Peroxyesters as precursors to peroxyl radical clocks

The reactions of peroxyl radicals are at the center of the oxidative degradation of essentially all petroleum-derived hydrocarbons and biological lipids and consequently, the inhibition of these processes by radical-trapping antioxidants. Recently described peroxyl radical clocks offer a simple, convenient, and inexpensive method of determining rate constants for H-atom transfer reactions to peroxyl radicals, greatly enabling the kinetic and mechanistic characterization of compounds with antioxidant properties. We follow up our preliminary communication on the development of a methodology utilizing tert-butyl styrylperacetate as a precursor to a versatile peroxyl radical clock with the present paper, wherein we describe a novel naphthyl analogue, which provides for much improved product resolution for analysis, and provide the complete details associated with its development and application. Using this new precursor, and with consideration of the expanded set of reaction products, inhibition rate constants were measured for a variety of representative phenolic and diarylamine radical-trapping antioxidants. We also provide details for the use of this methodology for the determination of mechanistic information, such as kinetic solvent effects, Arrhenius parameters, and kinetic isotope effects.     

Peroxyl radical acceptors released by polymer materials into the gas phase

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 973–974, April, 1991.     

Molecular orbital calculations of ring opening of the isoelectronic cyclopropylcarbinyl radical, cyclopropoxy radical, and cyclopropylaminium radical cation series of radical clocks

Detailed molecular orbital calculations were directed to the cyclopropylcarbinyl radical (1), the cyclopropoxy radical (2), and the cyclopropylaminium radical cation (3) as well as their ring-opened products. Since a considerable amount of data are published about cyclopropylcarbinyl radicals, calculations were made for this species and related ring-opened products as a reference for 2 and 3 and their reactions. Radicals 1-3 have practical utility as "radical clocks" that can be used to time other radical reactions. Radical 3 is of further interest in photoelectron-transfer processes where the back-electron-transfer process may be suppressed by rapid ring opening. Calculations have been carried out at the UHF/6-31G*, MP4//MP2/6-31G*, DFT B3LYP/6-31G*, and CCSD(T)/cc-pVTZ//QCISD/cc-pVDZ levels. Energies are corrected to 298 K, and the barriers between species are reported in terms of Arrhenius E(a) and log A values along with differences in enthalpies, free energies, and entropies. The CCSD(T)-calculated energy barrier for ring opening of 1 is E(a) = 9.70, DeltaG* = 8.49 kcal/mol, which compares favorably to the previously calculated value of E(a) = 9.53 kcal/mol by the G2 method, but is higher than an experimental value of 7.05 kcal/mol. Our CCSD(T)-calculated E(a) value is also higher by 1.8 kcal/mol than a previously reported CBS-RAD//B3LYP/6-31G* calculation. The cyclopropoxy radical has a very small barrier to ring opening (CCSD(T), E(a) = 0.64 kcal/mol) and should be a very sensitive time clock. Of the three series studied, the cyclopropylaminium radical cation is most complex. In agreement with experimental data, bisected cyclopropylaminium radical cation is not found, but instead a ring-opened species is found. A perpendicular cyclopropylaminium radical cation (4) was found as a transition-state structure. Rotation of the 2p orbital in 4 to the bisected array results in ring opening. The minimum onset energy of photoionization of cyclopropylamine was calculated to be 201.5 kcal/mol (CCSD(T)) compared to experimental values of between about 201 and 204 kcal/mol. Calculations were made on the closely related cyclopropylcarbinyl and bicyclobutonium cations. Stabilization of the bisected cyclopropylcarbinyl conformer relative to the perpendicular species is much greater for the cations (29.1 kcal/ mol, QCISD) compared to the radicals (3.10 kcal/mol, QCISD). A search was made for analogues to the bicyclobutonium cation in the radical series 1 and 2 and the radical cation series 3. No comparable species were found. A rationale was made for some conflicting calculations involving the cyclopropylcarbinyl and bicyclobutonium cations. The order of stability of the cyclopropyl-X radicals was calculated to be X = CH2 > X = O > X = NH2+, where the latter species has no barrier for ring opening. The relative rate of ring opening for cyclopropyl-X radicals X = CH2 to X = O was calculated to be 3.1 x 10(6) s(-1) at 298 K (QCISD).     

Opto-chemical micro-capillary clocks

Opto-chemical capillary clocks are presented that are based on the measurement of a colored segment in a microchannel (a capillary). Color is created by a chromogenic chemistry involving the oxidation of a (virtually colorless) leuco-dye. Poly(ethylene glycol) (PEG) is used as a solvent, and indigo and thioindigo (in their reduced leuco forms) act as oxygen-sensitive dyes. The clock is started by removing one seal at the end of the capillary. A visible color change occurs as air diffuses into the microchannel due to an irreversible color reaction. The length of the colored segment is proportional to the time elapsed. PEGs of different average molar mass affect the diffusion rate of oxygen in the microchannel and thereby affect the rate of the migration of the color front. Both temperature and relative humidity exert a strong effect. Six types of such clocks are described that enable times to be determined in the range from 1 day to 6 months, possibly of even decades.

Revisiting the mechanism of P450 enzymes with the radical clocks norcarane and spiro[2,5]octane

Norcarane (1) and spiro[2.5]octane (2) yield different product distributions depending on whether they are oxidized via concerted, radical, or cationic mechanisms. For this reason, these two probes were used to investigate the mechanisms of hydrocarbon hydroxylation by two mammalian and two bacterial cytochrome P450 enzymes. Products indicative of a radical intermediate with a lifetime ranging from 16 to 52 ps were detected during the oxidation of norcarane by P450(cam) (CYP101), P450(BM3) (CYP102), CYP2B1, and CYP2E1. Trace amounts of the cation rearrangement product were observed with norcarane for all but CYP2E1, while no cation or radical rearrangement products were observed for spiro[2.5]octane. The results for the oxidation of norcarane with a radical rearrangement rate of 2 x 10(8) s(-1) are consistent with the involvement of a two-state radical rebound mechanism, while for the slower (5 x 10(7) s(-1)) spiro[2,5]oct-4-yl radical rearrangement products were beyond detection. Taken together with earlier data for the hydroxylation of bicyclo[2.1.0]pentane, which also suggested a 50 ps radical lifetime, these three structurally similar and functionally simple substrates show a consistent pattern of rearrangement that supports a radical rebound mechanism for this set of cytochrome P450 enzymes.     

Nature of the Transition State in Peroxyl Radical Recombination

We have carried out an ab initio calculation of the potential surface for the reaction CH₃O₄H CH₂=O + O₂ + H₂O. We have established the structure of the transition state and studied the dependence of the energy barrier on the size of the basis and whether electron correlation is taken into account. We have studied the electronically excited terms for the participants in this reaction and we have established the mechanism for the formation of chemiluminescence emitters in this reaction.     

Fluctuation theorem and mesoscopic chemical clocks

The fluctuation theorems for dissipation and the currents are applied to the stochastic version of the reversible Brusselator model of nonequilibrium oscillating reactions. It is verified that the symmetry of these theorems holds far from equilibrium in the regimes of noisy oscillations. Moreover, the fluctuation theorem for the currents is also verified for a truncated Brusselator model.     

Thiophenols,Promising Scavengers of Peroxyl Radicals: Mechanisms and kinetics

The activity of 12 thiophenols as primary antioxidants in aqueous solution has been studied using density functional theory. Twelve different substituted thiophenols were tested as peroxyl radicals scavengers. Single electron transfer (SET) and formal hydrogen transfer (FHT) were investigated. The SET mechanism was found to be the main mechanism, with rate constants that are close to the diffusion limit, which means that these thiophenolic compounds have the capacity to scavenge peroxyl radicals before they can damage biomolecules. All 12 thiophenolic compounds react faster with methylperoxyl than with hydroperoxyl radicals. In addition, it was found that pH plays an important role in the reactivity of these compounds. © 2019 Wiley Periodicals, Inc.     

Biological clocks: mechanisms and developments.

Almost all organisms ranging from unicellular protists to mammals were found to show biological rhythms. Many workers have performed various kinds of experiment to understand the mechanism as well as to find the origin of the clock responsible for these rhythms. However, there is no doubt about the existence of a biologically controlled clock in almost all organisms; yet its origin and mechanism still remain a mystery. Many theories have been put forward to explain the mechanism of these biological clocks and it seems that the cell membrane may play a key role. The existence of a very high electric field of the order of 10(5) V cm-1 across the cell membrane may have some role in the mechanism of the biological clock. Of all the factors which have the effects on biological rhythms, light and temperature are found to be the most common. Also, the study of these biological clocks can help to solve the sleeping problems of international travellers and shift workers as well as to improve diagnosis, cure and prevention from diseases.     

Rate Constants of the Interaction of 2-Thio-6-Aminouracil with Peroxyl Radicals

Kinetics and Catalysis - It was shown that 2-thio-6-aminouracil (TAU) is an inhibitor of the radical-chain oxidation of ethylbenzene and methyl oleate. The reactivity of structurally different...     

基于羟自由基体系的流动注射-化学发光检测水中的焦性没食子酸

建立了在酸性条件下基于羟自由基(.OH)反应的流动注射-化学发光检测水中焦性没食子酸的新方法。羟自由基由Fe3 和过氧化氢在线混合产生。它能氧化罗丹明6G产生微弱的光,而焦性没食子酸能显著的增强这一反应。方法的检出限为2.7×10-7g/L;线性范围为8.0×10-7~1.0×10-4g/L;线性方程为ΔI=25.436C 21.822(C:μg/L,r=0.9996)。对2.0×10-6g/L的焦性没食子酸平行测定11次,其相对标准偏差为4.80%。该方法成功的应用于环境水中焦性没食子酸的检测,其回收率在91.1%~108.8%。并探讨了该反应可能的机理。     

Transition State Geometry and Polar Effect in the Addition of Peroxyl Radicals to Olefins

Transition-state interatomic distances in the addition of peroxyl radicals to the double bond of olefins are estimated from experimental data (activation energies and rate constants) using a new algorithm combining quantum chemical and parabolic model calculations. An aromatic ring in the α-position with respect to the double bond elongates the ? distance by 0.02 × 10^?10 m. Polar groups adjacent to the double bond affect this distance considerably. The geometric parameters of the transition states in the abstraction and addition of peroxyl radicals are compared.     

The Elucidation of Peroxyl Radical Reactions in Aqueous Solution with the Help of Radiation-Chemical Methods

Whenever free radicals are formed, independent of whether this occurs thermally, is induced by UV or ionizing irradiation, or takes place in redox reactions, they are converted rapidly into the corresponding peroxyl radicals in the presence of oxygen. Peroxyl radical reactions in aqueous environments are observed not only in aquatic systems (e.g., rivers, lakes and oceans) but also in the living cell and to a considerable degree even in the atmosphere (in water droplets). The peroxyl radical chemistry occurring in this medium is often very different from that observed in the gas phase or in organic solvents. In spite of the great importance of these reactions in medicine (for example in anti-cancer irradiation therapy and ischaemia) there have been comparatively few studies of peroxyl reactions in aqueous media. Radiation-chemical techniques such as pulse radiolysis offer the best means for carrying out such studies, so that it is not surprising that the majority of the information available in this area has been obtained with the help of radiation-chemical methods. The radiation chemistry of water can be con trolled in such a manner that the main products are ^˙OH radicals (90 % yield), which react with substrate molecules to give substrate radicals and in the presence of oxygen to give substrate peroxyl radicals. The experimental conditions can also be varied in such a way that HO/O radicals can be formed in 100 % yield and caused to react with substrates. We therefore have a simple access to these intermediates, which are extremely important in biological systems. A detailed product analysis, supported by kinetic studies carried out with the help of pulse radiolysis, has been used to clarify the chemistry of a series of peroxyl radicals, so that sufficient material is now available to justify a review of the variety of the peroxyl radical reactions studied by means of radiation-chemical methods. A more general survey of the physical properties of the peroxyl radicals and their unimolecular and bimolecular reactions will be followed by a discussion of selected examples of various classes of substance. Because of the great biological importance of radical-induced DNA damage this area will also be treated briefly.     

Roles of circadian clocks in cancer pathogenesis and treatment

Circadian clocks are ubiquitous timing mechanisms that generate approximately 24-h rhythms in cellular and bodily functions across nearly all living species. These internal clock systems enable living organisms to anticipate and respond to daily changes in their environment in a timely manner, optimizing temporal physiology and behaviors. Dysregulation of circadian rhythms by genetic and environmental risk factors increases susceptibility to multiple diseases, particularly cancers. A growing number of studies have revealed dynamic crosstalk between circadian clocks and cancer pathways, providing mechanistic insights into the therapeutic utility of circadian rhythms in cancer treatment. This review will discuss the roles of circadian rhythms in cancer pathogenesis, highlighting the recent advances in chronotherapeutic approaches for improved cancer treatment.Subject terms: Circadian rhythms, Targeted therapies     

用数据处理新模型测定H2O2分解的活化能

对H2O2催化分解传统实验的数据处理方法和实验手段中存在的问题进行了分析,并通过优化配置,结合一级反应数据处理新模型不用测定V∝的理论和皂膜流量计短时间量气稳定性好的优点,共同完成了H2O2催化分解的动力学测定实验,不仅解决了实验过程的稳定性问题,而且打破了传统实验中只能测定一个温度下的速率常数的局限,同时在准确测定多个温度下的速率常数基础上求出了该反应的活化能,从而丰富了实验内容,提升了实验水平,从根本上改善了传统实验中存在的诸多问题。     

黄酮类化合物与α-羟乙基过氧自由基反应的脉冲辐解研究

由于脂质过氧化反应(LPO)是导致人体疾病(如肝炎、肝硬化、动脉硬化、脑溢血等)的主要原因, 而黄酮类化合物是一类很强的过氧化反应抑制剂, 因此有必要研究其化学结构与过氧化反应的关系及其抗氧化机理.本文选择α-羟乙基过氧自由基为脂质过氧自由基的模拟物, 采用脉冲辐解方法研究了乙醇溶液中4种典型的黄酮类化合物(槲皮素、芦丁、儿茶素以及黄岑甙)与α-羟乙基过氧自由基的反应动力学, 测得其反应活性顺序为:芦丁>槲皮素>黄岑甙>儿茶素. 同时以黄酮体和邻苯二酚为黄酮类化合物不同结构特征的模型化合物, 用脉冲辐解法测得二者与α-羟乙基过氧自由基的反应速率常数分别为(1.7±0.1)×10⁶和(2.9±0.1)×10⁵ mol^-1·dm³·s^-1.实验结果表明, 在黄酮类化合物与α-羟乙基过氧自由基的反应中, A环C₅位的羟基, C环C₂＝C₃或B-C环的大π键和B环邻二羟基共存时清除α-羟乙基过氧自由基活性最好, 而且C环C₂＝C₃或B-C环大π键的清除活性好于B环邻二羟基, 同时C环是否含有C₃-醣甙结构对清除作用没有明显影响. 因此我们推测在黄酮类化合物抑制脂质过氧化反应过程中, 起主要作用的是C环C₂＝C₃或B-C环的大π键与脂质过氧自由基的双键加成反应.     

Enhancing Antioxidant Effect against Peroxyl Radical‐Induced Oxidation of DNA: Linking with Ferrocene Moiety!

As a major member in the family of reactive oxygen species, peroxyl radical is able to abstract hydrogen atom from 4‐position of ribose, leading to the collapse of DNA strand. Thus, inhibiting oxidative stress with exogenous antioxidants acts as a promising strategy to protect the integrity of DNA structure and is thereby suggested to be a pathway against developments of related diseases. Ferrocene as an organometallic scaffold is widely applied in the design of organometallic drugs, and redox of Fe(II)/Fe(III) in ferrocene offers advantage for providing electron to radicals. Presented herein are our ongoing studies on ferrocene‐appended antioxidants, including McMurry reaction applied to construct ferrocifen; Aldol condensation used to prepare ferrocenyl curcumin; Povarov reaction employed to prepare ferrocenyl quinoline; Biginelli reaction used to construct ferrocenyl dihydropyrimidine; Groebke reaction used to synthesize ferrocenyl imidazo[1,2‐a]pyridine; and Passerini three‐component reaction as well as Ugi four‐component reaction applied to synthesize α‐acyloxycarboxamide and bisamide, respectively. It is found that ferrocene moiety is able to enhance antioxidative effect of the aforementioned scaffolds even without the aid of phenolic hydroxyl group. The role of ferrocene in enhancing antioxidative effect can be attributable to trapping radicals, decreasing oxidative potential, and increasing the affinity toward DNA strand. Therefore, ferrocene is worthy to be taken into consideration in the design of drugs in relation to DNA oxidation.     

Multi‐faceted Reactivity of Alkyltellurophenols Towards Peroxyl Radicals: Catalytic Antioxidant Versus Thiol‐Depletion Effect

Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO^. radicals with rate constants as high as 10⁷ M ^?1 s^?1 at 303 K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO^. radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro‐oxidative (thiol depletion) when thiol concentrations are low.