Dealkylation Reactions Research Articles

Methylation and dealkykation of tin compounds by sulfate- and nitrate-reducing bacteria

In this study, axenic cultures of sulfate-reducing (SRB) and nitrate-reducing (NRB) bacteria were examined for their ability to methylate inorganic tin and to methylate or dealkylate butyltin compounds. Environmentally relevant concentrations of natural abundance tributyltin (TBT) and 116Sn-enriched inorganic tin were added to bacterial cultures to identify bacterial-mediated methylation and dealkylation reactions. The results show that none of the Desulfovibrio strains tested was able to induce any transformation process. In contrast, Desulfobulbus propionicus strain DSM-6523 degraded TBT either under sulfidogenic or non-sulfidogenic conditions. In addition, it was able to alkykate 116Sn-enriched inorganic tin leading to the formation of more toxic dimethyltin and trimethyltin. A similar capacity was observed for incubations of Pseudomonas but with a much greater dealkykation of TBT. As such, Pseudomonas sp. ADR42 degraded 61% of the initial TBT under aerobic conditions and 35% under nitrate-reducing conditions. This is the first work reporting a simultaneous TBT degradation and a methylation of both inorganic tin species and TBT dealkykation products by SRB and NRB under anoxic conditions. These reactions are environmentally relevant as they can control the mobility of these compounds in aquatic ecosystems; as well as their toxicity toward resident organisms.

Demonstration of In Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents.

After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE.

Effect of crystal size on the catalytic performance of HZSM-5 Zeolite in the methanol to aromatics reaction

ABSTRACTThe effect of crystal size on the lifetime and product distribution of HZSM-5 catalysts in methanol to aromatics reaction has been investigated. Increasing crystal size results in a reduction of the lifetime. Though the initial selectivity of total aromatics is approximately the same, larger crystal size favors the dealkylation reactions of polymethylbenzenes, cracking of C5–C9 non-aromatics and hydrogen transfer reaction, leading to different product distribution. The longer lifetime of HZSM-5 with smaller crystal size can be attributed to its larger specific surface area, pore volume and diameter and short residence time of the reaction products in the zeolite pores.

Visbreaking of Heavy Oil under Supercritical Water Environment

The visbreaking of heavy oil under high-pressure N2 or supercritical water (SCW) environment was experimentally investigated. Despite the difference in the reaction media, the visbreaking follows the same mechanism, that is, dealkylation and condensation of aromatics. The presence of SCW makes it possible that the visbreaking of heavy oil is transferred to the SCW phase with superior diffusivity by which the visbreaking tends to be controlled by intrinsic reaction kinetics rather than by diffusion. Accordingly, dealkylation occurring in the SCW phase, which is vital to the viscosity reduction of heavy oil, responds sensitively to the increase in reaction temperature. Being the secondary reaction of dealkylation at moderate temperatures, condensation is effectively suppressed with reduced reaction time required for dealkylation. By the introduction of SCW and the adoption of an appropriate reaction temperature, the visbreaking efficiency could be drastically improved together with guaranteed stability of v...

The oximes HI-6 and MMB-4 fail to reactivate soman-inhibited human and guinea pig AChE: A kinetic in vitro study

Acetylcholinesterase (AChE) inhibited by the organophosphorus nerve (OP) agent soman underlies a spontaneous and extremely rapid dealkylation (“aging”) reaction which prevents reactivation by oximes. However, in vivo studies in various, soman poisoned animal species showed a therapeutic effect of oximes, with the exact mechanism of this effect remaining still unclear. In order to get more insight and a basis for the extrapolation of animal data to humans, we applied a dynamic in vitro model with continuous online determination of AChE activity. This model allows to simulate the in vivo toxico- and pharmacokinetics between human and guinea pig AChE with soman and the oximes HI-6 and MMB-4 in order to unravel the species dependent kinetic interactions. It turned out that only HI-6 was able to slow down the ongoing inhibition of human AChE by soman without preventing final complete inhibition of the enzyme. Continuous perfusion of AChE with soman and simultaneous or delayed (8, 15 or 40min) oxime perfusion did not result in a relevant reactivation of AChE (less than 2%). In conclusion, the results of the present study indicate a negligible reactivation of soman-inhibited AChE by oximes at conditions simulating the in vivo poisoning by soman. The observed therapeutic effect of oximes in soman poisoned animals in vivo must be attributed to alternative mechanisms which may not be relevant in humans.

Why is Aged Acetylcholinesterase So Difficult to Reactivate?

Organophosphorus agents are potent inhibitors of acetylcholinesterase. Inhibition involves successive chemical events. The first is phosphylation of the active site serine to produce a neutral adduct, which is a close structural analog of the acylation transition state. This adduct is unreactive toward spontaneous hydrolysis, but in many cases can be reactivated by nucleophilic medicinal agents, such as oximes. However, the initial phosphylation reaction may be followed by a dealkylation reaction of the incipient adduct. This reaction is called aging and produces an anionic phosphyl adduct with acetylcholinesterase that is refractory to reactivation. This review considers why the anionic aged adduct is unreactive toward nucleophiles. An alternate approach is to realkylate the aged adduct, which would render the adduct reactivatable with oxime nucleophiles. However, this approach confronts a considerable—and perhaps intractable—challenge: the aged adduct is a close analog of the deacylation transition state. Consequently, the evolutionary mechanisms that have led to transition state stabilization in acetylcholinesterase catalysis are discussed herein, as are the challenges that they present to reactivation of aged acetylcholinesterase.

The metabolism and drug–drug interaction potential of the selective prostacyclin receptor agonist selexipag

1. The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified.2. The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces.3. The formation of the active metabolite ACT-333679 is catalysed by carboxylesterases, while the oxidation and dealkylation reactions are metabolized by CYP2C8 and CYP3A4. CYP2C8 is the only P450 isoform catalysing the aromatic hydroxylation to P10. CYP2C8 together with CYP3A4 are also involved in the formation of several minor ACT-333679 metabolites. UGT1A3 and UGT2B7 catalyse the glucuronidation of ACT-333679.4. The potential of selexipag to inhibit or induce cytochrome P450 enzymes or drug transport proteins was studied in vitro. Selexipag is an inhibitor of CYP2C8 and CYP2C9 and induces CYP3A4 and CYP2C9 in vitro. Also, selexipag inhibits the transporters OATP1B1, OATP1B3, OAT1, OAT3, and BCRP. However, due to its low dose and relatively low unbound exposure, selexipag has a low potential for causing drug–drug interactions.

Biotransformation of total coumarins of Radix Glehniae by Lecanicillium attenuatum W-1-9

The biotransformation of total coumarins of Radix Glehniae by Lecanicillium attenuatum W-1-9 yielded three new products, lecaniside A (1), lecaniside B (2), and lecaniside C (3). The chemical structures of these metabolites were elucidated based on extensive spectral data, including 2D NMR and HRMS. The hydrogenation, dealkylation, glycosylation, and O-methylation reactions of these metabolites were observed in the present study. In the in vitro assays, compound 1 displayed a little PTP1B inhibitory activity.

Electrochemical simulation of biotransformation reactions of citrinin and dihydroergocristine compared to UV irradiation and Fenton-like reaction.

Mycotoxins occur widely in foodstuffs and cause a variety of mold-related health risks to humans and animals. Elucidation of the metabolic fate of mycotoxins and the growing number of newly discovered mycotoxins have enhanced the demand for fast and reliable simulation methods. The viability of electrochemistry coupled with mass spectrometry (EC/ESI-MS), Fenton-like oxidation, and UV irradiation for the simulation of oxidative phase I metabolism of the mycotoxins citrinin (CIT) and dihydroergocristine (DHEC) was investigated. The specific reaction products are compared with metabolites produced by human and rat liver microsomes in vitro. Depending on the applied potential between 0 and 2000mV vs. Pd/H2 by using a flow-through cell, CIT and DHEC are oxidized to various products. Besides dehydrogenation and dealkylation reactions, several hydroxylated DHEC and CIT species are produced by EC and Fenton-like reaction, separated and analyzed by LC-MS/MS and ESI-HRMS. Compared to reaction products from performed microsomal incubations, several mono- and dihydroxylated DHEC species were found to be similar to the reaction products of EC, Fenton-like reaction, and UV-induced oxidation. Consequentially, nonmicrosomal efficient and economic simulation techniques can be useful in early-stage metabolic studies, even if one-to-one simulation is not always feasible.

Benzene co-reaction with methanol and dimethyl ether over zeolite and zeotype catalysts: Evidence of parallel reaction paths to toluene and diphenylmethane

The reactivity of methanol (MeOH) and dimethyl ether (DME) toward benzene was studied over zeolitic materials with different topology and acid strength (H-ZSM-5, H-SSZ-24, and H-SAPO-5) at 250–350°C. Higher rates of methylation, and subsequent de-alkylation reactions, were observed with DME compared to MeOH. In addition, significant differences in product distribution based on the choice of methylating agent were observed. For reactions between MeOH and benzene a fraction of diphenylmethanes (DPMs) was formed, while this product group was nearly absent during reactions between DME and benzene. A range of co-feed and isotopic labeling experiments was performed, mainly over H-ZSM-5, in order to elucidate mechanistic information on the pathway from methanol and benzene to DPMs. Overall, these studies revealed that DPM formation involves the dehydrogenation of methanol to formaldehyde on the Brønsted acid site, followed by subsequent reaction with two benzene molecules. Theoretical calculations confirmed the higher reactivity of DME compared to MeOH toward benzene methylation and suggested a plausible route from formaldehyde and benzene to DPM.

Facile Hydrogenolysis of C(sp3)–C(sp3) σ Bonds

AbstractThe modification of benzylic quaternary, tertiary, and secondary carbon centers through palladium‐catalyzed hydrogenolysis of C(sp3)–C(sp3) σ bonds is presented. When benzyl Meldrum's acid derivatives bearing quaternary benzylic centers are treated under mild hydrogenolysis conditions – palladium on carbon and atmospheric pressure of hydrogen – aromatics substituted with tertiary benzylic centers and Meldrum's acid are obtained with good to excellent yield. Analogously, substrates containing tertiary or secondary benzylic centers yield aromatics substituted with secondary benzylic centers or toluene derivatives, respectively. Furthermore, this strategy is used for the high yielding synthesis of diarylmethanes. The scope of the reductive dealkylation reaction is explored and the limitations with respect to steric and electronic factors are determined. A mechanistic analysis of the reaction is described that consisted of deuterium labelling experiments and hydrogenolysis of enantioenriched derivatives. The investigation shows that the C(sp3)–C(sp3) σ bond‐cleaving events occur through a hybrid SN1/SN2 mechanism, in which the palladium center displaces a carbon‐based leaving group, namely Meldrum's acid, with inversion of configuration, followed by reductive elimination of palladium to furnish a C−H bond.magnified image

Obesity and atrial fibrillation

This study explored the feasibility of coupling N2O decomposition with ethylbenzene (EB) oxidative dehydrogenation, as an alternative approach for greenhouse gas elimination and styrene (ST) production, on the Co-Al mixed oxides and K-modified catalysts. It was found that N2O could decompose completely over the K/Co2AlO4 catalyst, accompanied with 62.0% of EB conversion and 85.1% of styrene selectivity, which were much better than the existing catalyst systems for EB oxidative dehydrogenation. Characterization results showed that despite the decreased specific surface area of the catalysts with increasing the Co/Al molar ratio, the improved reducibility, the reduced acid properties as well as the higher ratio of Co3+/Co2+ were responsible for the enhanced performance. The K modification not only changed the electronic properties of active metal, resulting from the charge transfer from K cation to the Co species, but also weakened the binding energy of Co3+-O−, leading to the complete decomposition of N2O. Furthermore, the optimized strong acid properties inhibited the dealkylation or ring-opening reactions and significantly reduced the coke deposition on the catalyst surface, thus improving the ST selectivity.

Upgrading of Omani heavy oil with bimetallic amphiphilic catalysts

Upgrading of Omani heavy oil was studied under aquathermolytic conditions in the presence of amphiphilic catalysts of NiMo, CoMo and their mixture of 1:1wt ratio. The optimum reaction parameters were 300°C, 5wt% water concentration and 2wt% catalyst concentration. For viscosity reduction, the catalyst efficiency follows the trend (CoMo+NiMo)> NiMo>CoMo. The maximum viscosity reduction observed at optimum conditions was 95% after 24h of reaction on CoMo+NiMo mixture. Upgrading products distribution showed an increase in <C14 components and a reduction in >C21 components – suggesting cracking of longer carbon chains. Fourier Transform-Infrared Spectroscopy (FT-IR) confirmed the formation of alkenes as well as shortening of CH2 bonds following upgrading. Nuclear Magnetic Resonance (NMR) confirmed the occurrence of dealkylation reactions as well as cleavage of side chains on aromatics. X-ray fluorescence (XRF) indicated a reduction in sulfur content of up to 15% and confirmed the importance of CS bond cleavage and hydrogenation in reduction of heavy oil viscosity. Results obtained indicated that amphiphilic catalysts are useful in the upgrading of Omani heavy oil, which will lead to an increase in recovery of higher value hydrocarbons.

The role of butylbenzene carbenium ions in the acid catalyzed cracking of polystyrene. Transformation of n-butylbenzene, sec-butylbenzene, iso-butylbenzene, tert-butylbenzene, 4-phenyl-1-butene, n-propylbenzene and n-hexylbenzene over silicaalumina and alumina acid catalysts

The obtained results show that styrene dimers, which are the primary transition products of PS cracking undergo consecutive reactions over acid centers of high acid strength (SiO2–Al2O3(45 %); −10.8 −3.3) at sufficiently high reaction temperatures (723–773 K). It is proposed that phenylbutenyl carbenium ion obtained due to dealkylation reaction converts into coke by the successive elimination of H+ and H− ions, which in turn take part in hydrogen transfer reactions resulting in the hydrogenation of styrene dimers to diphenylbutane. The dealkylation of this compound leads to active γ-butylbenzene carbenium ion which is a key intermediate for the formation of indane and naphthalene derivatives.

Catalytic Dealkylation of Ethers to Alcohols on Metal Surfaces

AbstractOn‐surface synthesis has prompted much interest in recent years because it provides an alternative strategy for controlling chemical reactions and allows for the direct observation of reaction pathways. Herein, we combined scanning tunneling microscopy and density functional theory to provide extensive evidence for the conversion of alkoxybenzene‐containing ethers into alcohols by means of surface synthesis. The reported dealkylation reactions are finely controlled by the annealing parameters, which govern the onset of successive alkyl chains dissociations. Moreover, density functional theory calculations elucidate the details of the reaction pathways, showing that dealkylation reactions are surface‐assisted and very different from their homogeneous analogues in solution.

Catalytic Dealkylation of Ethers to Alcohols on Metal Surfaces.

On-surface synthesis has prompted much interest in recent years because it provides an alternative strategy for controlling chemical reactions and allows for the direct observation of reaction pathways. Herein, we combined scanning tunneling microscopy and density functional theory to provide extensive evidence for the conversion of alkoxybenzene-containing ethers into alcohols by means of surface synthesis. The reported dealkylation reactions are finely controlled by the annealing parameters, which govern the onset of successive alkyl chains dissociations. Moreover, density functional theory calculations elucidate the details of the reaction pathways, showing that dealkylation reactions are surface-assisted and very different from their homogeneous analogues in solution.

Solar photocatalytic decomposition of ethyl paraben in zinc oxide suspensions

The photocatalytic degradation of ethyl paraben (EP) in zinc oxide (ZnO) suspensions under simulated solar radiation was investigated. The effect of EP concentration (500–1500μg/L), ZnO concentration (100–500mg/L), reaction time (3–9min), initial pH (3–9), light intensity (7.3 10−7–1.1 10−6 einstein/(L.s)) and the water matrix (0–10mg/L of humic acid) on degradation was evaluated implementing a factorial design methodology. Of the six variables tested, EP concentration, ZnO concentration, reaction time and the water matrix were found to be statistically significant variables, and also important was the second order interaction of EP concentration with reaction time. With the exception of the water matrix, all other effects were positive with respect to the concentration of EP removed.Experiments at increased EP concentration (20mg/L) were performed to identify transformation products (TPs) and assess the extent of mineralization. LC-TOF-MS analysis revealed the formation of seven early-stage TPs through hydroxylation and dealkylation reactions and a plausible reaction pathway was proposed. Besides the identified TPs, other unidentified TPs were also formed as has been verified measuring the extent of mineralization and performing a carbon balance in the liquid phase. EP at 20mg/L exhibited mild estrogenic activity, which was partially removed upon oxidation. The stability of ZnO was evaluated measuring the extent of zinc leaching, which was just 1.5%; moreover, ZnO was found to be more active than reference P25 TiO2 for EP degradation and mineralization.

Friedel-Crafts dealkylation reaction mediated by a stereoselective proton transfer in the fragmentation of protonated cyclic indolyl α-amino esters.

Chiral cyclic indolyl α-amino esters are valuable substructures of peptides and peptidomimetics. Systematically exploring the fragmentation behavior of the protonated cyclic indolyl α-amino esters by a combination of high-resolution high-energy collisional dissociation mass spectrometry, hydrogen-deuterium exchange experiments and density functional theory (DFT) calculations is useful for further understanding their intrinsic properties and the fragmentation mechanisms of peptidomimetics constructed with them. All high-resolution high-energy collisional dissociation tandem mass spectrometry experiments were carried out using electrospray ionization hybrid Quadrupole-Orbitrap mass spectrometry in positive ion mode. Only the labile hydrogens were exchanged with deuterium in hydrogen-deuterium exchange experiments. Theoretical calculations were carried out by the DFT method at the B3LYP level with the 6-311G(d,p) basis set in the Gaussian 03 package of programs. In the fragmentation of protonated cyclic indolyl α-amino esters, when the two labile hydrogens on the N(8) position are successively transferred to the C(3) and C(4) positions, a Friedel-Crafts dealkylation reaction takes place spontaneously, with concomitant formation of an ion-neutral complex of [cyclic N-sulfonyl ketimino esters/protonated indoles]. Direct separation of this complex formed the protonated indoles, while a stereoselective proton transfer between the two components in the complex gave rise to protonated cyclic N-sulfonyl ketimino esters, which coincided with the hydrogen-deuterium experiments. Using H/D exchange experiments combined with theoretical calculations, a Friedel-Crafts dealkylation reaction mediated by a stereoselective proton transfer in the [cyclic N-sulfonyl ketimino esters/protonated indoles] complex was proposed for the fragmentation of protonated cyclic indolyl α-amino esters in high-energy collisional dissociation tandem mass spectrometry for the first time. Copyright © 2016 John Wiley & Sons, Ltd.

Degradation of ethyl paraben by heat-activated persulfate oxidation: statistical evaluation of operating factors and transformation pathways.

A factorial design methodology was implemented to evaluate the importance of ethyl paraben (EP) concentration (500-1500μg/L), sodium persulfate concentration (400-500mg/L), temperature (40-60°C), reaction time (2-30min), water matrix (pure water or secondary treated wastewater), and initial solution pH (3-9) on EP removal by heat-activated persulfate oxidation. All individual effects, except the solution pH, were statistically significant and so were the second-order interactions of ethyl paraben concentration with temperature or the reaction time. The influence of the water matrix was crucial, and the efficiency of the process was lower in secondary treated wastewater due to the presence of natural organic matter and inorganic salts that compete with ethyl paraben for the reactive oxygen species. Liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) was employed to identify major transformation by-products (TBPs); 13 compounds were detected as TBPs of EP. Degradation occurred through (i) hydroxylation, (ii) dealkylation, and (iii) oligomerization reactions leading to TBPs with ether and biphenyl structures. Oligomerization reactions were found to be the dominant pathway during the first steps of the reaction. The toxicity of 500μg/L EP in secondary treated wastewater was tested against marine bacteria Vibrio fischeri; toxicity increased during the first minutes due to the production of several TBPs, but it consistently decreased thereafter.

Efforts toward treatments against aging of organophosphorus-inhibited acetylcholinesterase.

Aging is a dealkylation reaction of organophosphorus (OP)-inhibited acetylcholinesterase (AChE). Despite many studies to date, aged AChE cannot be reactivated directly by traditional pyridinium oximes. This review summarizes strategies that are potentially valuable in the treatment against aging in OP poisoning. Among them, retardation of aging seeks to lower the rate of aging through the use of AChE effectors. These drugs should be administered before AChE is completely aged. For postaging treatment, realkylation of aged AChE by appropriate alkylators may pave the way for oxime treatment by neutralizing the oxyanion at the active site of aged AChE. The other two strategies, upregulation of AChE expression and introduction of exogenous AChE, cannot resurrect aged AChE but may compensate for lowered active AChE levels by in situ production or external introduction of active AChE. Upregulation of AChE expression can be triggered by some peptides. Sources of exogenous AChE can be whole blood or purified AChE, either from human or nonhuman species.