Reactivity of thio (amino) derivatives of the ω-(4-hydroxyaryl)alkyl type in radical reactions

The enthalpies, activation energies, and rate constants of the reactions of thio (amino) alkylphenols of different structures were calculated and compared with those of the reactions of alkyl-substituted phenols, alkoxyl and alkyl radicals, hydroperoxides, and nitrogen dioxide, as well as the reactions of phenoxyl radicals with molecules of the substrate being oxidized. The calculation was performed by the intersecting parabolas method using O-H bond energy data for phenols. The correlation between the molecular structure of the thio (amino) alkylphenols and their reactivity in radical reactions is considered.     

Synthesis and antioxidant activity of [60]fullerene-BHT conjugates

Fullerene derivatives incorporating one or two 3,5-di-tert-butyl-4-hydroxyphenyl groups were synthesized by 1,3-dipolar cycloaddition of azomethine ylides to C(60). The O-H bond dissociation enthalpies (BDEs) of these compounds were estimated by studying, by means of EPR spectroscopy, the equilibration of each of these phenols and 2,6-di-tert-butyl-4-methylphenol (BHT) with the corresponding phenoxyl radicals. The antioxidant activity of the investigated phenols was also determined by measuring the rate constants for their reaction with peroxyl radicals in controlled autoxidation experiments and compared to that recorded under identical experimental settings for [60]fullerene itself and unlinked BHT. The results indicate that linking of the BHT structure to C(60) does not substantially alter the thermochemistry and kinetics of its reaction with peroxyl radicals, but such adducts may behave as interesting bimodal radical scavengers. The inherent rate constant for trapping of peroxyl radicals by C(60) per se (k(inh)=3.1+/-1.1 x 10(2) m(-1) s(-1)) indicates that, contrary to previous reports, [60]fullerene is an extremely weak chain-breaking antioxidant.     

Electronic and hydrogen bonding effects on the chain-breaking activity of sulfur-containing phenolic antioxidants

A kinetic and thermodynamic investigation of phenols para-substituted with thiyl (SR), sulfinyl (SOR), and sulfonyl (SO(2)R) groups and ortho-substituted with thiyl groups is reported. The effect of the sulfur substituents on the O-H bond dissociation enthalpy values, BDE(O-H), was measured by means of the EPR radical equilibration technique and the reactivity toward peroxyl radicals, k(inh), of these phenolic antioxidants was determined by inhibited autoxidation studies. An inverse correlation between these two parameters was found. A p-SMe substituent decreased the BDE(O-H) value to a lesser extent than a p-OMe group (-3.6 vs -4.4 kcal/mol), whereas the effect of the same groups in an ortho position showed an opposite trend (-0.85 vs -0.2 kcal/mol). The latter result is explained in terms of the different strength of the intramolecular hydrogen bond between the OH proton and the sulfur or oxygen substituents in ortho derivatives. ESI-MS analysis of the products formed by reacting the sulfides with peroxyl radicals from the azoinitiator AIBN revealed the formation of a complex mixture of products, which may play an important role in determining the overall antioxidant activity of the parent compounds.     

Why Static O-H Bond Parameters Cannot Characterize the Free Radical Scavenging Activity of Phenolic Antioxidants: ab initio Study

Recently, selecting high efficient phenolic antioxidants with low toxicity was paid much attention1-4. Moreover, quantitative structure-activity relationships (QSAR) for phenolic antioxidants have been investigated to accelerate the selection process5-7. Hence, how to theoretically characterize the free radical scavenging activity of phenolic antioxidants is important and significant. Although the parameters characterizing O-H bond dissociation energy or enthalpy (BDE) correlate well with …     

Electronic effects on O-H proton dissociation energies of phenolic cation radicals: a DFT study

The electronic effects on O-H proton dissociation energies (PDEs) of para- and meta-substituted phenolic cation radicals have been investigated by density functional theory (DFT) using B3LYP function on a 6-31G(d, p) basis set. The calculation results indicate that electron-donating groups raise the O-H PDE and electron-withdrawing groups reduce the parameter, which are opposite to the electronic effects on O-H bond dissociation energies (BDEs). In addition, the electronic effects on O-H PDE are much stronger than those on O-H BDE. The differences result from the distinct electronic effects on stabilities of phenolic cation radicals and parent phenols. The finding also implies the proton-transfer process is unlikely a rate-controlling step for phenolic antioxidants to scavenge free radicals. Moreover, like O-H BDE, O-H PDE correlate better with the resonance parameter R+ than with field/inductive parameter F. Therefore, O-H PDEs of para-substituted phenolic cation radicals are mainly governed by the resonance effect.     

Investigation of the influence of hydroxy groups on the radical scavenging ability of polyphenols

Recently, O-H bond dissociation enthalpies (BDEs) have been successfully used to express the free radical scavenging ability of polyphenolic antioxidants. In this work, the BDEs of phenol, catechol, resorcinol, hydroquinone, pyrogallol, phloroglucinol, 1,2,4-benzenetriol, and 5-hydroxypyrogallol have been calculated at B3LYP/6-311G++(3df, 3pd) and used to elucidate the effect of OH groups. Increasing the number of OH groups in the adjacent (vicinal) position decreases the BDE of phenols. Increasing the number of O-H groups in the alternative position C(1,3) as in resorcinol and C(1,3,5) as in phloroglucinol does not show any notable change in the BDEs when compared to that of OH in C(1) as in phenol. 5-Hydroxypyrogallol has the smallest BDE (250.3 kJ mol(-1)) followed by pyrogallol (289.4 kJ mol(-1)), then 1,2,4-benzenetriol (294.8 kJ mol(-1)), and then catechol (312.8 kJ mol(-1)). Overall, our results indicated that the presence of ortho and para hydroxy groups reduces the BDEs. An intramolecular hydrogen bond (IHB) develops due to the ortho arrangement of OH's and plays a dominant role in decreasing the BDEs. This key study on phenols showed that the reactive order of OH position in the benzene ring is the following: 5-hydroxypyrogallol > pyrogallol > 1,2,4-benzenetriol > catechol > hydroquinone > phenol approximately resorcinol approximately phloroglucinol.     

Effect of ortho-SR groups on O-H bond strength and H-atom donating ability of phenols: a possible role for the Tyr-Cys link in galactose oxidase active site?

Rotation about the Ar-S bond in ortho-(alkylthio)phenols strongly affects the bond dissociation enthalpy (BDE) and the reactivity of the OH group. Newly synthesized sulfur containing heterocycles 3 and 4, where the -SR group is almost coplanar with the phenolic ring, are characterized by unusually low BDE(O-H) values (79.6 and 79.2 kcal/mol, respectively) and by much higher reactivities toward peroxyl radicals than the ortho-methylthio derivative 1 (82.0 kcal/mol). The importance of the intramolecular hydrogen bond (IHB) in determining the BDE(O-H) was demonstrated by FT-IR experiments, which showed that in heterocycles 3 and 4 the IHB between the phenolic OH group and the S atom is much weaker than that present in 1. Since the IHB can be formed only if the -SR group adopts an out-of-plane geometry, this interaction is possible only in the methylthio derivative 1 and not in 3 and 4. The additive contribution to the phenolic BDE(O-H) of the -SR substituent therefore varies from -3.1 to +2.8 kcal/mol for the in-plane and out-of-plane conformations, respectively. These results may be relevant to understanding the role of the tyrosine-cysteine link in the active site of galactose oxidase, an important enzyme that catalyzes the two-electron aerobic oxidation of primary alcohols to aldehydes. The switching of the ortho -SR substituent between perpendicular and planar conformations may account for the catalytic efficiency of this enzyme.     

Energetic differences between the five- and six-membered ring hydrocarbons: strain energies in the parent and radical molecules

The C-H bond dissociation enthalpies (BDEs) for the five- and six-membered ring alkanes, alkenes, and dienes were investigated and discussed in terms of conventional strain energies (SEs). New determinations are reported for cyclopentane and cyclohexane by time-resolved photoacoustic calorimetry and quantum chemistry methods. The C-H BDEs for the alkenes yielding the alkyl radicals cyclopenten-4-yl and cyclohexen-4-yl and the alpha-C-H BDE in cyclopentene were also calculated. The s-homodesmotic model was used to determine SEs for both the parent molecules and the radicals. When the appropriate s-homodesmotic model is chosen, the obtained SEs are in good agreement with the ones derived from group additivity schemes. The different BDEs in the title molecules are explained by the calculated SEs in the parent molecules and their radicals: (1) BDEs leading to alkyl radicals are ca. 10 kJ mol (-1) lower in cyclopentane and cyclopentene than in cyclohexane and cyclohexene, due to a smaller eclipsing strain in the five-membered radicals relative to the parent molecules (six-membered hydrocarbons and their radicals are essentially strain free). (2) C-H BDEs in cyclopentene and cyclohexene leading to the allyl radicals are similar because cyclopenten-3-yl has almost as much strain as its parent molecule, due to a synperiplanar configuration. (3) The C-H BDE in 1,3-cyclopentadiene is 27 kJ mol (-1) higher than in 1,4-cyclohexadiene due to the stabilizing effect of the conjugated double bond in 1,3-cyclopentadiene and not to a destabilization of the cyclopentadienyl radical. The chemical insight afforded by group additivity methods in choosing the correct model for SE estimation is highlighted.     

Critical re-evaluation of the O-H bond dissociation enthalpy in phenol

The gas-phase O-H bond dissociation enthalpy, BDE, in phenol provides an essential benchmark for calibrating the O-H BDEs of other phenols, data which aids our understanding of the reactivities of phenols, such as their relevant antioxidant activities. In a recent review, the O-H BDE for phenol was presented as 90 +/- 3 kcal mol(-1) (Acc. Chem. Res. 2003, 36, 255-263). Due to the large margin of error, such a parameter cannot be used for dynamic interpretations nor can it be used as an anchor point in the development of more advanced computational models. We have reevaluated the existing experimental gas-phase data (thermolyses and ion chemistry). The large errors and variations in thermodynamic parameters associated with the gas-phase ion chemistry methods produce inconsistent results, but the thermolytic data has afforded a value of 87.0 +/- 0.5 kcal mol(-1). Next, the effect of solvent has been carefully scrutinized in four liquid-phase methods for measuring the O-H BDE in phenol: photoacoustic calorimetry, one-electron potential measurements, an electrochemical cycle, and radical equilibrium electron paramagnetic resonance (REqEPR). The enthalpic effect due to solvation, by, e.g., water, could be rigorously accounted for by means of an empirical model and the difference in hydrogen bond interactions of the solvent with phenol and the phenoxyl radical. For the REqEPR method, a second correction is required since the calibration standard, the O-H BDE in 2,4,6-tri-tert-butylphenol, had to be revised. From the gas-phase thermolysis data and three liquid-phase techniques (excluding the electrochemical cycle method), the present analysis yields a gas-phase BDE of 86.7 +/- 0.7 kcal mol(-1). The O-H BDE was also estimated by state-of-the-art computational approaches (G3, CBS-APNO, and CBS-QB3) providing a range from 86.4 to 87.7 kcal mol(-1). We therefore recommend that in the future, and until further refinement is possible, the gas-phase O-H BDE in phenol should be presented as 86.7 +/- 0.7 kcal mol(-1).     

烷烃中碳氢键离解能的估算及其应用

将烷烃中的C－H键看成氢原子H与烷基Ri相连接而成的Ri－H键，以烷基的 HOMO能级和氢原子的轨道能来关联Ri－H键的离解能BDE。研究表明，烷烃分子中 Ri－H键的离能BDE与烷基Ri的极化效应指数PEI（Ri）有良好的线性关系：BDE＝ c+dPEI(Ri)。所得方程具有良好的估算精度。烷基Ri极化效应指数PEI（Ri）在羟 基自由基与烷烃反应速度常数的定量相关中，也得到良好的应用。     

Synthesis and antioxidant activity of [60]fullerene-flavonoid conjugates

Chalcone, flavone, and arylideneflavanone derivatives bearing one or two 3,5-di-tert-butyl-4-hydroxyphenyl groups were synthesized from 2′,4′-dihydroxyacetophenone and 3,5-di-tert-butyl-4-hydroxybenzaldehyde. These flavonoids were converted into the corresponding malonates and then reacted with C₆₀ to yield the title compounds. The O-H bond dissociation enthalpies (BDE) and the chain-breaking antioxidant activity of the flavonoid derivatives and the corresponding C₆₀ conjugates were evaluated. These results are consistent with the phenolic moiety being the main responsible for the reaction with peroxyl radicals, while the C₆₀ part of the molecule acts synergically by trapping alkyl radicals under reduced O₂ partial pressure. These novel C₆₀-flavonoid conjugates are therefore promising leads for broad-spectrum radical scavengers.     

Mechanism of action of sensors for reactive oxygen species based on fluorescein-phenol coupling: the case of 2-[6-(4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid

We demonstrate the ability of a sensor containing a tethered fluorescein-phenol structure to react with peroxyl radicals and with an oxidizing agent such as potassium ferricyanide. This latter reaction yields the corresponding peroxyl radical as observed by EPR analysis. We propose that the reaction of the sensor with peroxyl and alkoxyl radicals is also initiated by the formation of the phenoxyl radicals, which is followed by radical-radical reactions and product hydrolysis responsible for the release of fluorescein. The proposed mechanism is based on results obtained by laser flash photolysis, HPLC and EPR studies of the reaction of peroxyl and alkoxyl radicals with 4-phenoxylphenol, a molecule used to mimic the behavior of the sensor.     

Theoretical calculations of carbon-oxygen bond dissociation enthalpies of peroxyl radicals formed in the autoxidation of lipids

Theoretical calculations were carried out to provide a framework for understanding the free radical oxidation of unsaturated lipids. The carbon[bond]hydrogen bond dissociation enthalpies (BDEs) of organic model compounds and oxidizable lipids (R[bond]H) and the carbon[bond]oxygen bond dissociation enthalpies of peroxyl radical intermediates (R[bond]OO*) have been calculated. The carbon[bond]hydrogen BDEs correlate with the rate constant for propagation of free radical autoxidation, and the carbon[bond]oxygen BDEs of peroxyl radicals correlate with rate constants for beta-fragmentation of these intermediates. Oxygen addition to intermediate carbon radicals apparently occurs preferentially at centers having the highest spin density. The calculated spin distribution therefore provides guidance about the partitioning of oxygen to delocalized carbon radicals. Where the C[bond]H BDEs are a function of the extent of conjugation in the parent lipid and the stability of the carbon radical derived therefrom, C[bond]OO* BDEs are also affected by hyperconjugation. This gives way to different rates of beta-fragmentation of peroxyl radicals formed from oxygen addition at different sites along the same delocalized radical. We have also studied by both theory and experiment the propensity for benzylic radicals to undergo oxygen addition at their ortho and para carbons which, combined, possess an equivalent unpaired electron spin density as the benzylic position itself. We find that the intermediate peroxyl radicals in these cases have negative C[bond]OO* BDEs and, thus, have rate constants for beta-fragmentation that exceed the diffusion-controlled limit for the reaction of a carbon-centered radical with oxygen.     

Rate constants and transition‐state geometry of reactions of alkyl,alkoxyl, and peroxyl radicals with thiols

Enthalpy, activation energy, and rate constant of 9 alkyl, 3 acyl, 3 alkoxyl, and 9 peroxyl radicals with alkanethiols, benzenethiol, and L ‐cysteine are calculated. The intersection parabolas model is used for activation energy calculations. Depending on the structure of attacking radical, the activation energy of reactions with alkylthiols varies from 3 to 43 kJ mol^?1 for alkyl radicals, from 7 to 9 kJ mol^?1 for alkoxyl, and from 18 to 35 kJ mol^?1 for peroxyl radicals. The influence of adjacent π‐bonds on activation energy is estimated. The polar effect is found in reactions of hydroxyalkyl and acyl radicals with alkylthiols. The steric effect is observed in reactions of alkyl radicals with tert‐alkylthiols. All these factors are characterized via increments of activation energy. Quantum chemical calculations of activation energy and geometry of transition state were performed for model reactions: C^?H₃ + CH₃SH, CH₃O^? + CH₃SH, and HO₂^? + CH₃SH with using density functional theory and Gaussian‐98. © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 41: 284–293, 2009     

Determination of the substituent effect on the O-H bond dissociation enthalpies of phenolic antioxidants by the EPR radical equilibration technique

The bond dissociation enthalpies (BDE) of several phenols containing electron-withdrawing substituents in the para position have been determined by means of the EPR radical equilibration technique. It has been found that CN, NO(2), CHO, COOR, and COOH induce an increase of the BDE value of the O-H bond, thus producing a worsening of the antioxidant activity of phenols, while Cl, Ph, and CH[double bond]CHPh show an opposite effect. The contributions of these substituents for the calculation of the BDE values in polysubstituted phenols by using the group additivity rule have also been derived. It is shown that this rule provides quite reliable predictions of bond strengths, so that the method can be conveniently used to estimate new data on substituted phenols.     

Thermochemical and kinetic studies of a bisphenol antioxidant

The results of a thermodynamic and kinetic investigation on the homolytic reactivity of 3,3'-di-tert-butyl-5,5'-dimethyl(1,1'-biphenyl)-2,2'-diol (1) are reported. EPR studies of the equilibration between 1, 2,4,6-trimethylphenol, and the corresponding radicals obtained by abstraction of a hydroxylic hydrogen allowed us to determine the OH bond dissociation energy (BDE) of investigated bisphenol as 83.10 kcal/mol. This value is considerably larger than that reported for the structurally related 2,6-di-tert-butyl-4-methylphenol (BHT), i.e., 81.02 kcal/mol. Absolute rate constants for the reaction of 1 with alkyl, alkoxyl, and peroxyl radicals, at or nearly to room temperature, were also determined by competition kinetics in the first two cases and by autoxidation studies under controlled conditions in the last one. The experimental data indicate that this bisphenol is a moderately efficient antioxidant and polymerization inhibitor.     

O-H bond dissociation enthalpies of oximes: a theoretical assessment and experimental implications

By using a multilayer composite ab initio method ONION-G3B3, we calculated O-H bond dissociation enthalpies (BDEs) of 58 oximes that were measured experimentally. Experimental BDEs derived from thermal decomposition kinetics and calorimetric measurements were found to be consistent with the theory. However, the electrochemical method was found to give questionably high BDEs possibly due to errors in the measurement of pKa's or redox potentials. Subsequently, the performances of a variety of DFT functionals including B3LYP, B3P86, B3PW91, BHandH, BHandHLYP, BMK, PBE1PBE, MPW1KCIS, mPWPW91, MPW1B95, and MPW1K were tested to calculate oxime O-H BDEs, where ROBHandHLYP was found to be the most accurate. By using this method, we calculated O-H BDEs of over 140 oximes in a systematic fashion. All of the calculated O-H BDEs fell in the range from 76.8 to 89.8 kcal/mol. An amino group on the azomethine carbon was found to strengthen the O-H bond, whereas bulky alkyl substituents on oximes decreased O-H BDEs due to their large steric-strain-relieving effects in the process of O-H bond cleavage. Para substituents had little effect on the BDEs of benzaldoximes and phenyl methyl ketoximes. Finally, on the basis of a spin distribution calculation, aryl-, alkyl-, and carbonyl-substituted iminoxyl radicals were found to be sigma-radicals, whereas amino-substituted iminoxyl radicals were of pi-structure.     

SET and HAT/PCET acid-mediated oxidation processes in helical shaped fused bis-phenothiazines

Helical shaped fused bis-phenothiazines 1 – 9 have been prepared and their red-ox behaviour quantitatively studied. Helicene radical cations (Hel^.+) can be obtained either by UV-irradiation in the presence of PhCl or by chemical oxidation. The latter process is extremely sensitive to the presence of acids in the medium with molecular oxygen becoming a good single electron transfer (SET) oxidant. The reaction of hydroxy substituted helicenes 5 – 9 with peroxyl radicals (ROO^.) occurs with a ‘classical’ HAT process giving HelO^. radicals with kinetics depending upon the substitution pattern of the aromatic rings. In the presence of acetic acid, a fast medium-promoted proton-coupled electron transfer (PCET) process takes place with formation of HelO^. radicals possibly also via a helicene radical cation intermediate. Remarkably, also helicenes 1 – 4 , lacking phenoxyl groups, in the presence of acetic acid react with peroxyl radicals through a medium-promoted PCET mechanism with formation of the radical cations Hel^.+. Along with the synthesis, EPR studies of radicals and radical cations, BDE of Hel-OH group (BDE_OH), and kinetic constants (k_inh) of the reactions with ROO^. species of helicenes 1 – 9 have been measured and calculated to afford a complete rationalization of the redox behaviour of these appealing chiral compounds.     

Antioxidant activity of hydroxystilbene derivatives in homogeneous solution

The antioxidant activity of the cis and trans isomers of several analogues of resveratrol and pterostilbene has been investigated, especially with regard to the effect of the stereochemistry about the olefinic double bond. The antioxidant power of these compounds was estimated by measuring the rate constants for their reactions with peroxyl radicals and, with two of them, the bond dissociation enthalpy (BDE) of the phenolic O-H bond which is cleaved in the inhibition reaction. The present data show that in homogeneous solution the various hydroxystilbenes investigated behave as mild antioxidants with the notable exceptions of the trans isomer of 4 and 6, whose activities are only slightly lower than that of alpha-tocopherol (vitamin E). The rate constants of the inhibition reaction show that the antioxidant activity of the cis-hydroxystilbene is in all the examined cases worse, by a factor ranging between 2 and 6, than that of the corresponding trans isomers. This lower reactivity depends on enthalpy factors as it can be inferred by the experimental values of the O-H bond dissociation enthalpy in the two geometric isomers of 3',5'-di-tert-butyl-4'-hydroxy-3,5-dimethoxystilbene showing that the strength of the O-H bond in the cis isomer is larger by 1.8 kcal/mol. DFT calculations provide a rationalization of this result, indicating that, although the cis geometry implies a destabilization with respect to the trans species of both phenoxyl radical and parent hydroxystilbene, the destabilization of the radical is larger because the folding of the structure strongly reduces the delocalization of the unpaired electron on the styryl group. A comparison of these results with previously reported data on the proapoptotic activity of these stilbenoids suggests that these two properties are not correlated.