analysis data, are given for the new compounds.     

Study on the reactions of fluoroalkanesulfonyl azides with pyrazine and its derivatives

The thermal reactions of fluoroalkanesulfonyl azides R_fSO₂N₃ with pyrazine and its derivatives are studied in detail. All the reactions involved the fluoroalkanesulfonyl nitrene intermediates R_fSO₃N: which was captured by pyrazine to give the pyrazinium N-fluoroalkanesulfonyl ylides C₄NH₄N⁺-⁻NSO₂R_f and hydrogen abstraction product R_fSO₂NH₂, but no corresponding N-pyrazinyl fluoroalkanesulfonyl amide derivatives R_fSO₂NHC₄N₂H₃ were isolated. Excess azides did not afford the bisN-ylide product R_fSO₂N⁻-⁺NC₄H₄N⁺-⁻NSO₂R_f.