H-atom Transfer Mechanism Research Articles

Structure and Reactivity of Alloxan Monohydrate in the Liquid Phase.

Alloxan is an important toxic glucose analogue used to induce diabetes in lab test animals. Once regarded as a "problem structure," the condensed-phase structure of anhydrous alloxan has largely been settled, but literature inconsistencies remain for the structure of the typically employed reagent alloxan monohydrate. Due to the criticality of structure-function relationships, we have used 1H/13C{1H} NMR, IR spectroscopy, as well as quantum mechanical (QM) calculations to probe the liquid-phase structure and reactivity of alloxan monohydrate. In protic solvents (D2O and acetic acid-d4), hydration at the C5 carbonyl of alloxan monohydrate occurs quantitatively to form the C5 gem-diol (5,5'-dihydroxybarbituric acid). In the aprotic solvent dimethyl sulfoxide (DMSO)-d6, there exists a mixture of the C5 gem-diol and planar tetraketo form of alloxan monohydrate. QM calculations explain the solvent-dependent hydration reactivity, where a solvent-assisted H-atom transfer mechanism lowers the activation energy of water addition at the C5 carbonyl by ∼16 or 27 kcal/mol in water or acetic acid, respectively, compared to the unassisted hydration reaction. Prompt recrystallization of alloxan monohydrate from boiling water does not alter the structure of the reagent. These findings probe the exact structure of alloxan monohydrate to guide future research efforts in biological sciences and in organic synthesis.

Antioxidative and α-glucosidase inhibitory constituents of Polyscias guilfoylei: experimental and computational assessments.

Searching for bioactive agents from medicinal plants, eleven constituents were isolated from Polyscias guilfoylei stem for the first time, including a nucleoside uracil (1), two sterols β-sitosterol (2) and daucosterol (3), a saponin androseptoside A (4), two lignans (+)-pinoresinol (5) and (+)-syringaresinol (6), four phenolic acids protocatechuic acid (7), methyl protocatechuate (8), caffeic acid (9), and 5-O-caffeoylquinic acid (10), and a flavonoid quercitrin (11). Metabolites 1, 4, and 6-11 have never been observed in genus Polyscias before. Phenolic compounds 7 and 9 possessed the respective IC50 values of 21.33 and 13.88µg/mL in DPPH (2,2-diphenyl-1-picrylhydrazyl) antioxidative assay, as compared with that of the positive control resveratrol (IC50 = 13.21µg/mL). From density functional theory (DFT) calculated approach, the DPPH free radical scavenging capacity of two compounds 7 and 9 can be explained by the role of OH groups at carbons C-3 and C-4. Antioxidative actions of these two potential agents are followed HAT (H atom transfer) mechanism by OH bond disruption in gas, but SPLET (sequential proton loss electron transfer) mechanism in solvents water and methanol. Compared to 4-OH group, 3-OH group showed better bond disruption enthalpies and better kinetic energies since it reacted with HOO• and DPPH radicals. Sterols 2-3 and flavonoid 11 induced the IC50 values of < 2.0µg/mL better than the positive control acarbose (IC50 = 184.0µg/mL) in α-glucosidase inhibitory assay. Their interactions with human intestinal C- and N-terminal domains of α-glucosidase were explored using molecular docking study. The obtained results proved that compounds 2, 3, and 11 bind relatively stronger with the C-terminal domain than to the N-terminal domain through pivotal residues in the binding site and could be hypothesized as mixed inhibitors.

Enantioselective radical C-H amination for the synthesis of β-amino alcohols.

Asymmetric, radical C–H functionalizations are rare, yet powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regio-selective C–H amination of alcohols to access medicinally valuable, chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol is transiently converted to an imidate radical that undergoes intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C–H amination enables broad access to chiral β-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl, and propargyl C–H bonds. Mechanistic experiments reveal triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity – enabling the synthesis of several important classes of chiral β-amines by enantioselective, radical C–H amination.

Photoprotective properties of natural antioxidant flavonoids: A DFT and TD‐DFT study on acridone derivatives

AbstractAntioxidant and photoprotective properties of two natural acridone derivatives namely Paratrimerin C (1) and Citrusinine‐I (2) have been studied by DFT and TD‐DFT at the M05‐2X/6‐311++G(3df, 3p)//M05‐2X/6‐31+G(d) level of theory. Three common mechanisms characterized for the antioxidant properties including H‐atom transfer (HAT) and proton transfer (PT) towards HOO●/HO● radicals and single electron transfer (SET) were investigated in the gas phase, water and pentyle thanoate. The DFT results revealed that both compounds can efficiently scavenge HOO● and HO● radicals via HAT mechanism in all media. Particularly, the HAT reactions of 2 with HO● radical in water are the most favored reaction (∆H ‐37.7 kcal/mol). In addition, the efficient UV‐absorption ability of the studied compound was elucidated by TD‐DFT. All compounds can absorb UV radiations in the range of 200‐335 nm, for which the easiest excitations are at 334‐332 nm and the strongest absorptions were found at 234‐227 nm, for 1 and 2, respectively. The HOMO to LUMO and HOMO‐3 to LUMO (π‐π*) transitions are assigned for the corresponding UV‐absorption.

Experimental and theoretical studies of the doubly substituted methyl-ethyl Criegee intermediate: Infrared action spectroscopy and unimolecular decay to OH radical products.

The infrared (IR) action spectrum of the doubly substituted methyl-ethyl Criegee intermediate (MECI) is observed in the CH stretch overtone region with detection of OH products. The MECI exhibits four conformers, all of which undergo unimolecular decay via a 1,4 H-atom transfer mechanism, followed by the rapid release of OH products. Conformers with different orientations of the carbonyl oxide group with respect to the methyl and ethyl substituents (i.e., anti and syn) decay via distinct transition state barriers (16.1 kcal mol-1 and 15.4 kcal mol-1, respectively). The observed IR action spectrum is in good agreement with the predicted anharmonic IR absorption spectrum, but exhibits significant congestion, which is attributed to couplings between spectroscopic bright states and nearby dark states. Energy-dependent OH appearance rates are measured upon IR excitation of the strongest features in the IR action spectrum and are found to be on the order of 106-107 s-1. The experimental rates are in good agreement with computed Rice-Ramsperger-Kassel-Marcus rates for the unimolecular decay of MECI at these energies, which incorporate quantum mechanical tunneling and sophisticated hindered rotor treatments, as well as high-level theoretical calculations of the TS barrier heights, rovibrational properties, and torsional barriers associated with the MECI conformers. Master equation modeling is used to predict thermal rates for the unimolecular decay of anti- and syn-MECI of 473 s-1 and 660 s-1, respectively. Comparison with other previously studied Criegee intermediate systems provides insights into substituent effects on unimolecular decay under both energy-dependent and thermal conditions.

Photocatalytic debromination of polybrominated diphenyl ethers (PBDEs) on metal doped TiO2 nanocomposites: Mechanisms and pathways

Nanoparticles of four noble metal doped titanium dioxide (i.e., Pd/TiO2, Ag/TiO2, Pt/TiO2 and Cu/TiO2) were synthesized and investigated for their effectiveness to degrade polybrominated diphenyl ethers (PBDEs) under UV light. All the investigated noble metal additives can greatly enhance the performance of TiO2 to degrade 2,2′,4′,4′-tetrabromodiphenyl ether (BDE-47). However, the debromination pathways of BDE-47 in Ag/TiO2 and Cu/TiO2 systems are just contrary to those in Pd/TiO2 and Pt/TiO2 systems, and there was an induction period in the former systems but not in the latter systems. The hydrogenation experiment suggests a direct H-atom transfer mechanism in Pd/TiO2 and Pt/TiO2 systems, while in Ag/TiO2 and Cu/TiO2 systems, electron transfer is still the dominant mechanism. Electronic method was applied to explain why BDE-47 exhibit different debromination pathways based on different degradation mechanism. In addition, oxygen was proved to be able to capture both electrons and H atoms, and thus can greatly inhibit the degradation of PBDEs in all investigated systems. Finally, the merit and demerit of each metal doped TiO2 were discussed in detail, including the reactivity, stability and the generation of byproducts. We proposed our study greatly enhance our understanding on the mechanisms of PBDE degradation in various metal doped TiO2 systems.

Catalytic β C-H amination via an imidate radical relay.

The first catalytic strategy to harness imidate radicals for C-H functionalization has been developed. This iodine-catalyzed approach enables β C-H amination of alcohols by an imidate-mediated radical relay. In contrast to our first-generation, (super)stoichiometric protocol, this catalytic method enables faster and more efficient reactivity. Furthermore, lower oxidant concentration affords broader functional group tolerance, including alkenes, alkynes, alcohols, carbonyls, and heteroarenes. Mechanistic experiments interrogating the electronic nature of the key 1,5 H-atom transfer event are included, as well as probes for chemo-, regio-, and stereo-selectivity.

Debromination of polybrominated biphenyls (PBBs) by zero valent metals and iron-based bimetallic particles: Mechanisms, pathways and predicting descriptor

Polybrominated biphenyls (PBBs) are toxic and persistent brominated flame retardant. Yet their debromination by zero valent metal (ZVM) or iron based bimetals has received far less attention. Here we reported the kinetics and debromination pathways of PBBs in nanoscale zerovalent iron (n-ZVI), microscale zerovalent zinc (m-ZVZ), n-ZVI/Ag and n-ZVI/Pd systems. The results show that the singly occupied molecular orbital (SOMO) of PBB anion can be well correlated with the debromination pathways of PBBs by n-ZVI, which verify its ability to predict their debromination pathways through electron transfer (e-transfer) mechanism. We also found that the reaction rates of PBBs in m-ZVZ, n-ZVI/Ag and n-ZVI/Pd systems are much faster than that in n-ZVI system, and the debromination pathways of PBBs in n-ZVI, m-ZVZ and n-ZVI/Ag are exactly the same, suggesting that n-ZVI/Ag debrominate PBBs through an e-transfer mechanism. However, Pd was found to be able to utilize H2 to debrominate PBBs and the debromination pathways of PBBs in Pd-H2 system was the same to those in n-ZVI/Pd system, but was partially different from those in n-ZVI, m-ZVZ and n-ZVI/Ag systems, suggesting that n-ZVI/Pd debrominate PBBs through a H-atom transfer mechanism.

Structure, antioxidative potency and potential scavenging of OH[rad] and OOH[rad] of phenylethyl-3,4-dihydroxyhydrocinnamate in protic and aprotic media: DFT study

DFT methods including B3LYP, B3PW91 and M05–2x associated to 6–31+G(d,p) were used for the structural and antioxidant potency studies of phenylethyl-3,4-dihydroxy-hydrocinnamate (PDH). Solvents were employed according to their protric and aprotic character. So, calculated structures agree with the experimental data. O4H4 is propitious to scavenge radicals whatever the medium except in water where O3H3 and O4H4 are competitive. The explicit solvents of dichloromethane (DCM) and water present a disparity of OH bond dissociation enthalpy and free energy (BDE and BDFE). These parameters are low in continuum except in water. The ionization potentials (IP) and potential affinities (PA) are low in solvents. BDE, IP and PA are each, approximatively constant in mixed solvent treatment in water using n-H2O (n=3,5,8). Elsewhere, H-atom transfer (HAT) mechanism is favoured in vacuum and DCM, whereas sequential proton loss electron transfer (SPLET) is likely in protic solvents. A discord between HAT and SPLET in benzene is observed. The PDH compound is more antioxidant and resistant to oxidation than caffeic acid phenethyl ester (CAPE). The potential of scavenging of OH and OOH whatever the reaction channel shows that they decay rapidly in any media through HAT. PDH is easily deprotonated in the protic solvents and the resulting product is the most antioxidant and the least resistant to oxidation.

The degradation mechanism of sulfamethoxazole under ozonation: a DFT study.

Sulfamethoxazole (SMX), a kind of antibiotic, remains in the environment and threatens public health. Ozone as a strong and green oxidant was widely used for selective oxidation degradation of residual SMX. However, it is hard to elucidate the detailed oxidation mechanism through current experimental approaches. A theoretical study has been carried out herein for exploring possible ozonation pathways of SMX. Two reaction mechanisms, viz., direct addition (DA) and H atom transfer (HAT), are considered. The results show that the primary oxidation of aromatic rings (benzene or isoxazole rings) of SMX follows the DA mechanism, featuring an electrophilic addition. Whereas, the oxidation of amino and methyl groups of SMX follows the HAT mechanism. Following the proposed mechanisms, the primary oxidation products detected in previous experiments could reasonably be obtained according to the current calculations. More importantly, O3 molecules as an electrophilic agent feasibly attack the moiety having a large orbital contribution to the highest occupied molecular orbital (HOMO) of sulfonamides. This result suggests that the primary ozonation site of sulfonamides could be theoretically predictable through the information of their frontier molecular orbitals. Meanwhile, a positive correlation between the O3-mediated HAT energy barriers and bond dissociation energies has been found for N-H and C-H bond oxidations.

Antioxidant activities of [60]fullerene derivatives from chalcone, flavone and flavanone: A ONIOM approach via H-atom and electron transfer mechanism

Antioxidant properties of C60 flavonoid conjugates were computationally examined via their O–H bond dissociation enthalpies (BDEs) and ionization energies (IEs) using two-layer ONIOM and PM6 methods, respectively. Eight ONIOM((RO)B3LYP/6-311++G(2df,2p):PM6) models were evaluated by computing BDE(O–H)s of a series of polyphenol. Synthetic mechanism of C60 flavonoid conjugates was also explored via the potential energy surfaces of reaction between C60 and malonate flavonoid derivatives (chalcone, flavone and flavanone) at the B3LYP/6-31G(d)//PM6. Antioxidant activities of C60 flavonoid conjugates were discussed via hydrogen atom transfer, single electron transfer mechanisms and the effect of C60 on the BDE(O–H)s and IEs of these compounds.

Photochemistry and Photobiology of the Spore Photoproduct: A 50-Year Journey.

Fifty years ago, a new thymine dimer was discovered as the dominant DNA photolesion in UV-irradiated bacterial spores [Donnellan, J. E. & Setlow R. B. (1965) Science, 149, 308-310], which was later named the spore photoproduct (SP). Formation of SP is due to the unique environment in the spore core that features low hydration levels favoring an A-DNA conformation, high levels of calcium dipicolinate that acts as a photosensitizer, and DNA saturation with small, acid-soluble proteins that alters DNA structure and reduces side reactions. In vitro studies reveal that any of these factors alone can promote SP formation; however, SP formation is usually accompanied by the production of other DNA photolesions. Therefore, the nearly exclusive SP formation in spores is due to the combined effects of these three factors. Spore photoproduct photoreaction is proved to occur via a unique H-atom transfer mechanism between the two involved thymine residues. Successful incorporation of SP into an oligonucleotide has been achieved via organic synthesis, which enables structural studies that reveal minor conformational changes in the SP-containing DNA. Here, we review the progress on SP photochemistry and photobiology in the past 50 years, which indicates a very rich SP photobiology that may exist beyond endospores.

Antioxidative Potency and UV–Vis spectra features of the compounds resulting from the chelation of Fe2+ by Caffeic Acid Phenethyl Ester and two of its derivatives

Chelation of the solvated iron (II) cation (Fe(H2O)62+ and Fe(CH3OH)62+) by Caffeic Acid Phenethyl Ester (CAPE), 3-Methyl-2-Butenyl Caffeate (MBC) and Benzoic Caffeate (BC) has been investigated through the ONIOM(B3LYP/6-31G(d,p):UFF) calculation and 6-31+G(d) set for Fe2+. The chelates (Fe(CAPE)2+, Fe(MBC)2+ and Fe(BC)2+) were treated by the density functional theory (DFT) calculation and the four ligands (H2O or CH3OH) around the iron were treated by UFF calculation. Time dependent (TD-DFT) calculations were used to reproduce the electronic UV–Vis spectra of chelates. In the thermodynamic point of view, the results indicated that the chelation of Fe2+ by the three molecules was spontaneous and that MBC got the best capacity to chelate Fe2+. The complexes are more antioxidant than the free molecules (CAPE, MBC and BC). The CH3OH molecules appear as the good ligands to enhance the antioxidant efficiency of chelates. Elsewhere the homolytic H-atom transfer (HAT) mechanism was the likely HO2 radical scavenging process compared to the sequential ones. Therefrom the chelates without ligands were the best antioxidant. Considering the ligands, the chelates of CH3OH were the best antioxidant, mostly Fe(MBC)(CH3OH)42+. However the scavenging of the ionic radical O2− foresaw that the proton transfer followed by electron transfer (PT–ET) mechanism was the preferred process. This kept the antioxidant potency analyses of HAT mechanism. Moreover, the chelates absorbed the red and the infrared radiations confirming the quality of the antioxidative potency of chelates.

Antiradical potential of phenolic compounds fingerprints of propolis extracts: DFT approach

Phenolic compounds are the major chemical constituents of propolis extracts (PE) and are characterized by possessing antiradical activity. In this work the structure-antiradical properties relationship of flavonoids (chrysin, galangin, pinocembrin and pinostrobin) and phenolic acid (caffeic acid phenethyl ester) commonly found in PE was investigated trough M05-2X functional in conjunction with the 6-31G(d,p) and 6-31+G(d,p) basis sets, considering the structural properties, and free-radical inhibition mechanism: H-atom transfer (HAT), the stepwise electron-transfer–proton-transfer (SPLET) and the sequential proton loss electron transfer (SET–PT). To complement the ability of phenolic compounds to act as antiradical the chemical indexes and Fukui indexes were analyzed. Thermodynamically, the HAT mechanism contributes much in the antiradical activity of reactive group (O–H and C–H) of phenolic compounds. All compounds present a greater tendency to give electrons than to attract them. We found different reactive sites for nucleophilic, electrophilic and radical attack in molecules, which could mark differences in their antiradical activity.

On the role of ethylene bridge elongation in the antioxidant activity of polyhydroxylated stilbenes: A theoretical approach

Abstract The aim of this work is to investigate the elongation effect of the conjugated links of the 7–8 double bond of trans -resveratrol and its analogs on the antioxidant activity in vacuo and water using a quantum chemistry calculation by the Density Functional Theory (DFT) method. H atom transfer (HAT), single-electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) mechanisms were investigated. The highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), and the spin density were calculated. The results reveal that the elongation of the conjugated links plays an important role in promoting the antioxidant properties of molecules because of its lowering effect on BDE, spin density, AIP, and PA values. The higher antioxidant activity of 3,4 dihydroxystilbene (A 4 ) and trans , trans -3,4-dihydroxybistyryl (B 4 ) may be from the abstraction of the hydrogen atoms of the ortho-position hydroxyls. This abstraction can occur continuously to form a semiquinone structure, or even a quinone structure. On the other hand, the compounds bearing the 4,4′-DHS skeleton exhibit strong antioxidant activity due to their para-quinone structure. The results indicate correspondences between the theoretical and the experimental results. Moreover, our calculations suggest that the HAT mechanism is the most important and dominant mechanism in vacuo, the SPLET mechanism is the most thermodynamically favourable pathway in water, while the SET–PT mechanism is not preferred in all the environments studied.

Homolytic and heterolytic O–H bond cleavage in trans-resveratrol and some phenantrene analogs: A theoretical study

In this article, quantum chemical calculations based on the density functional theory (DFT) have been used to study the relationship between the structure and the antioxidant activity of trans-resveratrol (RSV) and its phenantrene analogs in the gas phase, benzene and water. Our investigation includes H-atom transfer (HAT), single electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) mechanisms. The calculated values were in good agreement with the experimental results. Like other phenolic compounds, the H-atom transfer mechanism is the thermodynamically preferred mechanism in vacuum, for the studied molecules. While, the SPLET mechanism is the thermodynamically favorable pathway in water. Our calculations suggest that, SET–PT is not the most preferred mechanism in all environments studied.

Density functional theory study of the structure–antioxidant activity of polyphenolic deoxybenzoins

Quantum chemical calculations based on the density functional theory (DFT) have been employed to study the relationship between the structure and the antioxidant activity of four polyphenolic deoxybenzoins (DOBs) in solvents and the gas phase. The three main working mechanisms, H-atom transfer (HAT), single electron transfer–proton transfer (SET–PT) and sequential proton loss electron transfer (SPLET) have been investigated. The calculated results closely matched experimental values. The results obtained prove that for the HAT mechanism, the most efficient system possessed ortho-dihydroxy functionality. The results suggested that HAT would be the most favourable mechanism for explaining the radical-scavenging activity of polyphenolic DOBs in the gas phase, whereas the SPLET mechanism is the thermodynamically favourable pathway in polar solvents.

A comparative study on the antioxidant properties of bractein and cernuoside by the DFT method

Density functional theory was employed to investigate the molecular properties of two flavonoids, bractein and cernuoside, that serve as antioxidants. The B3LYP/6-311G** protocol was used for all computations. Investigations were performed in the gas phase and in two solvents with different polarity (water and benzene); the present work was devoted mainly to the determination of the O–H bond dissociation enthalpies and the ionization potentials of the examined compounds, since these quantities represent the most important parameters on which biological activity can be rationalized. The rotational energy of pyrogallol and catechol moieties together with highest occupied molecular orbital–lowest unoccupied molecular orbital and dipole moment analysis are reported for the two flavonoids. The present analysis also includes the spin density distribution for the radicals formed after H atom removal on each OH site of both flavonoids. The theoretical bond dissociation enthalpy values for these systems follow the same trend in gas and solvent phases. On the basis of computed bond dissociation enthalpy and ionization potential values, the most reactive system that is able to transfer an H-atom and electron transfer mechanism is found to be bractein followed by cernuoside. All these results suggest bractein to be a potential antioxidant similar to quercetin. .

Theoretical study on the antioxidant properties of 2′-hydroxychalcones: H-atom vs. electron transfer mechanism

The free radical scavenging activity of six 2'-hydroxychalcones has been studied in gas phase and solvents using the density functional theory (DFT) method. The three main working mechanisms, hydrogen atom transfer (HAT), stepwise electron-transfer-proton-transfer (ET-PT) and sequential-proton-loss-electron-transfer (SPLET) have been considered. The O-H bond dissociation enthalpy (BDE), ionization potential (IP), proton affinity (PA) and electron transfer energy (ETE) parameters have been computed in gas phase and solvents. The theoretical results confirmed the important role of the B ring in the antioxidant properties of hydroxychalcones. In addition, the calculated results matched well with experimental values. The results suggested that HAT would be the most favorable mechanism for explaining the radical-scavenging activity of hydroxychalcone in gas phase, whereas SPLET mechanism is thermodynamically preferred pathway in aqueous solution.

Investigation of the scavenging mechanism of tyrosyl radical by hydroxybenzohydroxamic acid derivatives: A DFT study

The free radical scavenging activity of a series of hydroxybenzohydroxamic acid derivatives have been studied in gas phase, water and benzene environments, using the density functional theory. Different mechanisms of reactions have been considered: single electron transfer (SET), hydrogen atom transfer (HAT). Rate constants were determined to know if the radical scavenging activity of these compounds proceeds via an H-atom or an electron-transfer mechanism. Calculations showed that the presence of the adjacent hydroxyl groups on phenyl ring increases the radical stability through intramolecular hydrogen bonds. The calculated bond dissociation enthalpy (BDE) values for hydroxyl groups on phenyl ring of studied compounds revealed the important role of resonance in stability of radical obtained from the hydrogen atom abstraction by free radical. Results show that the radical scavenging capacity of trimidox is more than the other molecules. The results demonstrate that the H-atom transfer mechanism for scavenging of free radical is more preferable than the single-electron transfer in considered environments.