Heterolytic Mechanism Research Articles

General alkyl fluoride functionalization via short-lived carbocation-organozincate ion pairs

Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp2)-C(sp3) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force. This would be mechanistically different from previously reported radical reactions and overcome long-standing limitations of organometallic cross-coupling methodology, including competing β-hydride elimination, homodimerization and hydrodefluorination. Here, we show a practical Csp3-F bond functionalization method that expands the currently restricted synthetic space of unactivated primary, secondary and tertiary C(sp3)-F bonds but also uses benzylic, propargylic and acyl fluorides. Many functional groups and sterically demanding substrates are tolerated, which allows practical carbon-carbon bond formation and late-stage functionalization.

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.

Identifying the Activity Origin of a Single-Atom Au1/Nb2O5 Catalyst for Hydrodeoxygenation of Methylcatechol: A Stable Substitutional Au+ Site

Developing effective and stable single-atom catalysts (SACs) is a significant but challenging task, which requires the identification of single-atom metal sites and their configurations. Herein, we report a single-atom Au1/Nb2O5 catalyst for the hydrodeoxygenation of methylcatechol, a lignin model compound, which maintains stability in five consecutive conversions. Combined with the density functional theory (DFT) calculations, the Au+ located at the Nb lattice site with two concomitant oxygen vacancies (Au@Nbv–2Ov) is identified as the thermodynamically favorable Au single-atom species and dominates the activity for molecular H2 dissociation via a heterolytic mechanism. Moreover, the presence of oxygen vacancies in Au@Nbv–2Ov facilitates the adsorption of methylcatechol, resulting in efficient cleavage of C–O bonds. Consequently, we design a catalyst with more Au+ sites, which exhibits enhanced catalytic activity. This work systematically elucidates the structure–activity relationship and provides a promising strategy to optimize SACs for the hydrodeoxygenation reaction.

Direct B-H Functionalization of Icosahedral Carboranes via Hydrogen Atom Transfer.

The efficient and selective functionalization of icosahedral carboranes (C2B10H12) at the boron vertexes is a long-standing challenge owing to the presence of 10 inert B-H bonds in a similar chemical environment. Herein, we report a new reaction paradigm for direct B-H functionalization of icosahedral carboranes via B-H homolysis enabled by a nitrogen-centered radical-mediated hydrogen atom transfer (HAT) strategy. Both the HAT process of the carborane B-H bond and the resulting boron-centered carboranyl radical intermediate have been confirmed experimentally. The reaction occurs at the most electron-rich boron vertex with the lowest B-H bond dissociation energy (BDE). Using this strategy, diverse carborane derivatization, including thiolation, selenation, alkynylation, alkenylation, cyanation, and halogenation, have been achieved in satisfactory yields under a photoinitiated condition in a metal-free and redox-neutral fashion. Moreover, the synthetic utility of the current protocol was also demonstrated by both the scale-up reaction and the construction of carborane-based functional molecules. Therefore, this methodology opens a radical pathway to carborane functionalization, which is distinct from the B-H heterolytic mechanism in the traditional strategies.

Applications of Bond Energy‐Based Thermodynamic Analysis to the Feasibility of Unfunctionalized C−C Cross‐Coupling Reactions

AbstractCarbon‐Carbon bond forming reactions are ubiquitous in nature and important for chemical and drug synthesis. Modern methods mostly utilize activated reactants, and despite recent developments in organic synthesis, and theoretical understanding, these have had limited success with unactivated C−H bonds. Here we apply a simple yet powerful Bond Dissociation Energy (BDE)‐based Reaction Enthalpy (BDERE) analysis to model C−C cross‐coupling reactions. BDERE appears in classical textbooks (halogenation of alkanes) but has not been applied to cross‐coupling reactions. BDERE allows one to rationalize the ease of coupling reactions for both homolytic and heterolytic mechanisms for all six C−C bond hybridization types. It facilitates the identification of a simple but unexplored reaction for ethane synthesis. BDERE values give valuable insights into recent advancements in C−C cross‐couplings of fully unfunctionalized (UFCC) and semi‐functionalized (SFCC) reactants that utilize metal, photoredox, organo, and biocatalysis. BDERE analysis may enable others to investigate and design novel cross‐coupling reactions.

How Do Metalloproteins Tame the Fenton Reaction and Utilize •OH Radicals in Constructive Manners?

This Account describes the manner whereby nature controls the Fenton-type reaction of O-O homolysis of hydrogen peroxide and harnesses it to carry out various useful oxidative transformations in metalloenzymes. H2O2 acts as the cosubstrate for the heme-dependent peroxidases, P450BM3, P450SPα, P450BSβ, and the P450 decarboxylase OleT, as well as the nonheme enzymes HppE and the copper-dependent lytic polysaccharide monooxygenases (LPMOs). Whereas heme peroxidases use the Poulos-Kraut heterolytic mechanism for H2O2 activation, some heme enzymes prefer the alternative Fenton-type mechanism, which produces •OH radical intermediates. The fate of the •OH radical is controlled by the protein environment, using tight H-bonding networks around H2O2. The so-generated •OH radical is constrained by the surrounding H-bonding interactions, the orientation of which is targeted to perform H-abstraction from the Fe(III)-OH group and thereby leading to the formation of the active species, called Compound I (Cpd I), Por+•Fe(IV)═O, which performs oxidation of the substrate. Alternatively, for the nonheme HppE enzyme, the O-O homolysis catalyzed by the resting state Fe(II) generates an Fe(III)-OH species that effectively constrains the •OH radical species by a tight H-bonding network. The so-formed H-bonded •OH radical acts directly as the oxidant, since it is oriented to perform H-abstraction from the C-H bond of the substrate (S)-2-HPP. The Fenton-type H2O2 activation is strongly suggested by computations to occur also in copper-dependent LPMOs and pMMO. In LPMOs, the Cu(I)-catalyzed O-O homolysis of the H2O2 cosubstrate generates an •OH radical that abstracts a hydrogen atom from Cu(II)-OH and forms thereby the active species of the enzyme, Cu(II)-O•. Such Fenton-type O-O activation can be shared by both the O2-dependent activations of LPMOs and pMMOs, in which the O2 cosubstrate may be reduced to H2O2 by external reductants. Our studies show that, generally, the H2O2 activation is highly dependent on the protein environment, as well as on the presence/absence of substrates. Since H2O2 is a highly flexible and hydrophilic molecule, the absence of suitable substrates may lead to unproductive binding or even to the release of H2O2 from the active site, as has been suggested in P450cam and LPMOs, whereas the presence of the substrate seems to play a role in steering a Fenton-type H2O2 activation. In the absence of a substrate, the hydrophilic active site of P450BM3 disfavors the binding and activation of H2O2 and protects thereby the enzyme from the damage by the Fenton reaction. Due to the distinct coordination and reaction environment, the Fenton-type H2O2 activation mechanism by enzymes differs from the reaction in synthetic systems. In nonenzymatic reactions, the H-bonding networks are quite dynamic and flexible and the reactivity of H2O2 is not strategically constrained as in the enzymatic environment. As such, our Account describes the controlled Fenton-type mechanism in metalloenzymes, and the role of the protein environment in constraining the •OH radical against oxidative damage, while directing it to perform useful oxidative transformations.

Unveiling the reactions of triethylphosphite and its diethylamino substituted derivatives to carbon tetrachloride with a molecular electron density theory perspective

A molecular electron density theory study is presented herein for the reactions of triethylphosphite (TEP) and its diethylamino substituted derivatives (DEAP and MEAP) to carbon tetrachloride (CCl4). Analysis of the Electron localization function (ELF) has allowed characterizing the electronic structure of the reagents and the conceptual density functional theory (CDFT) study predicted the polar character of the reactions with the electronic flux from TEP, DEAP and MEAP to CCl4. Analysis of the relative energies along the potential energy surfaces has indicated energetically favoured attack on the chlorine atom of CCl4 relative to that on the carbon atom and the reactions became energetically more facile due to introduction of the electron donating diethylamino substituent. This allowed formulating the heterolytic mechanism of the reactions in which the quick exchange of CCl3- with the chlorine atom takes place for TEP, while the exchange is slowed down in DEAP and MEAP due to mesomeric stabilization of the phosphonium ion. The ELF and Atoms in molecules (AIM) studies indicated early transition states (TSs) with no new covalent bond formation, and the non-covalent interactions at the interatomic bonding regions of the TSs are analysed from the Independent Gradient Model (IGM) analysis based on the Hirshfield partition of electron density.

Cu/O Frustrated Lewis Pairs on Cu Doped CeO2(111) for Acetylene Hydrogenation: A First-Principles Study

In this work, the H2 dissociation and acetylene hydrogenation on Cu doped CeO2(111) were studied using density functional theory calculations. The results indicated that Cu doping promotes the formation of oxygen vacancy (Ov) which creates Cu/O and Ce/O frustrated Lewis pairs (FLPs). With the help of Cu/O FLP, H2 dissociation can firstly proceed via a heterolytic mechanism to produce Cu-H and O-H by overcoming a barrier of 0.40 eV. The H on Cu can facilely migrate to a nearby oxygen to form another O-H species with a barrier of 0.43 eV. The rate-determining barrier is lower than that for homolytic dissociation of H2 which produces two O-H species. C2H2 hydrogenation can proceed with a rate-determining barrier of 1.00 eV at the presence of Cu-H and O-H species., While C2H2 can be catalyzed by two O-H groups with a rate-determining barrier of 1.06 eV, which is significantly lower than that (2.86 eV) of C2H2 hydrogenated by O-H groups on the bare CeO2(111), showing the high activity of Cu doped CeO2(111) for acetylene hydrogenation. In addition, the rate-determining barrier of C2H4 further hydrogenated by two O-H groups is 1.53 eV, much higher than its desorption energy (0.72 eV), suggesting the high selectivity of Cu doped CeO2(111) for C2H2 partial hydrogenation. This provides new insights to develop effective hydrogenation catalysts based on metal oxide.

Electrochemically Modeling a Nonelectrochemical System: Hydrogen Peroxide Direct Synthesis on Palladium Catalysts.

Nonelectrochemical hydrogen peroxide direct synthesis (HPDS) under ambient conditions is an environmentally benign and energy-efficient process that produces a green oxidizer, yet the reaction mechanism of HPDS is still controversial. Inspired by the recently suggested heterolytic mechanism that involves electron and proton transfer at Pd catalysts, we propose a new electrochemical density functional theory (DFT) model that combines the Butler-Volmer equation and constant-potential DFT with hybrid explicit-implicit solvent treatment. Application of this model to Pd surfaces showed that the heterolytic mechanism has a lower barrier for the protonation steps for H2O2 production than for the nonelectrochemical hydrogenation steps, leading to advantageous kinetics for H2O2 production over H2O production, while the conventionally accepted Langmuir-Hinshelwood mechanism fails to explain the experimental kinetics. This work resolves the unanswered discrepancies between previous experimental and DFT results, and we expect that these results will readily help the systematic development of improved catalysts for HPDS.

Dehydration Leads to Hydrocarbon Gas Formation in Thermal Degradation of Gas-Phase Polyalcohols

To understand the molecular mechanisms of hydrocarbon gas formation in biomass gasification, gasification of simple polyalcohols (glycerol, propylene glycol, and ethylene glycol) were studied at 400, 600, and 800 °C (residence times: 0.9–1.4 s) from the viewpoint of dehydration reactions that form aldehydes with various substituents as intermediates to produce hydrocarbon gases. The results were also compared with those of glyceraldehyde and dihydroxyacetone, which are reported to produce syngas (H2 and CO) selectively. All polyalcohols became reactive at 600 °C to form condensable products in 15.7–24.7% yields (C-based), corresponding to 33.9–38.4% based on the amounts of reacted polyalcohols. These condensable products, mostly aldehydes, act as gas-forming intermediates, because the polyalcohols were completely gasified at 800 °C (hydrocarbon gas contents: 20.3–35.3%, C-based). Yields of the intermediates bearing alkyl groups at 600 °C were proportionally correlated to the yields of hydrocarbon gases at 800 °C, suggesting that the alkyl groups are further converted into hydrocarbon gases via the fragmentation of acyl radicals. Dehydration reactions were suggested to occur in both heterolytic and radical mechanisms by theoretical calculations. Glyceraldehyde tended to fragment directly into CO and H2, instead of forming a dehydration intermediate. These results are informative for controlling the product gas composition in biomass gasification.

Structural changes in lignin of thermally treated eucalyptus wood

Changes in the lignin structure of eight eucalypt species (E. botryoides, E. globulus, E. grandis, E. maculata, E. propinqua, E. rudis, E. saligna, and E. viminalis) upon mild thermal treatment, where the temperature was gradually raised from 160 to 230 °C over 3 h, were studied by solid-state carbon nuclear magnetic resonance (13C NMR) and after lignin isolation from the wood by acidolysis employing liquid-state 1D and 2D NMR techniques. The molecular weight of the isolated lignins was assessed by size exclusion chromatography (SEC) and their composition by analytic pyrolysis coupled with gas chromatography and mass spectrometry (Py-GC/MS). The thermal treatment induced in lignin partial demethylation (up to ca. 30% from total) and a remarkable reduction in β-O-4 structures (up to ca. 60%), in an extent depending on the ratio of syringyl and guaiacyl units of the specific lignins. The lignin molecular weight reduced only ca. 25% under the thermal treatment due to the likely occurrence of condensation reactions by homolytic and heterolytic mechanisms. The noticeable increase in phenylcoumaran (β-5) and pinoresinol/syringaresinol (β-β) structures in lignin after thermal treatment was tentatively explained by their relative thermal resistance and by newly formed structures as the result of radical coupling reactions occurred during homolytic dissociation of the β-O-4 linkages. Lignins in thermally treated wood contained more than twice phenolic hydroxyls and more aliphatic carboxyl groups than lignins in untreated wood.

Bis(pentafluorophenyl)phenothiazylborane - an intramolecular frustrated Lewis pair catalyst for stannane dehydrocoupling.

We synthesized a novel Lewis acidic aminoborane containing a phenothiazyl substituent and demonstrated its potential to catalytically promote the dehydrocoupling of tin hydrides. The observed reactivity would imply a homolytic frustrated Lewis pair type mechanism, however computational analysis suggests a heterolytic mechanism for this reaction. This result represents one of the first frustrated Lewis pair systems to dehydrocouple stannanes in a heterolytic fashion.

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.

The nature of Ni-O pairs for ethane activation on NiO(100) and NiO(110) surfaces

We investigated the activation of ethane on NiO(100) and NiO(110) surfaces with O vacancy or Ni vacancy. Our work demonstrates the role of Ni-O pairs for ethane activation on NiO(100) and NiO(110) surfaces. Ni-O pairs serve as the active sites for ethane dissociation, which proceeds via a heterolytic mechanism with acid-base interaction. Ethane activation is strongly preferred on NiO(110) surface than that on NiO(100) surface. The existence of O vacancy or Ni vacancy on NiO(100) surfaces has positive influence on C–H bond cleavage. But on NiO(110) surface, the presence of O vacancy or Ni vacancy may suppress the dissociation of ethane. This behavior is due to the reactivity of different Ni-O pairs. Hydrogen chemisorption, C2H5 chemisorption and bond strength may serve as potential descriptors for the nature of active sites. Based on the results of present work, it can be inferred that the strong chemisorption of hydrogen and C2H5 combined with the weaker bond strength of Ni-O pair can facilitate C–H bond cleavage and lower the barrier of ethane dissociation. Thus, surface is highly active toward ethane activation.

Inflammatory markers and cognitive performance in patients with schizophrenia treated with lurasidone

We investigated the activation of ethane on NiO(100) and NiO(110) surfaces with O vacancy or Ni vacancy. Our work demonstrates the role of Ni-O pairs for ethane activation on NiO(100) and NiO(110) surfaces. Ni-O pairs serve as the active sites for ethane dissociation, which proceeds via a heterolytic mechanism with acid-base interaction. Ethane activation is strongly preferred on NiO(110) surface than that on NiO(100) surface. The existence of O vacancy or Ni vacancy on NiO(100) surfaces has positive influence on C–H bond cleavage. But on NiO(110) surface, the presence of O vacancy or Ni vacancy may suppress the dissociation of ethane. This behavior is due to the reactivity of different Ni-O pairs. Hydrogen chemisorption, C2H5 chemisorption and bond strength may serve as potential descriptors for the nature of active sites. Based on the results of present work, it can be inferred that the strong chemisorption of hydrogen and C2H5 combined with the weaker bond strength of Ni-O pair can facilitate C–H bond cleavage and lower the barrier of ethane dissociation. Thus, surface is highly active toward ethane activation.

Quantitative and Mechanistic Mechanochemistry in Ferrocene Dissociation.

Ferrocene is classically regarded as being highly inert owing to the large dissociation energy of metal-cyclopentadienyl (Cp) bonds. We show that the Fe-Cp bond in ferrocene is the preferential site of mechanochemical scission in the pulsed ultrasonication of main-chain ferrocene-containing polybutadiene-derived polymers. Quantitative studies reveal that the Fe-Cp bond is similar in strength to the carbon-nitrogen bond of an azobisdialkylnitrile (bond dissociation energy < -0 kcal/mol), despite the significantly higher Fe-Cp bond dissociation energy (approximately 90 kcal/mol). Mechanistic studies are consistent with a predominately heterolytic mechanism of chain scission. DFT calculations provide insights into the origins of ferrocene's mechanical lability.

Radical Deoxychlorination of Cesium Oxalates for the Synthesis of Alkyl Chlorides.

A radical deoxychlorination of cesium oxalates has been developed for the preparation of hindered secondary and tertiary alkyl chlorides. The reaction tolerates a number of functional groups, including ketones, alcohols, and amides, and provides complementary reactivity to standard deoxychlorination reactions proceeding by heterolytic mechanisms. Preliminary studies demonstrate that the developed conditions can also be applied to deoxybromination and deoxyfluorination reactions.

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.