Oxygen Analog Research Articles

Quantum-Chemical Study of the Structure and Reactivity of Pyrazol-5-ones and Their Thio and Seleno Analogs: VI. Tautomeric and Acid-Base Properties of 3-Methyl-1-phenyl-4,5-dihydropyrazol-5-one, 3-Methyl- 1-phenyl-4,5-dihydropyrazole-5-thione, and 3-Methyl-1-phenyl-4,5-dihydropyrazole-5-selenone

The relative stabilities of tautomeric forms of 3-methyl-1-phenylpyrazol-5-one and its 5-thioxo and 5-selenoxo analogs, as well as their acid-base properties in the gas phase, were estimated in terms of nonempirical calculations and density functional theory. According to the results of both calculation methods, the CH tautomer of 3-methyl-1-phenylpyrazol-5-one is the most stable. The stabilities of the XH and CH forms of its heteroanalogs (X = S, Se) are comparable; the relative stability of the SeH (SH) tautomers increases when thermal corrections, zero-point energy, and electron correlation effects are taken into account. The two methods indicate increase in the gas-phase acidity of the title compounds on variation of the heteroatom in the series O <S < Se and fairly similar basicities of the oxygen and sulfur analogs.

Calculations Related to the Reactivity of Polycyclic Aromatic Hydrocarbon Episulfides

The opening reaction of S-protonated polycyclic aromatic hydrocarbon episulfides has been evaluated by means of ab initio, density-functional, and semiempirical calculations. Episulfides are predicted to open more easily than the corresponding O-protonated derivatives, epoxides, and diol epoxides. On the other hand, diol episulfides would present the slowest rate for opening, the syn isomers being expected to be more reactive than the anti isomers. Bay-region and methyl-substituted bay-region compounds were found to open more readily among the sulfur derivatives, following the same reactivity pattern as the oxygen analogs. The exothermicity of the opening process correlated with the charge delocalization in the resulting carbocation. This reaction step is very important in the carcinogenic pathway of the epoxide analogs. Thus, according to the present calculations, episulfides could possibly exert carcinogenic activity.

In vitro effects of chlorpyrifos, parathion, methyl parathion and their oxons on cardiac muscarinic receptor binding in neonatal and adult rats

Organophosphorus insecticides elicit toxicity by inhibiting acetylcholinesterase. Young animals are generally more sensitive than adults to these toxicants. A number of studies reported that some organophosphorus agents also bind directly to muscarinic receptors, in particular the m 2 subtype, in tissues from adult rats. As both the density and agonist affinity states of cardiac muscarinic receptors (primarily m 2) have been reported to change in an age-related manner, we evaluated the relative in vitro sensitivity of cardiac muscarinic receptors in tissues from neonatal (7–11 days of age) and adult (90 days of age) rats to selected organophosphorus compounds (chlorpyrifos, parathion, methyl parathion and their oxygen analogs or oxons). The effects of the cholinergic agonist carbachol (100 pM–5 μM) or an organophosphorus toxicant (50 pM–10 μM) on muscarinic receptor binding were determined using the nonselective muscarinic ligand [ 3H]quinuclidinyl benzilate or the m 2-preferential ligand [ 3H]oxotremorine-M acetate. Carbachol displaced [ 3H]oxotremorine labeling in adult and neonatal membranes in a relatively similar manner (IC 50=7–20 nM). The oxons all displaced [ 3H]oxotremorine binding in a concentration-dependent manner, with chlorpyrifos oxon being the most potent (IC 50: neonates, 15 nM; adults, 7 nM) and efficacious (maximum displacement: neonates, 42%; adults, 56%). Interestingly, methyl parathion was an extremely potent displacer of [ 3H]oxotremorine binding in adult tissues (IC 50=0.5 nM, maximum displacement=37%) but had no effect in neonatal tissues. The displacement of [ 3H]oxotremorine binding by chlorpyrifos oxon (10 μM) was still apparent after washing the tissues, suggesting the oxon irreversibly blocked agonist binding to the receptor while interaction with MePS appeared reversible. As effective concentrations of the oxons were relatively similar to their anticholinesterase potencies, these findings suggest that direct interaction with cardiac muscarinic receptors by some organophosphorus agents may occur at relevant exposure levels and contribute to cardiac toxicity.

ChemInform Abstract: Stability of Heteroazulene‐Substituted Tropylium Ions: Synthesis and Properties of the (2‐Oxo‐2H‐cyclohepta[b]thiophen‐3‐yl)tropylium Ion (Ia), and Its Oxygen and Nitrogen Analogues (Ib).

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Remarkable Thiocarbonyl and Ring-Size Effects on the Amide Bond Twisting

Abstract Remarkable thiocarbonyl and ring-size effects on the amide bond twisting were observed for N-acetylamides 1–3. The amide linkage of 2 is perpendicularly twisted, whereas the oxygen analog 1 and five-membered analog 3 are virtually planar, which were revealed by 13C NMR and IR spectroscopies, and X-ray analysis.

A Gaussian-2 ab Initio Study of the [C2H5S]-Potential Energy Surface: I. Structures and Energetics of [C2H5S]-Anions and Fragmentation Pathways of the Thioethoxide Anion

The thermochemical data for the five isomers/conformers of [C2H5S]-, CH3CH2S- (1), CH3CHSH- (2/3), and CH3SCH2- (4/5) have been calculated and compared with available experimental data. The structural and electronic properties of the isomers/conformers are also discussed. Contrary to its oxygen analogue, the 2-mercaptoethyl anion (HSCH2CH2-) is unstable with respect to the dissociation to HS- + C2H4 without an energy barrier. In addition, plausible elimination pathways and intramolecular rearrangements for 1 have also been studied. The 1,2-H2 elimination 1 → H2 + CH2CHS- and the 1,2-HS- elimination 1 → HS- + C2H4 have the lowest-energy barriers (260−267 kJ mol-1) among the plausible elimination reactions of 1 under investigation. Rearrangement 1 → 3 has an energy barrier of 259 kJ mol-1 and is energetically competitive with the aforementioned 1,2-elimination reactions. On the other hand, conversion of 1 to 4/5 may proceed via a dissociation and recombination mechanism. The estimated energy cost for 1 → 4/5 is ca. 285 kJ mol-1.

Derivatives of 1-phenyl-3-methylpyrazol-2-in-5-thione and their oxygen analogues in the crystalline phase and their tautomeric transformations in solutions and in the gas phase

1-Phenyl-3-methylpyrazol-2-in-5-thione, crystallised from methanol, was shown to exist in the tautomeric NH-form, stabilised by intermolecular NH⋯S hydrogen bonds. In solutions, however, the molecule is found predominantly as the SH-tautomer, accompanied (in low-polar solvents) by a small amount of the CH-tautomer. 1-Phenyl-3-methyl-4-benzoylpyrazol-2-in-5-thione occurs in the crystal as well as in solution in the SH-tautomeric form, stabilised by an intramolecular SH⋯O bridge. In dimethylsulfoxide solution indications were found for an additional SH-tautomer in a conformation lacking the intramolecular H-bridge. The structure of 1-phenyl-3-methylpyrazol-2-in-5-one was redetermined by X-ray single crystal diffraction at 120°K in order to obtain more accurate geometry and hydrogen bonding parameters.

An insensitive acetylcholinesterase confers resistance to methomyl in the beet armyworm Spodoptera exigua (Lepidoptera: Noctuidae).

Two forms of acetylcholinesterase were identified in field populations of the beet armyworm, Spodoptera exigua (Hübner), collected from cotton in San Joaquin Valley, CA. Strains (BESS and BKRR) homogeneous for each variant were isolated and their relative susceptibilities to methomyl, chlorpyrifos, and chlorpyrifos-oxon assessed by topical application bioassay. In comparisons with a laboratory susceptible strain (DOW), BKRR and BESS expressed 68-fold and sevenfold resistance, respectively, to the carbamate methomyl. Neither strain was cross-resistant to chlorpyrifos or its oxygen analog (chlorpyrifos-oxon). In biochemical studies, the BKRR AChE enzyme was approximately 30-fold and sixfold more insensitive to methomyl and chlorpyrifos-oxon, respectively, compared with the DOW enzyme. The correlation between the toxicological and biochemical studies provides strong evidence that target-site insensitivity is an important mechanism of resistance to methomyl. The lack of significant cross-resistance to chlorpyrifos suggests that the insensitive AChE in these field populations was selected by methomyl alone and not by the organophosphate.

Stability of heteroazulene-substituted tropylium ions: synthesis and properties of the (2-oxo-2H-cyclohepta[b]thiophen-3-yl)tropylium ion, and its oxygen and nitrogen analogues

Synthesis and properties of a novel type of heteroazulene-substituted tropylium tetrafluoroborate, 2-oxo-2H-cyclohepta[b]thiophen-3-yltropylium tetrafluoroborate, and its oxygen and nitrogen analogues, 9a–d·BF4− are reported. The synthesis is based on a simple reaction of the tropylium ion with the corresponding heteroazulenes in the presence of NEt3, followed by oxidative hydrogen abstraction with DDQ and subsequent exchange of the counter-anion by using aq. HBF4 solution. The stability of the tropylium ion derivatives 9a–d is found to be in the order 9a < 9b < 9c < 9d from pKR+ values of 3.2–5.7 obtained spectrophotometrically and reduction potentials measured by cyclic voltammetry (CV). The important canonical structures for the cations 9a–d are discussed on the basis of the 1H and 13C NMR spectral data and the energy levels of HOMOs of heteroazulenes as well as the stable conformation obtained by AM1 method (MOPAC97). A good linear correlation between the pKR+ values and the reduction potentials was obtained for cations 9a–d. The stabilizing effect of heteroazulenes toward cations 9a–d is similar to that of heteroazulene-substituted methyl cations based on the similarity of the regression line slopes.

Inhibition of jack bean urease by N-(n-butyl) thiophosphorictriamide and N-(n-butyl) phosphorictriamide: determination of the inhibition mechanism.

N-(n-butyl)thiophosphorictriamide (NBPT) and its oxygen analogue N-(n-butyl)phosphorictriamide (NBPTO) were studied as inhibitors of jack bean urease. NBPTO was obtained by spontaneous conversion of NBPT into NBPTO. The conversion under laboratory conditions was slow and did not affect NBPT studies. The mechanisms of NBPT and NBPTO inhibition were determined by analysis of the reaction progress curves in the presence of different inhibitor concentrations. The obtained plots were time-dependent and characteristic of slow-binding inhibition. The effects of different concentration of NBPT and NBPTO on the initial and steady-state velocities as well as the apparent first-order velocity constants obeyed the relationships for a one-step enzyme-inhibitor interaction, qualified as mechanism A. The inhibition constants of urease by NBPT and NBPTO were found to be 0.15 microM and 2.1 nM, respectively. The inhibition constant for NBPT was also calculated by steady-state analysis and was found to be 0.13 microM. NBPTO was found to be a very strong inhibitor of urease in contrast to NBPT.

Conformations and coordination properties of trialkyltrithiophosphites in copper(I) complexes

A series of complexes (RS)3P·CuBr with R=Et, Pr, Bu, i-Pr as well as the complex of (PrS)3P·CuSCN were studied by X-ray single-crystal diffraction. Coordination properties of thiophosphites were found to be essentially different from their oxygen and nitrogen analogues and depend on the nature of the metal center, substituents at sulfur atoms, the conditions of reactions and of the crystal growth. All trithiophosphites in the studied copper(I) complexes except the isopropyl derivative exhibit bidentate coordination with both phosphorus and sulfur participating in coordination bonds with copper.Trithiophosphites increase their conformational multiformity upon complexation regardless of the coordination mode, propyl and butyl derivatives being conformationally inhomogeneous in crystals. Unusual cis-conformations about the P–S bond, which are not observed for “free” trialkyltrithiophosphites or their phosphoryl and thiophosphoryl analogues, are realized in the complexes.The complexation results in the significant high-frequency shift of the symmetric and asymmetric PS3 stretching vibrations in the Raman spectra of complexes regardless of the coordination mode and in minor changes of the C–S stretching vibrations in comparison with the spectra of the “free” ligands.

The dissipation of malathion and dimethoate from the pea plants (Pisum sativum) under controlled conditions

14C‐malathion, [S‐1,2‐bis(ethoxycarbonyl)ethyl O,O‐dimethyl phosphorodithioate] and 14C‐dimethoate, [O,O‐dimethyl S‐(N‐methylcarbamoylmethyl)phosphorodithioate] have been administered to leaves of pea (Pisum sativum) plants under simulated tropical conditions in the greenhouse. The results show that l4C‐malathion dissipated faster than 14C‐dimethoate from the leaf surface: After 16 days, 5.7% of the radioactive dose applied as malathion remained on the surface of the treated leaves as surface (dislodgeable) residues. The extractable residues constituted 9% while the bound (non‐extractable) residues were 4.2% of the total initial radioactivity. 16.7% of the initial dose had been translocated from the treated leaves to the rest of the plant. 17.1% of the initial dose constituted 14C‐compounds other than 14CO2 recovered from the transpired water. The corresponding fractions of dimethoate were 21% dislodgeable, 17.4% extractable, and 5% bound residues. Only 4.6% of 14C‐dimethoate residues were distributed in the plant. Although dimethoate is 170 times more soluble in water than malathion, only 10.4% of the initial pesticide dose of dimethoate constituted 14C‐compounds in the transpired water. Dimethoate formed dimethoxon, the oxygen analogue, while malathion did not form malaoxon in the plant, as revealed by thin layer chromatography (TLC) and confirmed by gas chromato‐graphy‐mass spectrometry (GC‐MS).

The structures of [Ph 2XSNSPh 2NH] + cations (XNH, O)

Diphenyl(diphenylsulfodiimidoyl)(nitrido)sulfur(VI) ( 2) and diphenyl(diphenylsulfoximidoyl)(nitrido)sulfur(VI) ( 3) (Ph 2XSNSNPh 2N, X=NH, O) were prepared by the reaction of diphenyl(fluoro)(nitrido)sulfur(VI) (Ph 2FSN) with sodium salts of diphenyl-sulfodiimide (Ph 2S(NH) 2) and -sulfoximide (Ph 2OSNH). The nitrido-sulfur complexes 2 and 3 are considerably basic (p K a=7.86 and 7.60, respectively). Treatment of 2 and 3 with perchloric acid afforded quantitatively the corresponding μ- aza-bis[diphenyl(imido)sulfur(V)] perchlorate ( 4) and μ- aza-[diphenyl(imido)]-[diphenyl(oxo)]disulfur(V) perchlorate ( 5) ([Ph 2XSNSPh 2NH] +[ClO 4] −, X=NH, O). The crystal structures of 4 and 5 were determined by X-ray crystallographic analysis. The former has essentially C 2 symmetry with an SNS bond angle of 120.3(2)°, bridging SN bond lengths of 1.595(3) and 1.604(3) Å, and terminal SN bond lengths of 1.509(3) and 1.497(3); the latter cation is an unsymmetrically substituted oxygen analog with an SNS bond angle of 123.1(2)°, and bridging SN bond lengths of 1.607(4) and 1.568(4) Å, terminal SN and SO bond lengths of 1.501(3) and 1.438(2) Å. Single-point ab initio calculations were also carried out using the data from the crystal structures of 4 and 5.

Novel Urea Derivatives as Two-Step Redox Systems

The structurally novel urea derivatives 4−6 have been synthesized by treating the nucleophilic dipyridoimidazol-2-ylidene 1 with elemental chalcogens Y (Y = S, Se, Te). The oxygen analogue 8 has been obtained indirectly by alkylation of the seleno urea 5, followed by alkaline hydrolysis. All of these urea derivatives share two novel structural features: (i) their nitrogen centers represent the termini of the RED form of a two-step viologen-type redox system, and (ii) they can also be viewed as formally resulting from a cheletropic addition of CY to 2,2′-bipyridine. It has been demonstrated electrochemically that for Y = O, S, Se these ureas can be reversibly oxidized to the corresponding radical cations (SEM forms) at remarkably constant and negative potentials. This also applies to the heaviest congener of the series with Y = Te, except that in this case the oxidation process exhibits only quasi-reversibility. Electrochemical generation of the corresponding OX forms is observed quasi-reversibly at increasingly positive potentials with increasing mass of the chalcogen Y. However, the bis-oxidation of the telluro species 6 cannot be observed. These experimental results are discussed on the basis of semiempirical calculations for the RED, SEM, and OX forms under consideration. Semiempirical calculations also suggest that fragmentation of the novel urea derivatives into CY and 2,2′-bipyridine should be mildly endothermic for Y = O, but increasingly strongly endothermic with increasing mass of Y. This result is qualitatively in line with expectation considering the increasing reluctance of the heavier chalcogens to take part in multiple bonding to carbon. This phenomenon is also reflected in the mass spectrometric fragmentation patterns of the urea derivatives 4−6 and 8.

Solid-State Deuterium NMR and Molecular Modeling Studies of Conformational Dynamics in Carbohydrates

We report a deuterium nuclear magnetic resonance (NMR) investigation of octa-O-decanoylthio-‚,‚-trehalose (TTH-10) in the solid state. For the interpretation of deuterium NMR line shapes and spin-lattice relaxation rates, a two-site exchange model was invoked. The motional amplitude for the C-D vector in TTH-10 molecule was estimated to 72°, while the relative populations of the two sites were assumed to be temperature dependent. From the longitudinal deuterium relaxation rates, correlation times for the dynamic process were derived. We found these to be approximately 50 ns at 20 °C and 30 ns at 90 °C. In addition to NMR experiments, molecular dynamics (MD) computer simulations of octa-O-acetylthio-‚,‚-trehalose (TTH-2) and an oxygen analogue, octa-O-acetyl-‚,‚-trehalose (TH-2), were performed. The analysis of the two torsion angles relevant for the glycosidic linkage indicates that the conformations of the TTH-2 molecule essentially correspond to two states. This observation gives strong support for our assumption about the two-site exchange model used for interpretation of deuterium solid-state experiments.

Maturation-Dependent Effects of Chlorpyrifos and Parathion and Their Oxygen Analogs on Acetylcholinesterase and Neuronal and Glial Markers in Aggregating Brain Cell Cultures

An in vitro model, the aggregating brain cell culture of fetal rat telencephalon, has been used to study the maturation-dependent sensitivity of brain cells to two organophosphorus pesticides (OPs), chlorpyrifos and parathion, and to their oxon derivatives. Immature (DIV 5–15) or differentiated (DIV 25–35) brain cells were treated continuously for 10 days. Acetylcholinesterase (AChE) inhibitory potency for the OPs was compared to that of eserine (physostigmine), a reversible AChE inhibitor. Oxon derivatives were more potent AChE inhibitors than the parent compounds, and parathion was more potent than chlorpyrifos. No maturation-dependent differences for AChE inhibition were found for chlorpyrifos and eserine, whereas for parathion and paraoxon there was a tendency to be more effective in immature cultures, while the opposite was true for chlorpyrifos-oxon. Toxic effects, assessed by measuring protein content as an index of general cytotoxicity, and various enzyme activities as cell-type-specific neuronal and glial markers (ChAT and GAD, for cholinergic and GABAergic neurons, respectively, and GS and CNP, for astrocytes and oligodendrocytes, respectively) were only found at more than 70% of AChE inhibition. Immature compared to differentiated cholinergic neurons appeared to be more sensitive to OP treatments. The oxon derivates were found to be more toxic on neurons than the parent compounds, and chlorpyrifos was more toxic than parathion. Eserine was not neurotoxic. These results indicate that inhibition of AChE remains the most sensitive macromolecular target of OP exposure, since toxic effects were found at concentrations in which AChE was inhibited. Furthermore, the compound-specific reactions, the differential pattern of toxicity of OPs compared to eserine, and the higher sensitivity of immature brain cells suggest that the toxic effects and inhibition of AChE are unrelated.

From Carbohydrates to the Discovery of Pronounced Heteroatomic Effects on Anionically Accelerated [3,3]-Sigmatropic Rearrangements

The (Z)-(iodovinyl)oxetane 12 was prepared from D-glucose and the acyclic analog 18 was obtained from D-mannitol. Following the generation of their lithium derivatives by halogen−metal exchange, coupling to the enantiopure vinyl-substituted norbornanones 20, 23, and 29 proceeded exclusively via endo attack to deliver the targeted exo-carbinols. The anionic oxy-Cope rearrangements of 21 and 24 were seen to differ appreciably in rate. While the sulfur derivative 24 experiences [3,3] sigmatropy with a half-life of less than a minute at −78 °C, its oxygen analogue 21 proved unreactive below −20 °C under entirely comparable conditions. This phenomenon is critically examined in a synthetic context involving 26 and 30, where the heavily functionalized acyclic side chain involved previously is supplanted by an oxetane assembly. In the sulfur example, isomerization occurs very rapidly as before with 100% transfer of chirality. The kinetic response of vinyl ether 26 now proved to be entirely comparable. However, the pathway followed in this instance was intramolecular nucleophilic attack by the “naked” alkoxide at the less substituted C−O bond of the oxetane with ring cleavage and formation of alcohol 28. The global findings provide a glimpse of the subtle way in which [3,3]-sigmatropic transpositions can be modulated by heteroatomic substitution.

Oxidation of cholinesterase-inhibiting pesticides: A simple experiment to illustrate the role of bioactivation in the toxicity of chemicals

A simple undergraduate laboratory experiment that can be used in Biochemistry and Toxicology courses to illustrate the importance of metabolic reactions in the toxicity of chemical substances is reported. It involves the experimental confirmation that oxidized phosphorothionate esters, commonly used as insecticides, are stronger cholinesterase inhibitors and therefore exhibit higher toxicity than do their sulphur analogs starting from which the first are formed by in vivo oxidative desulphuration. Two separated aliquots of a bovine blood sample are incubated with parathion and paraoxon, its oxygen analog, and compared for cholinesterase activity with “normal” blood. Previously, a standard sample of paraoxon was obtained by oxidation of the thiono group of parathion with bromine vapour by reaction TLC. The comparison of the inhibitory capacity of both compounds is made by a colorimetric procedure using acetylthiocholine as substrate of the enzyme and 5,5′-dithiobis-(2-nitrobenzoic acid) as chromogen.

Oxidation of cholinesterase-inhibiting pesticides: A simple experiment to illustrate the role of bioactivation in the toxicity of chemicals

A simple undergraduate laboratory experiment that can be used in Biochemistry and Toxicology courses to illustrate the importance of metabolic reactions in the toxicity of chemical substances is reported. It involves the experimental confirmation that oxidized phosphorothionate esters, commonly used as insecticides, are stronger cholinesterase inhibitors and therefore exhibit higher toxicity than do their sulphur analogs starting from which the first are formed by in vivo oxidative desulphuration. Two separated aliquots of a bovine blood sample are incubated with parathion and paraoxon, its oxygen analog, and compared for cholinesterase activity with “normal” blood. Previously, a standard sample of paraoxon was obtained by oxidation of the thiono group of parathion with bromine vapour by reaction TLC. The comparison of the inhibitory capacity of both compounds is made by a colorimetric procedure using acetylthiocholine as substrate of the enzyme and 5,5′-dithiobis-(2-nitrobenzoic acid) as chromogen.

Molecular structures, conformations, and vibrational spectra of bicyclo[3.1.0]hexane and its oxygen analogues

The molecular structures and ring-puckering potential energy profiles of bicyclo[3.1.0]hexane and its three oxygen analogues—6-oxabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, and 3,6-dioxa[3.1.0]hexane—have been reexamined using both ab initio (HF and MP2) and density functional theory (B3LYP) methods. The calculated structural parameters and ring-puckering potential profiles of those molecules have been compared to the previously reported microwave, electron diffraction, and far-infrared data. Our computational results show that the inclusion of electron correlation effects is crucial for the precise prediction of geometrical parameters of such bicyclic systems. The calculated ring-puckering potential energy profiles using the B3LYP method reproduce the experimental profiles more accurately than those predicted by MM3 force-field methods. Vibrational frequency calculations of 6-oxabicyclo[3.1.0]hexane have been also performed to compare with those measured from the infrared and Raman spectroscopy. Comparison of the calculated and experimental results indicates that the B3LYP method has led to the prediction of more accurate vibrational frequencies than the HF and MP2 methods.