Peroxide Linkage Research Articles

Stereodivergent Total Synthesis of Ethyl Plakortide Z.

Plakortides make up a subclass of marine endoperoxides with diverse biological activities. Their structural particularity is derived from the C4 and C6 positions of the endoperoxide, which are substituted by ethyl groups. The ethyl plakortide Z has the simplest side chain among its congeners and is an excellent target for testing a universal strategy for the synthesis of this subfamily. Accordingly, we have synthesized for the first time a six-membered pla-kortide using asymmetric Enders alkylation, regioselective cyclobutanol oxidative expansion, and peroxycarbenium ion-mediated diastereoselective C-C bond formation as key steps. Preparative HPLC separation of the various diastereomers yielded a pure sample of synthetic ethyl plakortide Z, constituting the first total synthesis. Despite the lack of selectivity inherent in the synthesis of peroxide linkages involving radical reactions, the diastereomer separation step was offset by an efficient synthesis in just 11 steps and 4.2% overall yield.

Atomic-displacement threshold energies and defect generation in irradiated β-Ga2O3: A first-principles investigation

Gallium oxide is an emerging wide-bandgap semiconductor with promise for applications in space systems that may be exposed to energetic particles. We use molecular dynamics simulations, based on first principles density-functional methods, to determine the nature and stability of the defects generated by atoms knocked-out by particle irradiation at near threshold energies (found to be 28±1eV for Ga and 14±1eV for O). For Ga atoms, several types of low energy knock-out events result in defect complexes, but the final structures depend critically on the initial displacement direction. In contrast, a vacancy plus a peroxide linkage occurs in all types of low energy knock-out events of O atoms. Based on energy-barrier calculations, there is a low (high) probability for Ga (O) defect recombination. The electronic structure of residual, relaxed defects generated by Ga knock-outs reveals defect levels near the band edges.

Structure-Activity Relationships of Cytotoxic Lactones as Inhibitors and Mechanisms of Action

Some lactones prevent protein Myb-dependent gene expression. The object is to calculate inhibitors of Myb-brought genetic manifestation. Linear quantitative structure-potency relations result expanded, among sesquiterpene lactones of a variety of macrocycles (pseudoguaianolides, guaianolides, eudesmanolides and germacranolides), to establish which part of the molecule constitutes their pharmacophore, and predict their inhibitory potency on Myb-reliant genetic manifestation, which may result helpful as leads for antileukaemic therapies with a new mechanism of action. Several count indices are connected with structure-activity. The α-methylene-γ-lactone ML functional groups increase, whereas OH groups decrease the activity. Hydrophobicity provides to increase cell toxicity. Four counts (ML, number of α, β-unsaturated CO groups, etc.), connected with the number of oxygens, present a positive association, owing to the partial negative charge of oxygen. The s-trans-strans- germacranolide molecule presents maximal potency. The OH groups decrease the potency owing to the positive charge of hydrogen. The numbers of π-systems and atoms, and polarizability increase the potency. Following least squares, every standard error of the coefficients is satisfactory in every expression. The most predictive linear expressions for lactones, pseudoguaianolides and germacranolides are corroborated by leave-group-out cross-validation. Quadratic equations do not make the correlation better. Likely action mechanisms for lactones are argued with a diversity of functional groups in the lactone annulus, including artemisinin with its uncommon macrocycle characteristic, 1,2,4-trioxane cycle (pharmacophoric peroxide linkage -O1-O2- in endoperoxide ring), which results in the foundation for its sole antimalarial potency.

Understanding the Synergistic Effect in Oxygen Evolution Reaction Catalysis from Chemical Kinetics Point of View: An Iron Oxide/Nickel Oxide Case Study

The Oxygen Evolution reaction (OER) is still an enigmatic process, and a few research efforts have been deployed to understand its thermodynamic aspects. However, to date, no significant attention has been given to understand the chemical kinetics of the OER. Herein, the oxides of nickel and iron, and their heterostructure were chosen for the investigation. The electrocatalytic activity was found to augment synergistically when a heterostructure was formed between iron oxide and nickel oxide. The metal oxide catalyzed OER was an entropy-driven process and followed the peroxide linkage formation pathway. The rate-determining step was found to be different for the reactions catalyzed by different oxides. For the first time, Distribution of relaxation time (DRT) plots were utilized to study the chemical kinetics of OER, and the inference obtained from this analysis agreed well with the reaction mechanism. The kinetic barrier for the charge transfer process was found to decrease, and the surface group formation attained a moderate value after the heterostructure formation. These aspects had been the key player behind the synergistic increment in OER catalytic activity of the heterostructure. This investigation will lead a new pathway towards the development of strategies to understand the kinetics of an electrochemical reaction.

Redox-Induced Oxidative C-C Bond Cleavage of 2,2'-Pyridil in Diruthenium Complexes.

In the recent years, there has been an emerging research interest in the domain of C-C bond-cleavage reactions. The present contribution deals with the redox-mediated dioxygen activation and C-C bond cleavage in a diruthenium complex [(acac)2 RuII (μ-L1)RuII (acac)2 ], 1 (acac=acetylacetonate) incorporating 2,2'-pyridil (L1) as the bridging ligand. The above process leads to a C-C-cleaved monomeric product [(acac)2 RuIII (pic- )], 2 (pic- =piconilate). Intriguingly, similar diastereomeric complexes [(acac)2 RuII (μ-L2)RuII (acac)2 ], meso (ΔΛ): 3 a and rac (ΔΔ/ΛΛ): 3 b, involving an analogous diimine bridge (L2=N1,N2-diphenyl-1,2-di(pyridin-2-yl)ethane-1,2-diimine), were stable towards such oxidative transformations. Electrochemical and spectroelectrochemical studies, in combination, establish the potential non-innocent feature of the 2,2'-Pyridil (L1) and its derivative (L2) both in oxidation and reduction processes. Additionally, theoretical calculations have been employed to verify the redox states and their behavior. Furthermore, transition state (TS) calculations at the M06L/6-31G*/LANL2DZ level of theory together with detailed kinetic studies outline a putative mechanism for the selective transformation of 1→2 involving the formation of an intermediate bearing peroxide linkage to complex 1.

Catalytic Reduction of Graphene Oxide Nanosheets by Glutathione Peroxidase Mimetics Reveals a New Structural Motif in Graphene Oxide

A catalytic reduction of graphene oxide (GO) by glutathione peroxidase (GPx) mimics is reported. This study reveals that GO contains peroxide functionalities, in addition to the epoxy, hydroxyl and carboxylic acid groups that have been identified earlier. It also is shown that GO acts as a peroxide substrate in the GPx-like catalytic activity of organoselenium/tellurium compounds. The reaction of tellurol, generated from the corresponding ditelluride, reduces GO through the glutathione (GSH)-mediated cleavage of the peroxide linkage. The mechanism of GO reduction by the tellurol in the presence of GSH involves the formation of a tellurenic acid and tellurenyl sulfide intermediates. Interestingly, the GPx mimics also catalyze the decarboxylation of the carboxylic acid functionality in GO at ambient conditions. Whereas the selenium/tellurium-mediated catalytic reduction/decarboxylation of GO may find applications in bioremediation processes, this study suggests that the modification of GO by biologically relevant compounds such as redox proteins must be taken into account when using GO for biomedical applications because such modifications can alter the fundamental properties of GO.

Ozonolysis of Bicyclic 1,2-Dioxines: Initial Scope and Mechanistic Insights

The ozonolysis of bicyclic 1,2-dioxines was investigated using a variety of 1,4-disubstituted 1,2-dioxines along with a 1,3-dialkyl and steroidal example, with yields ranging from moderate to excellent. Two different pathways were observed upon reaction of the 1,4-disubstituted 1,2-dioxines with ozone; one pathway saw the "expected" results, that is, cleavage of the olefinic moiety with generation of 1,4-dicarbonyl 1,2-dioxines, while the other pathway revealed a previously unobserved rearrangement involving cleavage of the peroxide linkage along with loss of either CO or CO(2). Several unsymmetrical ozonolyses were also performed to further investigate the origins of this rearrangement, and initial mechanistic insights into the fragmentation pathways are discussed.

Growth, photosynthetic efficiency and metabolic alterations associated with exogenous hydrogen peroxide in Artemisia annua: Overproduction of artemisinin

Artemisinin, a sesquiterpene lactone with a peroxide linkage, has been held responsible for antimalarial activity of the Artemisia annua L. Recently, it was reported that reactive oxygen species (ROS) play important role in the biosynthesis of artemisinin by catalyzing some important intermediate steps. The effect of exogenously supplied hydrogen peroxide (1.00 mM and 2.00 mM H2O2), in two ways, foliar and as soil drench, was worked out in terms of growth, alteration in photosynthesis, oxidative damage, antioxidant defense enzymes and artemisinin level in exposed plants. Application of H2O2 positively affect the growth of the treated plants; and increment in net photo synthetic rate, stomatal conductance, internal CO2 and chlorophyll content in the H2O2 exposed A. annua plants was noted. A significant upregulation in antioxidant enzymes viz. catalase (CAT), peroxidase (POX) and superoxide dismutase (SOD) was observed as a result of exogenous H2O2 treatment when applied foliarly or as soil drench. H2O2application either by 1.00 mM or 2.00 mM stimulated artemisinin levels, however, 2.00 mM H2O2 applied as soil drench elicited artemisinin production more rapidly compared to other treatments. Therefore, results suggest that exogenous H2O2 may stimulate growth by inducing antioxidant defense system and increase the artemisinin levels in Artemisia annua plants.

Antioxidation reaction mechanism studies of phenolic lignans, identification of antioxidation products of secoisolariciresinol from lipid oxidation

The chain-breaking antioxidation reaction mechanism of a phenolic lignan in a lipid oxidation system was investigated. The 2,2′-azobis(isobutyronitrile) (AIBN)-induced radical oxidation reaction in a large amount of ethyl linoleate in the presence of secoisolariciresinol, one of the potent antioxidative lignans widely distributed in edible plants, produced two types of peroxides as radical termination products, as well as a cyclic derivative. The isolation and structure determination of the peroxides revealed that they have a peroxide linkage with ethyl linoleate or isobutyronitrile at the 1-position of the benzene ring of secoisolariciresinol. The cyclic derivative was also identified as lariciresinol by spectroscopic analysis. Based on the chemical structures of these products, a reaction pathway for the antioxidation reaction of secoisolariciresinol in oxidising lipid media was proposed.

Carbenoid Insertion into the Peroxide Bond vs the Olefin Bond of Cyclic Peroxides

Herein we report examples of the insertion of a carbenoid into a peroxide linkage. This study reveals that intramolecular insertion of carbenes into the peroxide linkage of 3,6-dihydro-1,2-dioxines is preferred over olefin insertion. The initial scope of the reaction and mechanistic considerations, have been probed. This methodology also generates unusual bicyclic hemiacetals (2) and tricyclic peroxides (3).

Cyclisation of 1,2-dioxines containing tethered hydroxyl and carboxylic acid functionality: synthesis of tetrahydrofurans and dihydrofuran-2(3 H)-ones

Herein we outline cyclisations of tethered hydroxyl and carboxylic acid moieties onto the olefinic motif of 1,2-dioxines to generate tetrahydrofurans and dihydrofuran-2(3 H)-ones, whilst maintaining the peroxide linkage intact. This work demonstrates the first examples of intramolecular cyclisation of tethered hydroxyl groupings onto 1,2-dioxines generating functionalised THFs in a highly stereoselective manner and includes improved methods for previously reported carboxylic acid tether cyclisations. Additionally, improved methods for the oxidation of 1,2-dioxines containing tethered alcohols to furnish tethered carboxylic acids are also detailed. Subsequent reduction of the peroxide linkage enables the generation of functionalised tetrahydrofurans and dihydrofuran-2(3 H)-ones, which are useful building blocks for the construction of natural products.

Synthesis of bromo-conduritol-B and bromo-conduritol-C as glycosidase inhibitors

For the synthesis of bromo-conduritol-B skeleton, bromo-1,4-benzoquinone was subjected to bromination followed by the reduction of the carbonyl groups with NaBH 4. Substitution of bromides bonded to sp 3-hybridized carbon atoms with AgOAc gave the bromo-conduritol-B tetraacetate in high yield. For the construction of bromo-conduritol-C skeleton, 2,2-dimethyl-3a,7a-dihydro-1,3-benzodioxole was used as the starting material. Photooxygenation of the diene unit gave an unsaturated bicyclic endoperoxide. Bromine was incorporated into the molecule by the addition of bromine to the double bond. Opening of the peroxide linkage followed by HBr elimination and reduction of the carbonyl group provided the conduritol-C structure in good yield. Bromo-conduritol-B exhibited strong enzyme-specific inhibition against α-glycosidase.

Synthesis and Chemistry of 2,3-Dioxabicyclo[2.2.2]octane-5,6-diols

1,4-Disubstituted 2,3-dioxabicyclo[2.2.2]oct-5-enes were dihydroxylated with osmium tetroxide to yield diols anti to the peroxide linkage in a highly selective manner. Reduction of the peroxide bond furnished cyclohexane-1,2,3,4-tetraols with toxocarol relative stereochemistry in excellent yield. This new methodology was employed to synthesize the natural product (1S,2R,3S,4R,5R)-2-methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-tetrol (1) in a short sequence from (R)-alpha-phellandrene. Moreover, during the study of the chemistry of 2,3-dioxabicyclo[2.2.2]octane-5,6-diols a hitherto unknown rearrangement was discovered which has wide applicability for the synthesis of 1,4-dicarbonyls, including optically enriched synthons. A broad range of mechanistic investigations applicable to this rearrangement are also reported.

Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.

A theoretical and experimental study on the molecular and electronic structures of artemisinin and related drug molecules

The equilibrium structures of artemisinin and a selection of its derivatives (potent antimalarial drugs) have been studied with the density functional theory ansatz B3LYP. Of the five rings of the artemisinin framework, it is only the pyranose ring B that exhibits a marked conformational flexibility, especially on addition of a pendant side chain at C-10. For the derivatives, the β isomer with the axial substituent group is found to be energetically more stable than the α isomer with the equatorial group. The assignment of the vibrational fundamentals has been supported by calculations on related model molecules and a normal coordinate analysis. This allows for a reliable characterization of the normal modes, mainly involving the peroxide linkage, in the claimed fingerprint region of 1,2,4-trioxanes. The electronic structures have also been studied by measuring and calculating significant features of the NMR, photoelectron and electron transmission spectra. In particular, a representative set of NMR chemical shifts and nuclear spin–spin coupling constants, obtained with DFT formalisms, compares favourably with experiment and fits expectation in terms of stereoelectronic effects of the vicinal oxygen lone pairs. Based on ab initio outer valence Green’s function calculations, a consistent interpretation of the uppermost bands in the photoelectron spectra of artemisinin and derivatives has been advanced. The top ionization energies reflect a complex interaction of the various oxygen lone pair orbitals. Electron transmission spectroscopy is applied for the first time to compounds containing the peroxide bond and elucidates the empty level electronic structure of artemisinin and derivatives in the 0–6 eV energy range, with the support of MO calculations and comparison with the spectra of reference molecules. Electron attachment to the lowest-lying empty σ ∗ MO, mainly localized on the O–O bridge, occurs at an energy (1.7 eV) exceptionally low for compounds not containing third-row or heavier elements.

Effects of reactive low‐profile additives on the volume shrinkage and internal pigmentability for low‐temperature cure of unsaturated polyester

AbstractThe effects of reactive poly(vinyl acetate)‐block‐poly(methyl methacrylate) (PVAc‐b‐PMMA) and poly(vinyl acetate)‐block‐polystyrene (PVAc‐b‐PS) as low‐profile additives (LPA) on the volume shrinkage characteristics and internal pigmentability for low‐shrink unsaturated polyester resins (UP) during the cure at 30°C were investigated. These reactive LPAs, which contained peroxide linkages in their backbones, were synthesized by suspension polymerizations, using polymeric peroxides (PPO) as initiators. Depending on the LPA composition and molecular weight, the reactive LPA could lead to a reduction of cyclization reaction for UP resin during the cure, and would be favorable for the decrease of intrinsic polymerization shrinkage after the cure. The experimental results have been explained by an integrated approach of measurements for the static phase characteristics of the styrene (ST)/UP/LPA system, reaction kinetics, cured sample morphology, and microvoid formation by using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), optical microscopy (OM), and image analysis. Based on the Takayanagi mechanical model, factors leading to both a good volume shrinkage control and acceptable internal pigmentability for the molded parts have been explored. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 967–979, 2006

Effect of Substrate Temperature on the Plasma Polymerization of Poly(methyl methacrylate)

AbstractLow‐power, plasma‐enhanced (PE)CVD together with polymerization of methyl methacrylate (MMA) can be used to deposit thin films of poly(methyl methacrylate) (PMMA) with minimal loss of functional groups, as shown by Fourier transform infrared (FTIR) spectroscopy, X‐ray photoelectron spectroscopy (XPS), and Raman spectrometry (RS). Retention of functional groups decreases with increased substrate temperature, corresponding to decreased deposition rates. From XPS data, the calculated percentage loss of functional groups ranges from 0.9 % to 43.4 %, changing as a function of deposition conditions. RS confirms the presence of C=C bonds in the polymer backbone as a result of scission of the ester group from MMA. The thermal properties of PECVD‐produced films from MMA can be tailored by varying the substrate temperature. Onset of thermal decomposition increases with increased substrate temperature by eliminating thermally labile peroxide linkages in the polymer backbone, and by crosslinking that occurs at radical sites generated via scission of functional group bonds. The post‐anneal thicknesses of the remaining polymer is of the order of 4 nm or less, indicating that low‐power PECVD of PMMA is a viable candidate to act as a sacrificial material for air‐gap fabrication.

Effects of reactive low‐profile additives on the properties of cured unsaturated polyester resins. I. Volume shrinkage and internal pigmentability

AbstractThe effects of reactive poly(methyl methacrylate) (PMMA) and poly(vinyl acetate)‐block‐PMMA as low‐profile additives (LPAs) on the volume shrinkage characteristics and internal pigmentability for low‐shrink unsaturated polyester (UP) resins during curing at 110°C were investigated. These reactive LPAs, which contained peroxide linkages in their backbones, were synthesized by suspension polymerization with polymeric peroxides as initiators. Depending on the LPA composition and molecular weight, the reactive LPAs led to a considerable volume reduction or even to a volume expansion after the curing of styrene (ST)/UP/LPA ternary systems; this was attributed mainly to the expansion effects of the LPAs on the ST‐crosslinked polyester microgel structures caused by the reduction in the cyclization reaction of the UP resin during curing as well as to the repulsive forces between the chain segments of UP and LPAs within the microgel structures. The experimental results were explained by an integrated approach of measurements for the static phase characteristics of the ST/UP/LPA system, reaction kinetics, cured sample morphology, and microvoid formation with differential scanning calorimetry, scanning electron microscopy, optical microscopy, and image analysis. With the aid of the Takayanagi mechanical model, the factors leading to both a good volume shrinkage control and acceptable internal pigmentability for the molded parts were also explored. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 264–275, 2005

Predicting chemical kinetics with computational chemistry: is QOOH→HOQO important in fuel ignition?

An overview of predictive chemical kinetics is presented, with an application to the simulation and design of homogeneous charge compression ignition (HCCI) engines. The engine simulations are sensitive to the details of hydroperoxyalkyl (QOOH) radical chemistry, which are only partially understood, and there is a significant discrepancy between the simulations and experiment that limits the usefulness of the simulations. One possible explanation is that QOOH decomposes by other channels not considered in existing combustion chemistry models. Rate constants for one of these neglected channels, the intramolecular radical attack on the QOOH peroxide linkage to form hydroxyalkoxyl (HOQO) radicals, are predicted using quantum chemistry (CBS-QB3), to test whether or not this proposed channel can explain the observed discrepancies in the engine simulations. Although this channel has a significant rate, the competing attack on the other O atom in the peroxide to form a cyclic ether+OH is computed to be an order of magnitude faster, so the HOQO channel does not appear to be fast enough to explain the discrepancy. Definitive judgement on the importance of this reaction channel will require a careful reconsideration of all the coupled chemically activated QOOH reaction channels using modern predictive chemical kinetics software.

Laser‐Induced Formation of Metal–Peroxide Linkages on the Surface of Lanthanum Sesquioxide under Oxygen

Laser‐Induced Formation of Metal–Peroxide Linkages on the Surface of Lanthanum Sesquioxide under Oxygen