Tert-butoxyl Radicals Research Articles

The dose-response relationships of the direct scavenging activity of amide-based local anesthetics against multiple free radicals.

This study aimed to illustrate the dose-response relationships of the direct scavenging activity of amide-based local anesthetics against multiple free radicals in vitro. We have demonstrated that amide-type local anesthetics selectively and directly scavenge some free radicals. Three kinds of free radicals were eliminated by all the four local anesthetics examined. Mepivacaine, lidocaine, bupivacaine, and dibucaine scavenged hydroxyl radicals in dose-dependent manners. Ascorbyl free radicals were also scavenged in dose-dependent manners, and lastly singlet oxygen was scavenged in dose-dependent manners. Three other free radicals were not scavenged by all of the four local anesthetics; tert-butoxyl radical was scavenged by all the anesthetics examined but dibucaine, nitric oxide by mepivacaine but not by the other three, and tyrosyl radical by mepivacaine and lidocaine but not by the other two. Some free radicals (superoxide anion, tert-butyl peroxyl radical, DPPH) were not scavenged by any of the four local anesthetics. The local anesthetics were also shown to inhibit lipid peroxidation by TBARS assay. These results suggest that local anesthetics have antioxidant properties through their free radical scavenging activities.

Rapid and Accurate Estimation of Activation Free Energy in Hydrogen Atom Transfer-Based C-H Activation Reactions: From Empirical Model to Artificial Neural Networks.

A well-performing machine learning (ML) model is obtained by using proper descriptors and artificial neural network (ANN) algorithms, which can quickly and accurately predict activation free energy in hydrogen atom transfer (HAT)-based sp3 C–H activation. Density functional theory calculations (UωB97X-D) are used to establish the reaction system data sets of methoxyl (CH3O·), trifluoroethoxyl (CF3CH2O·), tert-butoxyl (tBuO·), and cumyloxyl (CumO·) radicals. The simplified Roberts’ equation proposed in our recent study works here [R2 = 0.84, mean absolute error (MAE) = 0.85 kcal/mol]. Its performance is comparable with univariate Mulliken-type electronegativity (χ) with the ANN model. The ANN model with bond dissociation free energy, χ, α-unsaturation, and Nolan buried volume (%Vburied) successively improves R2 and MAE to 0.93 and 0.54 kcal/mol, respectively. It reproduces the test sets of trichloroethoxyl (CCl3CH2O·) with R2 = 0.87 and MAE = 0.89 kcal/mol and accurately predicts the relative experimental barrier of the HAT reactions with CumO· and the site selectivity of CH3O·.

Visible-Light-Promoted Fe(III)-Catalyzed N-H Alkylation of Amides and N-Heterocycles.

The combination of the radical chemistry of ligand-to-metal charge transfer with metal catalysis by a single iron salt helps to realize the visible-light-promoted N-H alkylation of amides and N-heterocycles. A wide variety of amides and nitrogen-containing heterocycles were tolerated in our protocol to give N-alkylated products. The applicability of this protocol was further demonstrated by late-stage alkylation of N-H-containing pharmaceuticals. Moreover, N-H-alkylated α-amino tetrahydrofurans could be transformed into versatile ring-opened amino alcohols under reducing conditions. A mechanistic study revealed that hydrogen atom transfer by a tert-butoxyl radical and a chlorine radical was responsible for the activation of C(sp3)-H precursors.

Dose-dependent scavenging activity of the ultra-short-acting β1-blocker landiolol against specific free radicals.

Landiolol, a highly cardioselective ultra-short-acting β1-blocker, prevents perioperative atrial fibrillation associated with systemic inflammation and oxidative stress. We evaluated the direct scavenging activity of landiolol against multiple free radical species. Nine free radical species (hydroxyl, superoxide anion, ascorbyl, tert-butyl peroxyl, tert-butoxyl, singlet oxygen, 2,2-diphenyl-1-picrylhydrazyl, nitric oxide, and tyrosyl radicals) were directly quantified using an X-band ESR spectrometer with the spin-trapping method. IC50 and reaction rate constants were estimated from the dose-response curve for each free radical. Landiolol scavenged six of the free radical species examined: hydroxyl radical (IC50 = 0.76 mM, k landiolol = 1.4 × 10‍10 M‍-1 s‍-1, p<0.001), superoxide anion (58 mM, 2.1 M‍-1 s‍-1, p = 0.044), tert-butoxyl radical (4.3 mM, k landiolol/k CYPMPO = 0.77, p<0.001), ascorbyl free radical (0.31 mM, p<0.001), singlet oxygen (0.69 mM, k landiolol/k 4-OH ‍TEMP = 2.9, p<0.001), and nitric oxide (15 mM, 1.7 × 10 M‍-1 s‍-1, p<0.001). This study is the first to report that landiolol dose-dependently scavenges multiple free radical species with different reaction rate constants. These results indicate the potential clinical application of landiolol as an antioxidative and anti-inflammatory agent in addition to its present clinical use as an anti-arrhythmic agent.

New Cu(II), Co(II) and Ni(II) azo-Schiff base complexes: Synthesis, characterization, catalytic oxidation of alkenes and DFT study

Three new complexes with general formula of ML (M = Cu (1), Co (2), Ni (3)) containing an azo-Schiff base ligand (H2L) derived from 2,3-butanediamine and 4-(benzeneazo) salicylaldehyde were synthesized by template method. Characterization of the ligand and complexes were accomplished with FT-IR, UV–Vis, and 1H NMR. The catalytic activity of the complexes (1–3) were tested for the oxidation of various alkenes (cyclooctene, cyclohexene, styrene, α-methyl styrene, and norbornene) applying tert-butyl hydroperoxide (TBHP) as an oxidizing agent, and it was found that they were acceptable catalysts. Under the optimized reaction conditions, CuL complex displayed 94% conversion for the oxidation of cyclooctene, and CoL and NiL complexes exhibited 90 and 85% conversions for oxidizing α-methyl styrene, respectively. Based on our density functional computations, diffuse functions are compulsory in the basis set for geometry optimization of these systems. Therefore, the most stable structures and the vibrational frequencies were calculated at the M06-2X/6–311++G(d,p) level. By establishing the correlation between observed and calculated frequencies, the assignment of the vibrational modes was performed. Based on natural charge analysis (NAO), the back electron transfer from ML to the TBHP breaks the OO bond and facilitates the formation of tert-butoxyl radicals.

Revealing the Iron-Catalyzed β-Methyl Scission of tert-Butoxyl Radicals via the Mechanistic Studies of Carboazidation of Alkenes.

We describe here a mechanistic study of the iron-catalyzed carboazidation of alkenes involving an intriguing metal-assisted β-methyl scission process. Although t-BuO radical has frequently been observed in experiments, the β-methyl scission from a t-BuO radical into a methyl radical and acetone is still broadly believed to be thermodynamically spontaneous and difficult to control. An iron-catalyzed β-methyl scission of t-BuO is investigated in this work. Compared to a free t-BuO radical, the coordination at the iron atom reduces the activation energy for the scission from 9.3 to 3.9 ~ 5.2 kcal/mol. The low activation energy makes the iron-catalyzed β-methyl scission of t-BuO radicals almost an incomparably facile process and explains the selective formation of methyl radicals at low temperature in the presence of some iron catalysts. In addition, a radical relay process and an outer-sphere radical azidation process in the iron-catalyzed carboazidation of alkenes are suggested by density functional theory (DFT) calculations.

Electron Transfer Reactions: KO tBu (but not NaO tBu) Photoreduces Benzophenone under Activation by Visible Light.

Long-standing controversial reports of electron transfer from KO tBu to benzophenone have been investigated and resolved. The mismatch in the oxidation potential of KO tBu (+0.10 V vs SCE in DMF) and the first reduction potential of benzophenone (of many values cited in the literature, the least negative value is -1.31 V vs SCE in DMF), preclude direct electron transfer. Experimental and computational results now establish that a complex is formed between the two reagents, with the potassium ion providing the linkage, which markedly shifts the absorption spectrum to provide a tail in the visible light region. Photoactivation at room temperature by irradiation at defined wavelength (365 or 400 nm), or even by winter daylight, leads to the development of the blue color of the potassium salt of benzophenone ketyl, whereas no reaction is observed when the reaction mixture is maintained in darkness. So, no electron transfer occurs in the ground state. However, when photoexcited, electron transfer occurs within a complex formed from benzophenone and KO tBu. TDDFT studies match experimental findings and also define the electronic transition within the complex as n → π*, originating on the butoxide oxygen. Computation and experiment also align in showing that this reaction is selective for KO tBu; no such effect occurs with NaO tBu, providing the first case where such alkali metal ion selectivity is rationalized in detail. Chemical evidence is provided for the photoactivated electron transfer from KO tBu to benzophenone: tert-butoxyl radicals are formed and undergo fragmentation to form (acetone and) methyl radicals, some of which are trapped by benzophenone. Likewise, when KOC(Et)3 is used in place of KO tBu, then ethylation of benzophenone is seen. Further evidence of electron transfer was seen when the reaction was conducted in benzene, in the presence of p-iodotoluene; this triggered BHAS coupling to form 4-methylbiphenyl in 74% yield.

Iminoxyl radicals vs. tert-butylperoxyl radical in competitive oxidative C-O coupling with β-dicarbonyl compounds. Oxime ether formation prevails over Kharasch peroxidation.

Oxidative coupling of oxime and β-dicarbonyl compounds dominates in a β-dicarbonyl compound/oxime/Cu(ii)/t-BuOOH system; in the absence of oxime, oxidative coupling of t-BuOOH and a β-dicarbonyl compound (Kharasch peroxidation) takes place. The proposed conditions for oxidative coupling of oximes with dicarbonyl compounds require only catalytic amounts of copper salt and t-BuOOH serves as a terminal oxidant. The C–O coupling reaction proceeds via the formation of tert-butoxyl, tert-butylperoxyl and iminoxyl radicals. Apparently, tert-butylperoxyl radicals oxidize oxime into iminoxyl radical faster than they react with β-dicarbonyl compounds forming the Kharasch peroxidation product. Iminoxyl radicals are responsible for the formation of the target C–O coupling products; the yields are up to 77%.

Facile synthesis of Co(II) and Cu(II) complexes of 2-hydroxybenzophenone: An efficient catalyst for oxidation of olefins and DFT study

Two diketone complexes of Cu(II) and Co(II) were easily synthesized in reaction of M(CH3COO)2 with 2-Hydroxybenzophenone (bpoH). The complexes of M(bpo)2 were characterized by UV–vis, IR spectroscopy, and elemental analysis. The complexes are active catalysts for the oxidation of styrene using TBHP as an oxidant. Under the optimized reaction conditions, 100% conversion of styrene with 63.5% selectivity for Benzaldehyde and 36.5% for Styrene oxide were obtained by Cu(bpo)2. Also, the effect of imidazole was investigated. Results confirmed that the addition of imidazole accelerates the oxidation of styrene. Our DFT results confirmed the necessity of diffuse functions in the basis set and including an accurate treatment of the dispersion energy for obtaining the most stable structure in these systems. Therefore, the geometry optimization and the vibrational frequencies were calculated at the M06−2X/6−311++G(d,p) level. The scaled theoretical frequencies and the structural parameters are in excellent agreement with the experimental data. The natural charge analysis indicated that an electron is transferred from Cu(bpo)2 back to the TBHP to break the OO bond and formation of tert-butoxyl radicals. Coordination of imidazole in the axial position of the Cu(bpo)2 significantly assists in moving back of electron and increases the activity of the complex in oxidation.

Competitive Hydrogen Atom Transfer to Oxyl- and Peroxyl Radicals in the Cu-Catalyzed Oxidative Coupling of N-Aryl Tetrahydroisoquinolines Using tert-Butyl Hydroperoxide

The question of whether hydrogen atom transfer (HAT) or electron transfer (ET) is the key step in the activation of N-aryl tetrahydroisoquinolines in oxidative coupling reactions using CuBr as catalyst and tert-butyl hydroperoxide (tBuOOH) has been investigated. Strong indications for a HAT mechanism were derived by using different para-substituted N-aryl tetrahydroisoquinolines, showing that electronic effects play a minor role in the reaction. Hammett plots of the Cu-catalyzed reaction, a direct time-resolved kinetic study with in situ generated cumyloxyl radicals, as well as density functional calculations gave essentially the same results. We conclude from these results and from kinetic isotope effect experiments that HAT is mostly mediated by tert-butoxyl radicals and only to a lesser extent by tert-butylperoxyl radicals, in contrast to common assumptions. However, reaction conditions affect the competition between these two pathways, which can significantly change the magnitude of kinetic isotope ef...

Novel antioxidant capacity assay for lipophilic compounds using electron paramagnetic resonance spectroscopy.

A novel antioxidant capacity assay for lipophilic compounds was developed using electron paramagnetic resonance (EPR) spectroscopy. The assay is based on antioxidant’s scavenging ability against the tert-butoxyl radical generated photolytically from di-tert-butyl peroxide in ethyl acetate, and named the tert-butoxyl-based antioxidant capacity (BAC) assay. The radical was trapped by spin trap, 5,5-dimethyl-1-pyrroline-N-oxide, and EPR signal intensity of the spin adduct was used as a quantitative marker of radical levels. Signal intensity decreased in a dose-dependent manner in the presence of an antioxidant that competitively reacts with the radical, which was utilized to evaluate BAC values.The BAC method enabled the accurate estimation of antioxidant capacity for lipophilic materials that may counteract lipid peroxidation in biological membranes. The BAC values for quercetin and caffeic acid are 0.639 ± 0.020 and 0.118 ± 0.012 trolox equivalents, respectively, which are much smaller than values obtained by other aqueous methods such as H-ORAC and ORAC-EPR. Thus, antioxidants present in a non-aqueous environment should be evaluated using a non-aqueous system. In combination with in situ ascorbate reduction, the BAC method was capable of accurately determining the antioxidant capacity of water-insoluble materials that may be reduced in living cells.

Mechanism of protection of adenosine from tert-butoxyl radicals and repair of adenosine radicals by α-tocopherol in aqueous solution

The rates of oxidation of adenosine and α-tocopherol by tert-butoxyl radicals (t-BuO•) were studied spectrophotometrically. Radicals (t-BuO•) were generated by the photolysis of tert-butyl hydroperoxide (t-BuOOH) in presence of tert-butyl alcohol to scavenge •OH radicals. The rates and the quantum yields () of oxidation of α-tocopherol by t-BuO• radicals were determined in the absence and presence of varying concentrations of adenosine. An increase in the concentration of adenosine was found to decrease the rate of oxidation of α-tocopherol, suggesting that adenosine and α-tocopherol competed for t-BuO• radicals. From competition kinetics, the rate constant of α-tocopherol reaction with t-BuO• was calculated to be 7.29 x 108 dm3 mol-1 s-1. The quantum yields expt and cal values suggested that α-tocopherol not only protected adenosine from t-BuO• radicals, but also repaired adenosine radicals, formed by the reaction of adenosine with t-BuO• radicals.

Chiral N-hydroxybenzamides as potential catalysts for aerobic asymmetric oxidations.

Chiral N-hydroxybenzamides (1H-3H) have been synthesized as precursors of chiral short-lived N-oxyl radicals 1(•)-3(•). The latter species have been generated by oxidation of 1H-3H with Pb(OAc)4 or hydrogen abstraction from 1H-3H by the tert-butoxyl radical and characterized by UV-vis spectrophotometry and EPR spectroscopy. Through a kinetic study of the hydrogen atom transfer processes promoted by 1(•)-3(•) from three chiral benzylic substrates (1-phenylethylamine, 1-phenylethanol, and α-vinylbenzyl alcohol), a moderate chiral discrimination has been found, with selectivity factors 0.5 ≤ k(H)(S)/k(H)(R) ≤ 2.

Detection of radicals in single droplets of oil-in-water emulsions with the lipophilic fluorescent probe BODIPY665/676 and confocal laser scanning microscopy

Lipid oxidation is a widespread phenomenon in foods and other systems of biological origin. Detection methods for early stages of lipid oxidation are in demand to understand the progress of oxidation in space and time. The fluorescence spectrum of the nonpolar fluorescent probe BODIPY665/676 changes upon reacting with peroxyl radicals originating from 2,2′-azobis(2,4-dimethyl)valeronitrile and tert-butoxyl radicals generated from di-tert-butylperoxide. The excitation wavelength of the main peak of BODIPY665/676 was 675nm in the fluorometer, and 670nm under the microscope, and the optimum excitation wavelength for the secondary peak of BODIPY665/676 was 580nm. Advantages of using BODIPY665/676 are fewer problems with autofluorescence and the possibility of combining several fluorescent probes that are excited and emitted at lower wavelengths. However, because of the spectrum of the probe, specific lasers and detectors are needed for optimal imaging under the microscope. Furthermore, BODIPY665/676 is resistant to photobleaching at both excitation wavelengths, 670 and 580nm. In diffusion studies, BODIPY665/676 is highly lipophilic, remaining in the lipid phase and not diffusing into the aqueous phase or between lipid droplets.

Detection and Kinetic Characterization of a Highly Reactive Heme–Thiolate Peroxygenase Compound I

The extracellular heme-thiolate peroxygenase from Agrocybe aegerita (AaeAPO) has been shown to hydroxylate alkanes and numerous other substrates using hydrogen peroxide as the terminal oxidant. We describe the kinetics of formation and decomposition of AaeAPO compound I upon its reaction with mCPBA. The UV-vis spectral features of AaeAPO-I (361, 694 nm) are similar to those of chloroperoxidase-I and the recently described cytochrome P450-I. The second-order rate constant for AaeAPO-I formation was 1.0 (±0.4) × 10(7) M(-1) s(-1) at pH 5.0, 4 °C. The relatively slow decomposition rate, 1.4 (±0.03) s(-1), allowed the measurement of its reactivity toward a panel of substrates. The observed rate constants, k2', spanned 5 orders of magnitude and correlated linearly with bond dissociation enthalpies (BDEs) of strong C-H bond substrates with a log k2' vs BDE slope of ∼0.4. However, the hydroxylation rate was insensitive to a C-H BDE below 90 kcal/mol, similar to the behavior of the tert-butoxyl radical. The shape and slope of the Brønsted-Evans-Polanyi plot indicate a symmetrical transition state for the stronger C-H bonds and suggest entropy control of the rate in an early transition state for weaker C-H bonds. The AaeAPO-II Fe(IV)O-H BDE was estimated to be ∼103 kcal/mol. All results support the formation of a highly reactive AaeAPO oxoiron(IV) porphyrin radical cation intermediate that is the active oxygen species in these hydroxylation reactions.

Kinetics of oxidation of tyrosine by a model alkoxyl radical

Oxidation of tyrosine moieties by radicals involved in lipid peroxidation is of current interest; while a rate constant has been reported for reaction of lipid peroxyl radicals with a tyrosine model, little is known about the reaction between tyrosine and alkoxyl radicals (also intermediates in the lipid peroxidation chain reaction). In this study, the reaction between a model alkoxyl radical, the tert-butoxyl radical and tyrosine was followed using steady-state and pulse radiolysis. Acetone, a product of the β-fragmentation of the tert-butoxyl radical, was measured; the yield was reduced by the presence of tyrosine in a concentration- and pH-dependent manner. From these data, a rate constant for the reaction between tert-butoxyl and tyrosine was estimated as 6 ± 1 × 107 M−1 s−1 at pH 10. Tyrosine phenoxyl radicals were also monitored directly by kinetic spectrophotometry following generation of tert-butoxyl radicals by pulse radiolysis of solutions containing tyrosine. From the yield of tyrosyl radicals (measured before they decayed) as a function of tyrosine concentration, a rate constant for the reaction between tert-butoxyl and tyrosine was estimated as 7 ± 3 × 107 M−1 s−1 at pH 10 (the reaction was not observable at pH 7). We conclude that reaction involves oxidation of tyrosine phenolate rather than undissociated phenol; since the pKa of phenolic hydroxyl dissociation in tyrosine is ∼ 10.3, this infers a much lower rate constant, about 3 × 105 M−1 s−1, for the reaction between this alkoxyl radical and tyrosine at pH 7.4.

Reaction kinetics of resveratrol with tert-butoxyl radicals

The rate constant for the reaction of t-butoxyl radicals with resveratrol was studied under pseudo-first order conditions. The rate constant was determined by measuring the phenoxyl radical formation rate at 390nm as function of resveratrol concentration in acetonitrile. The rate constant was determined to be 6.5×108M−1s−1. This high value indicates the high reactivity consistent with the strong antioxidant activity of resveratrol.

ChemInform Abstract: Reactivity of tert.-Butoxyl Radicals Towards Substituted Indole Derivatives

Tert-butoxyl radicals react with indole and methyl substituted derivatives by hydrogen abstraction. For those compounds which are unsubstituted at the N-atom, hydrogen abstraction takes place almost exclusively at the NH bond. The reactivity of these compounds correlates with their donor electron capacity, pointing to significant contribution of charge transfer to the transition state stability. Substitution at the N atom considerably decreases the reactivity.

ChemInform Abstract: Reactions of tert-Butoxyl Radicals with Cyclic Ethers Studied by the Radical Trapping Technique.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Reactions of tert-Butoxyl Radicals with Acyclic Ethers Studied by the Radical Trapping Technique.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.