Homolytic Mechanism Research Articles

Anionic oxyl radical formed on CrVI-oxo anchored on the defect site of the UiO-66 node facilitates methane to methanol conversion.

The direct conversion of methane to methanol has attracted increasing interest due to abundant and low-cost natural gas resources. Herein, by anchoring Cr-oxo/-oxyhydroxides on UiO-66 metal-organic frameworks, we demonstrate that reactive anionic oxyl radicals can be formed by controlling the coordination environment based on the results of density functional theory calculations. The anionic oxyl radicals produced at the completely oxidized CrVI site acted as the active species for facile methane activation. The thermodynamically stable CrVI-oxo/-oxyhydroxides with the anionic oxyl radicals catalyze the activation of the methane C-H bond through a homolytic mechanism. An analysis of the results showed that the catalytic performance of the active oxyl species correlates with the reaction energy of methane activation and H adsorption energies. Following methanol formation, N2O can regenerate the active sites on the most stable CrVI oxyhydroxides, i.e., the Cr(O)4Hf species. The present study demonstrated that the anionic oxyl radicals formed on the anchored CrVI oxyhydroxides by tuning the coordination environment enabled facile methane activation and facilitated methanol production.

Emerging Strategies for Modifying Cytochrome P450 Monooxygenases into Peroxizymes.

ConspectusCytochrome P450 monooxygenase is a versatile oxidizing enzyme with great potential in synthetic chemistry and biology. However, the dependence of its catalytic function on the nicotinamide cofactor NAD(P)H and redox partner proteins limits the practical catalytic application of P450 in vitro. An alternative to expensive cofactors is low-cost H2O2, which can be used directly to exploit the catalytic potential of P450s. However, the peroxide shunt pathway is generally inefficient at driving P450 catalysis compared to normal NAD(P)H-dependent activity. Over the last few decades, the scientific community has made continuous efforts to use directed evolution or site-directed mutagenesis to modify P450 monooxygenases into their peroxizyme modes─peroxygenase and peroxidase. Despite significant progress, obtaining efficient P450 peroxizymes remains a huge challenge. Here, we summarize our efforts to modulate peroxizyme activity in P450 monooxygenases and exploit their catalytic applications in challenging selective C-H oxidation, oxygenation, and oxyfunctionalization over the past seven years. We first developed a dual-functional small molecule (DFSM) strategy for transforming P450BM3 monooxygenase into peroxygenase. In this strategy, the typical DFSM, such as N-(ω-imidazolyl)-hexanoyl-l-phenylalanine (Im-C6-Phe), binds to the P450BM3 protein with an anchoring group at one end and plays a general acid-base catalytic role in the activation of H2O2 with an imidazolyl group at the other end. Compared with the O-O homolysis mechanism in the absence of DFSM, the addition of DFSM efficiently enables the heterolytic O-O cleavage of the adduct Fe-O-OH, thus being favored for the formation of active species compound I, which has been demonstrated by combining crystallographic and theoretical calculations. Furthermore, protein engineering showed the unique catalytic performance of DFSM-facilitated P450 peroxygenase for the highly difficult selective oxidation of C-H bonds. This catalytic performance was demonstrated during the chemoselective hydroxylation of gaseous alkanes, regioselective O-demethylation of aryl ethers, highly (R)-enantioselective epoxidation of styrene, and regio- and enantiomerically diverse hydroxylation of alkylbenzenes. Second, we demonstrated that DFSM-facilitated P450BM3 peroxygenase could be effectively switched to an efficient peroxidase mode through mechanism-guided protein engineering of redox-sensitive residues. Utilizing the peroxidase function of P450 enabled the direct nitration of unsaturated hydrocarbons including phenols, aromatic amines, and styrene derivatives, which was not only the P450-catalyzed direct nitration of phenols and aromatic amines for the first time but also the first example of the direct biological nitration of olefins. Finally, we report an H2O2 tunnel engineering strategy to enable peroxygenase activity in several different P450 monooxygenases for the first time, providing a general approach for accessing engineered P450 peroxygenases. In this Account, we highlight the emerging strategies we have developed for producing practical P450 peroxizyme biocatalysts. Although the DFSM strategy is primarily applied to P450BM3 to date, both strategies of redox-sensitive residue engineering and H2O2 tunnel engineering show great potential to extend to other P450s. These strategies have expanded the scope of applications of P450 chemistry and catalysis. Additionally, they provide a unique solution to the challenging selective oxidation of inert C-H bonds in synthetic chemistry.

Theoretical investigation on the structure-activity relationship for methane activation in Cu-CHA zeolite

The active sites and structure–activity relationship for methane activation over Cu-CHA were investigated by Density Functional Theory (DFT) calculations. [CuOCu]2+, [CuO2Cu]2+, [CuOH]+ and [CuO]+ were employed as possible active sites, but the Ab initio thermodynamics analysis results indicate that [CuO]+ is thermodynamically prohibitive. Methane activation in Cu-CHA proceeds through a homolytic mechanism, and the activity of Cu complexes in CH bond activation of methane follows the sequence [CuOH]+ (doublet) < [CuOCu]2+ (triplet) < [Cu2O2]2+ (triplet) in the six-member ring (6MR) and eight-member ring (8MR). In addition, the structure–activity relationship was established: The more reactive site is due to the ability to stabilize the methyl radical intermediate.

Computational Screening of Supported Metal Oxide Nanoclusters for Methane Activation: Insights into Homolytic versus Heterolytic C–H Bond Dissociation

Since its discovery in zeolites, the [CuOCu]2+ motif has played an important role in our understanding of selective methane activation over supported metal oxide nanoclusters. Although there are two known C-H bond dissociation mechanisms, namely, homolytic and heterolytic cleavage, most computational studies on optimizing metal oxide nanoclusters for improved methane activation reactivity have focused only on the homolytic mechanism. In this work, both mechanisms were examined for a set of 21 mixed metal oxide complexes of the form of [M1OM2]2+ (M1 and M2 = Mn, Fe, Co, Ni, Cu, and Zn). Except for pure copper, heterolytic cleavage was found to be the dominant C-H bond activation pathway for all systems. Furthermore, mixed systems including [CuOMn]2+, [CuONi]2+, and [CuOZn]2+ are predicted to possess methane activation activity similar to pure [CuOCu]2+. These results suggest that both homolytic and heterolytic mechanisms should be considered in computing methane activation energies on supported metal oxide nanoclusters.

Unravelling the Mechanistic Pathway of the Hydrogen Evolution Reaction Driven by a Cobalt Catalyst

AbstractA cobalt complex bearing a κ‐N3P2 ligand is presented (1+ or CoI(L), where L is (1E,1′E)‐1,1′‐(pyridine‐2,6‐diyl)bis(N‐(3‐(diphenylphosphanyl)propyl)ethan‐1‐imine). Complex 1+ is stable under air at oxidation state CoI thanks to the π‐acceptor character of the phosphine groups. Electrochemical behavior of 1+ reveals a two‐electron CoI/CoIII oxidation process and an additional one‐electron reduction, which leads to an enhancement in the current due to hydrogen evolution reaction (HER) at Eonset=−1.6 V vs Fc/Fc+. In the presence of 1 equiv of bis(trifluoromethane)sulfonimide, 1+ forms the cobalt hydride derivative CoIII(L)‐H (22+), which has been fully characterized. Further addition of 1 equiv of CoCp*2 (Cp* is pentamethylcyclopentadienyl) affords the reduced CoII(L)‐H (2+) species, which rapidly forms hydrogen and regenerates the initial CoI(L) (1+). The spectroscopic characterization of catalytic intermediates together with DFT calculations support an unusual bimolecular homolytic mechanism in the catalytic HER with 1+.

Unravelling the Mechanistic Pathway of the Hydrogen Evolution Reaction Driven by a Cobalt Catalyst.

A cobalt complex bearing a κ-N3 P2 ligand is presented (1+ or CoI (L), where L is (1E,1'E)-1,1'-(pyridine-2,6-diyl)bis(N-(3-(diphenylphosphanyl)propyl)ethan-1-imine). Complex 1+ is stable under air at oxidation state CoI thanks to the π-acceptor character of the phosphine groups. Electrochemical behavior of 1+ reveals a two-electron CoI /CoIII oxidation process and an additional one-electron reduction, which leads to an enhancement in the current due to hydrogen evolution reaction (HER) at Eonset =-1.6 V vs Fc/Fc+ . In the presence of 1 equiv of bis(trifluoromethane)sulfonimide, 1+ forms the cobalt hydride derivative CoIII (L)-H (22+ ), which has been fully characterized. Further addition of 1 equiv of CoCp*2 (Cp* is pentamethylcyclopentadienyl) affords the reduced CoII (L)-H (2+ ) species, which rapidly forms hydrogen and regenerates the initial CoI (L) (1+ ). The spectroscopic characterization of catalytic intermediates together with DFT calculations support an unusual bimolecular homolytic mechanism in the catalytic HER with 1+ .

DFT investigates the mechanisms of cross-dehydrogenative coupling between heterocycles and acetonitrile

The mechanisms between CH3CN and 1,3-dimethyl-1H-indole, initiated by DCP (dicumyl peroxide), have been studied with the B3LYP-D3 method with def2TZVP basis set for all atoms, and the SMD model was applied to simulate the solvent of acetonitrile. The computational results show that the homolytic process of DCP, catalysed by CuCl or CuI, can decrease the energy barrier, and the recycle procedure of Cu catalyst has been described. Then the Csp3-H activation of CH3CN has been investigated. The introduction of the cyano group is an anti-Markovnikov reaction and region-selectivity would be fulfilled. Localised orbital bonding analysis, localised orbital locator (LOL) isosurfaces, and electron spin density isosurface graphs could be used to interpret the phenomena. The results could provide valuable insights into these types of interactions and related ones. Highlights The homolytic mechanisms of DCP catalyzed by CuCl or CuI are proposed. The anti-Markovnikov's reaction between 1,3-dimethyl-1H-indole and free radical is investigated. Localized orbital bonding analysis, localized orbital locator (LOL) isosurfaces and electron spin density isosurface graphs have been used to interpret the phenomena.

Single-atom metal tuned sulfur vacancy for efficient H2 activation and hydrogen evolution reaction on MoS2 basal plane

MoS2(001) basal plane, modified by doping transition metals (M) or creating S vacancies (Sv), has presented superior catalytic performance in hydrogen evolution, hydrogenation and hydrodeoxygenation reactions. However, the optimal active sites for H2 dissociation/ recombination, a crucial step in the aforementioned reactions, on the modified MoS2(001) are yet to be unequivocally elucidated. Using density functional theory calculations, we find that H2 dissociation activity generally follows the order: M modified Sv > unmodified Sv > M modified S > M modified Sv - M and Sv modified S > M and Sv modified S > Sv modified S > unmodified S. Compared to Mo, the increasing number of outer electrons in M causes less unpaired electrons to bind with S. This facilitates the removal of S, which leaves electrons to fill to the antibonding H2 states, thereby enhancing H2 dissociation through homolytic mechanism. M modified Sv also exhibits superior activity in H2 recombination and hydrogen evolution, indicating it to be the active site for these reactions. Among the dopants, Cu or Pd modified Sv show excellent activity for all the reactions. The energetic proportionality between Sv formation energy, integrated crystal orbital overlap/Hamilton populations and H adsorption energy together with BEP relations open the possibilities to design metal compound catalysts for important reactions involving hydrogen.

The Mechanochemistry of Carboranes

AbstractWe developedo‐carborane as a new mechanophore by showing that theo‐carborane cluster is the preferred scission site in chain‐centered polymers through ultrasonication mechanochemistry. Mechanistic studies are consistent with a predominately homolytic mechanism of chain scission. The mechanically generated monocarbaborane fragments are highly reactive toward alcohol nucleophiles. By contrast, carborane with a different regiochemistry (m‐carborane) maintained its high mechanical stability. DFT simulations provide insights into the origins of carborane's mechanical lability. This fundamental research provides a new stimulus for carborane cage activation.

The Mechanochemistry of Carboranes.

We developed o-carborane as a new mechanophore by showing that the o-carborane cluster is the preferred scission site in chain-centered polymers through ultrasonication mechanochemistry. Mechanistic studies are consistent with a predominately homolytic mechanism of chain scission. The mechanically generated monocarbaborane fragments are highly reactive toward alcohol nucleophiles. By contrast, carborane with a different regiochemistry (m-carborane) maintained its high mechanical stability. DFT simulations provide insights into the origins of carborane's mechanical lability. This fundamental research provides a new stimulus for carborane cage activation.

Titania-heteropolyacid composites (TiO2-HPA) as catalyst for the green oxidation of trimethylphenol to 2,3,5-trimethyl-p-benzoquinone

New catalysts containing phosphomolybdic acid (PMA) and vanadophosphomolybdic acid (VPMA) in a titania matrix were synthesized by the sol–gel process with different heteropolyacid loads (5%, 15%, and 30% (w/w): 5PMA-TiO2, 15PMA-TiO2, 30PMA-TiO2, 5VPMA-TiO2, 15VPMA-TiO2, and 30VPMA-TiO2). The techniques used to characterize the materials were XRD, DRS, SEM, FT-IR, 31P MAS-NMR, potentiometric titration with n-butylamine, and N2 physisorption at −196 °C. The materials were used as heterogeneous catalysts in the oxidation of 2,3,6-trimethylphenol (TMP) to 2,3,5-trimethyl-p-benzoquinone (TMBQ), a key intermediate in vitamin E synthesis. The catalysts allowed an ecofriendly TMBQ synthesis, using ethanol as solvent and aqueous hydrogen peroxide as a clean oxidizing agent, at room temperature. The conversion of TMP reached 90% and 99% for the samples with 15PMA-TiO2 and 15VPMA-TiO2, respectively, after 4 h. The amount of Mo and V in the reaction medium was determined by ICP-MS, which showed leaching of only 17–18% Mo, but 48% V. Reuse of the catalysts was performed. For 15PMA-TiO2, the conversion was maintained in the second cycle. A homolytic mechanism was proposed for TMBQ synthesis, which involved the formation of a peroxometallic species through an HPA-Ti center.

Lewis Acid Transition-Metal-Catalyzed Hydrogen Activation: Structures, Mechanisms, and Reactivities.

As a new type of bifunctional catalyst, the Lewis acid transition-metal (LA-TM) catalysts have been widely applied for hydrogen activation. This study presents a mechanistic framework to understand the LA-TM-catalyzed H2 activation through DFT studies. The mer(trans)-homolytic cleavage, the fac(cis)-homolytic cleavage, the synergetic heterolytic cleavage, and the dissociative heterolytic cleavage should be taken as general mechanisms for the field of LA-TM catalysis. Four typical LA-TM catalysts, the Z-type κ4 -L3 B-Rh complex tri(azaindolyl)borane-Rh, the X-type κ3 -L2 B-Co complex bis-phosphino-boryl (PBP)-Co, the η2 -BC-type κ3 -L2 B-Pd complex diphosphine-borane (DPB)-Pd, and the Z-type κ2 -LB-Pt complex (boryl)iminomethane (BIM)-Pt are selected as representative models to systematically illustrate their mechanistic features and explore the influencing factors on mechanistic variations. Our results indicate that the tri(azaindolyl)borane-Rh catalyst favors the synergetic heterolytic mechanism; the PBP-Co catalyst prefers the mer(trans)-homolytic mechanism; the DPB-Pd catalyst operates through the fac(cis)-homolytic mechanism, whereas the BIM-Pt catalyst tends to undergo the dissociative heterolytic mechanism. The mechanistic variations are determined by the coordination geometry, the LA-TM bonding nature, the electronic structure of the TM center, and the flexibility or steric effect of the LA ligands. The presented mechanistic framework should provide helpful guidelines for LA-TM catalyst design and reaction developments.

Homolytic Versus Heterolytic Bond Breaking in Functionalized [R-C20 H10 ]+ Systems.

The comprehensive theoretical investigation of stability of functionalized corannulene cations [R-C20 H10 ]+ with respect to two alternative bond-breaking mechanisms, namely, homolytic or radical ([R-C20 H10 ]+ → R• + C20 H10 +• ) and heterolytic or cationic ([R-C20 H10 ]+ → R+ + C20 H10 ), was accomplished. The special focus was on the influence of the nature of R-group on the energetics of the bond cleavage. Detailed study of energetics of both mechanisms has revealed that the systems with small alkyl groups such as methyl tend to undergo bond breaking in accordance with homolytic mechanism. Subsequent elongation of the chain of the R-group resulted in shifting the paradigm, making heterolytic path more energetically favorable. Subsequent analysis of different components of the bonding between R-group and corannulene polyaromatic core helped to shed light on trends observed. In both mechanisms, the covalent contribution was found to be dominating, whereas ionic part contributes ~25-27%. Two leading components of ΔEorb , C20 H10 → R and R → C20 H10 , were identified with NOCV-EDA approach. While the homolytic pathway is best described as R → C20 H10 process, the heterolytic mechanism shows domination of the C20 H10 → R term. Surprisingly, the preparation energy (ΔEprep ) was identified as a key player in stability tendencies found. In other words, the relative stability of corresponding molecular fragments (here R-groups as the corannulene fragment remains the same for all systems) in their cationic or radical forms determine the preference given to a specific bond breaking path and, as consequence, the total stability of target functionalized cations. These conclusions were further confirmed by extending a set of R-groups to conjugated (allyl, phenyl), bulky (iPr, tBu), β-silyl (CH2 SiH3 , CH2 SiMe3 ), and benzyl (CH2 Ph) groups. © 2019 Wiley Periodicals, Inc.

KINETICS OF THIOUREA DIOXIDE DECOMPOSITION IN WATER-ETHANOL-AMMONIA SOLUTION

A stoichiometric mechanism for thiourea dioxide decomposition in water- ethanol-ammonia solution is proposed based on dependences of concentrations of thiourea dioxide over time and literature data. The concentration of thiourea dioxide was measured with iodometry, while the intermediates were qualitatively detected using the polarography. The set of the obtained data allows to consider that at low concentration of alcohol (approximately up to 0.1 molar ratio) the thiourea dioxide decomposition proceeds on the heterolytic mechanism with formation of sulfoxylic acid, and at high concentrations of alcohol – on homolytic mechanism with the formation of anion radicals. Rate constants for individual stages of heterolytic mechanism are obtained by mathematical modeling, presented a system of differential equations. Absolute errors of rate constants, correlation coefficients, and F-factors were also calculated. The linear correlation was found between the equilibrium constant logarithm of the decay stage of thiourea dioxide and the inverse value of the dielectric constant of water-alcohol solutions. The kinetics of reduction of nickel ions with thiourea dioxide in an aqueous ammonia solution with ethanol additives was also studied. Сoncentration of nickel ions was determined using complexometric titration. Obtained kinetic data showed that at alcohol concentrations of 0.13 molar ratio and more, reaction kinetics is described by a first-order equation. At lower ethanol concentrations, a fractional order is observed on the concentration of nickel ions. A stoichiometric mechanism of this reaction is proposed due to sulfoxylic acid molecules with alcohol concentrations less than 0.1 molar ratio and due to radical ions with alcohol concentrations more than 0.1 molar ratio. Thus, the study of nickel ion reduction kinetics confirmed the conclusion about influence of alcohol concentration on the decomposition mechanism of thiourea dioxide.

An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids

We found previously that nitroxide radical of desferrioxamine (DFO•) could be produced from the interaction between the classic iron chelating agent desferrioxamine (DFO, an N-alkyl trihydroxamic acid) and tetrachlorohydroquinone (TCHQ), one of the carconogenic quinoind metabolites of the widely used wood preservative pentachlorophenol. However, the underlying molecular mechanism remains unclear. Here N-methylacetohydroxamic acid (N-MeAHA) was synthesized and used as a simple model compound of DFO for further mechanistic study. As expected, direct ESR studies showed that nitroxide radical of N-MeAHA (Ac-(CH3)NO•) can be produced from N-MeAHA/TCHQ. Interestingly and unexpectedly, when TCHQ was substituted by its oxidation product tetrachloro-1,4-benzoquinone (TCBQ), although Ac-(CH3)NO• could also be produced, no concurrent formation of tetrachlorosemiquinone radical (TCSQ•) and TCHQ was detected, suggesting that Ac-(CH3)NO• did not result from direct oxidation of N-MeAHA by TCSQ• or TCBQ as proposed previously. To our surprise, a new nitrogen-centered amidyl radical was found to be generated from N-MeAHA/TCBQ, which was observed by ESR with the spin-trapping agents and further unequivacally identified as Ac-(CH3)N• by HPLC-MS. The final product of amidyl radical was isolated and identified as its corresponding amine. Analogous radical homolysis mechanism was observed with other halogenated quinoid compounds and N-alkyl hydroxamic acids including DFO. Interestingly, amidyl radicals were found to induce both DNA strand breaks and DNA adduct formation, suggesting that N-alkyl hydroxamic acids may exert their potential side-toxic effects via forming the reactive amidyl radical species. This study represents the first report of an unexpected new pathway for nitroxide radical production via hydrogen abstration reaction of a more reactive amidyl radical intermediate during the detoxification of the carcinogenic polyhalogenated quinones by N-alkyl hydroxamic acids, which provides more direct experimental evidence to better explain not only our previous finding that excess DFO can provide effective but only partial protection against TCHQ (or TCBQ)-induced biological damage, and also the potential side-toxic effects induced by DFO and other N-alkyl hydroxamic acid drugs.

Influence of inherent alkali metal chlorides on pyrolysis mechanism of a lignin model dimer based on DFT study

In order to understand the catalytic effects of inherent inorganic elements in biomass on the pyrolysis mechanism of lignin, density functional theory with a Gaussian method of M06-2X and basic set of 6-31 + G(d,p) was employed to simulate the pyrolysis pathways of a β-O-4 type lignin dimer model compound (1-methoxy-2-(4-methoxyphenethoxy)benzene) catalyzed by NaCl and KCl which are major inorganic constituents of biomass at microscale level. The calculation results indicate that cations (Na+ and K+) in alkali metal chlorides are facile to combine with the oxygen-containing functional groups in the lignin dimer model compound. Both cations increase the Cβ−O bond length and shorten the Cα–Cβ bond length, which will further affect their bond dissociation energies. In the initial pyrolysis process of the lignin dimer model compound, NaCl and KCl can promote the Cβ–O homolytic reaction and concerted decomposition reaction, while restrain the Cα–Cβ homolytic reaction. Therefore, the lignin dimer model compound decomposes mainly through the concerted decomposition and Cβ–O homolytic mechanisms under NaCl and KCl catalytic pyrolysis conditions, producing 1-methoxy-4-vinylbenzene, 1-ethyl-4-methoxybenzene, 2-methoxyphenol, catechol and 2-hydroxybenzaldehyde, among which NaCl and KCl have inhibitory effect on 2-hydroxybenzaldehyde, but have promoting effect on the other pyrolytic products.

An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions

We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it is still not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damages even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 isotope-labeling studies. The same iminyl radical was observed when TCBQ was substituted by other halogenated quinones. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. Based on these data, we proposed that the reaction of 2-PAM and TCBQ might be through the following two competing pathways: a nucleophilic attack of 2-PAM on TCBQ forms an unstable transient intermediate, which can decompose not only heterolytically to form 2-CMP via double Beckmann fragmentation, but also homolytically leading to the formation of a reactive iminyl radical in double-steps, which then via H abstraction and further hydrolyzation to form its corresponding more toxic aldehyde. Analogous radical homolysis mechanism was observed with other halogenated quinones and pyridinium aldoximes. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain only the partial protection by 2-PAM against TCBQ-induced biological damages, and also the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.

P-227 - An unexpected double radical homolysis mechanism for the reactions between the pyridinium aldoxime nerve agent antidotes and polyhalogenated quinones under normal physiological conditions

We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it remains not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damage even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 2-PAM isotope-labeling studies. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. We proposed that the reaction of 2-PAM and TCBQ might be via the following two competing mechanisms: double Beckmann fragmentation vs double radical homolysis. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.

DFT study of the mechanisms of nonenzymatic DNA repair by phytophenolic antioxidants.

Reactive oxygen species (ROS) can oxidize and thus damage DNA. Exposure to high levels of ROS is therefore linked with the development of severe illnesses such as cancer, diabetes, and coronary heart disease. Effective treatments for these diseases are yet to be found, despite intensive research. However, it is known that the natural nonenzymatic repair of DNA damage using phytophenols occurs more rapidly than the corresponding enzymatic repair process. Carvacrol, thymol, thymohydroquinone, and p-cymene-2,3-diol are strong natural antioxidant phytophenols that are found in medicinal plants. Their antioxidant activities, which involve reacting with and eliminating ROS before they reach and damage DNA, were studied in this work. Homolytic and heterolytic antioxidant mechanisms that allow these phytophenol antioxidants to eliminate the ROS .OH and .O2- in both vacuum and water (physiological environment) were investigated using density functional theory (DFT). The results showed that the homolytic mechanism is preferred in vacuum, whereas the heterolytic mechanisms are more probable in polar environments. In addition, the electronic properties of these phytophenols were studied and correlated with their antioxidant activities. It appears that these phytophenols can be used as antioxidants in vitro and in vivo to protect living systems from dangerous ROS. Graphical abstract Antioxidant reaction of carvacrol with OH. and .O-2 radicals.

A Comprehensive Study on Pyrolysis Mechanism of Substituted β-O-4 Type Lignin Dimers.

In order to understand the pyrolysis mechanism of β-O-4 type lignin dimers, a pyrolysis model is proposed which considers the effects of functional groups (hydroxyl, hydroxymethyl and methoxyl) on the alkyl side chain and aromatic ring. Furthermore, five specific β-O-4 type lignin dimer model compounds are selected to investigate their integrated pyrolysis mechanism by density functional theory (DFT) methods, to further understand and verify the proposed pyrolysis model. The results indicate that a total of 11 pyrolysis mechanisms, including both concerted mechanisms and homolytic mechanisms, might occur for the initial pyrolysis of the β-O-4 type lignin dimers. Concerted mechanisms are predominant as compared with homolytic mechanisms throughout unimolecular decomposition pathways. The competitiveness of the eleven pyrolysis mechanisms are revealed via different model compounds, and the proposed pyrolysis model is ranked in full consideration of functional groups effects. The proposed pyrolysis model can provide a theoretical basis to predict the reaction pathways and products during the pyrolysis process of β-O-4 type lignin dimers.