Lowest Bond Dissociation Enthalpy Research Articles

On the antioxidant activity of ortho- and meta-substituted indolin-2-one derivatives

The antioxidant activity of ortho- and meta-substituted indolin-2-one derivatives was investigated in the gas phase and water. The reaction enthalpies of the individual steps of three antioxidant mechanisms of the studied derivatives were calculated and compared with the corresponding values of indolin-2-one. The results show that electron-withdrawing substituents increase the bond dissociation enthalpy and ionization potential, whereas electron-donating substituents increase the proton affinity. The indolin-2-one derivatives with the lowest bond dissociation enthalpy, ionization potential, and proton affinity values were identified as the compounds with high antioxidant activity. The results show that indolin-2-one derivatives with substituents in the ortho position are promising potential novel antioxidants. The results also show that the protective role of indolin-2-one derivatives occurs via hydrogen atom transfer and a sequential proton loss electron transfer mechanism in the gas phase and water, respectively. The calculated reaction enthalpies of the substituted indolin-2-ones are linearly dependent on the Hammett constants and E HOMO such that the latter can be utilized in the selection of suitable substituents for the synthesis of novel antioxidants based on indolin-2-one.

Predicting the substituent and solvent effects on the radical scavenger activity of ethoxyquin derivatives: a DFT/B3LYP study

The radical scavenger activity of X1- and X2-substituted ethoxyquin derivatives has been investigated in the gas phase and water. The reaction enthalpies of radical scavenger activity of the studied derivatives have been calculated and compared with corresponding values of ethoxyquin. Results show that electron-withdrawing group substituents increase the bond dissociation enthalpy and ionization potential, while electron-donating group substituents cause a rise in the proton affinity. The ethoxyquin derivatives with the lowest bond dissociation enthalpy, ionization potential, and proton affinity values were identified as the compounds with high radical scavenger activity. Results show that the substituents in the X1 position have high potential for synthesis of novel ethoxyquin derivatives. Results show that ethoxyquin derivatives can process their protective role via hydrogen atom transfer and sequential proton loss electron transfer mechanisms in the gas phase and solvent, respectively. The calculated reaction enthalpies of the substituted ethoxyquins have linear dependences with Hammett constants and energy of the highest occupied molecular orbital that can be utilized in the selection of suitable substituents for the synthesis of novel radical scavengers based on ethoxyquin.

Charge delocalization in Z-isomers of (4α → 6″, 2α → O → 1″)-phenylflavans with R = H, OH and OCH3. Effects on bond dissociation enthalpies and ionization potentials

The (2→O→1″)-bridged 4-phenylflavans comprise an interesting structure, included in natural antioxidants such as simple and dimeric A-type proanthocyanidins, catechins and condensed tannins. This work concerns the analysis of the stereoelectronic effects induced by substitution with R=H, OH and OCH3 in Z-isomers of (4α→6″, 2α→O→1″)-phenylflavans using density functional methods in order to deepen the understanding of the molecular and structural properties of these compounds. A fully relaxed scan procedure was performed. A topological study of the molecular charge density (Bader theory, Atoms in Molecules) and a Natural Bond Orbital (NBO) analysis at the B3LYP/6-311++G** level were carried out. The stereochemistry of the molecules was discussed in detail focusing on the factors related to their antioxidant properties. Bond dissociation enthalpies (BDEs), ionization potentials (IPs) and electron affinities (EAs) were calculated for the lowest energy conformers. The Nuclear Magnetic Resonance (NMR) chemical shifts were also calculated at the B3LYP/6-31G** level, and compared with the earlier reported experimental values, showing that the thermodynamically most stable conformer is also the most stable kinetically. The effects of substituents on chemical shifts were quantified. Through a donor acceptor map a qualitative comparison among the studied compounds is given. The lower (higher) BDE (IP) values found for R=OH (4α→6″, 2α→O→1″)-phenylflavans, were explained herein by specific mechanisms of charge delocalization. These findings highlight the key role played by hyperconjugative interactions in the stereoelectronic effects induced by substitution as an important factor in understanding the associated values of BDEs and IPs.

Calculated carbon–hydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drug substance molecules

The carbon–hydrogen bond dissociation enthalpy (BDE) concept is evaluated as a potential computed indicator of stability of pharmaceutical drug substance candidates – specifically for oxidative stability of these molecules. Computational methods are discussed. Accuracy and validity of the methods are evaluated. BDEs are computed for several well-known molecules, for which stability and degradant identification information is known. Anecdotal correlations are noted between the lowest BDE energies of familiar molecules (sertraline, ezlopitant and related structures, ziprasidone, trovafloxacin, and varenicline), the sites of oxidative lability on these molecules and the identities of oxidative degradants. A low BDE may correlate in general with a reactive site on a molecule, not just an oxidatively susceptible one.

Theoretical investigation on antioxidant activity of vitamins and phenolic acids for designing a novel antioxidant

Theoretical calculations have been performed to predict antioxidant property for two interesting classes of compounds including phenolic acids and vitamins. Important characteristics of antioxidants such as O–H bond dissociation enthalpy (BDE) and ionization potential (IP) were calculated in the gas-phase to analyze the effect of heterocyclic ring, intramolecular hydrogen bonding and presence of electron donating group near the O–H on the antioxidant activity. The results reveal that the presence of intramolecular hydrogen bonding through ortho-hydroxy group lowers BDE, IP and spin density. In general, phenolic acids were found to be more effective antioxidant than vitamins. The H-atom transfer (HAT) mechanism was selected to study the hydrogen abstraction from phenolic compounds by hydroperoxyl radical. It is found that the antioxidant with lower BDE undergoes hydrogen abstraction with low barrier and considerable exothermicity. On the basis of these results we were able to design a novel antioxidant with enhanced activity.

Combustion Pathways of the Alkylated Heteroaromatics: Bond Dissociation Enthalpies and Alkyl Group Fragmentations

The bond dissociation enthalpies (BDEs) of the alkyl groups of the alkyl-substituted heterocycles have been studied and compiled using DFT methodology, with the intent of modeling the larger heterocyclic functionalities found in coal. DFT results were calibrated against CBS-QB3 calculations, and qualitative trends were reproduced between these methods. Loss of hydrogen at the benzylic position provided the most favorable route to radical formation, for both the azabenzenes and five-membered heterocycles. The ethyl derivatives had lower BDE values than the methyl derivatives due to increased stabilization of the corresponding radicals. Calculated spin densities correlated well with bond dissociation enthalpies for these compounds, while geometric effects were minimal with respect to the heterocycles themselves. Temperature effects on the bond dissociation enthalpies were minor, ranging by about 5 kcal/mol from 298 to 2000 K; the free energies of reaction dropped significantly over the same range due to entropic effects. Monocyclic heteroaromatic rings were seen to replicate the chemistry of multicyclic heteroaromatic systems.

Homolytic SS Bond Dissociation of 11 Bis(thiocarbonyl)disulfides R‐C(S)SSC(S)R and Prediction of A Novel Rubber Vulcanization Accelerator

The structures and energetics of eight substituted bis(thiocarbonyl)disulfides (RCS(2))(2), their associated radicals RCS(2)(*), and their coordination compounds with a lithium cation have been studied at the G3X(MP2) level of theory for R = H, Me, F, Cl, OMe, SMe, NMe(2), and PMe(2). The effects of substituents on the dissociation of (RCS(2))(2) to RCS(2)(*) were analyzed using isodesmic stabilization reactions. Electron-donating groups with an unshared pair of electrons have a pronounced stabilization effect on both (RCS(2))(2) and RCS(2)(*). The S-S bond dissociation enthalpy of tetramethylthiuram disulfide (TMTD, R = NMe(2)) is the lowest in the above series (155 kJ mol(-1)), attributed to the particular stability of the formed Me(2)NCS(2)(*) radical. Both (RCS(2))(2) and the fragmented radicals RCS(2)(*) form stable chelate complexes with a Li(+) cation. The S-S homolytic bond cleavage in (RCS(2))(2) is facilitated by the reaction [Li(RCS(2))(2)](+)+Li(+)-->2 [Li(RCS(2))](*+). Three other substituted bis(thiocarbonyl) disulfides with the unconventional substituents R = OSF(5), Gu(1), and Gu(2) have been explored to find suitable alternative rubber vulcanization accelerators. Bis(thiocarbonyl)disulfide with a guanidine-type substituent, (Gu(1)CS(2))(2), is predicted to be an effective accelerator in sulfur vulcanization of rubber. Compared to TMTD, (Gu(1)CS(2))(2) is calculated to have a lower bond dissociation enthalpy and smaller associated barrier for the S-S homolysis.

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.

Substituent Effects on the Vibronic Coupling for the Phenoxyl/Phenol Self-Exchange Reaction

The impact of substituents on the vibronic coupling for the phenoxyl/phenol self-exchange reaction, which occurs by a proton-coupled electron transfer mechanism, is investigated. The vibronic couplings are calculated with a grid-based nonadiabatic method and a nuclear-electronic orbital nonorthogonal configuration interaction method. The quantitative agreement between these two methods for the unsubstituted phenoxyl/phenol system and the qualitative agreement in the predicted trends for the substituted phenoxyl/phenol systems provides a level of validation for both methods. Analysis of the results indicates that electron-donating groups enhance the vibronic coupling, while electron-withdrawing groups attenuate the vibronic coupling. Thus, if all other aspects of the reaction are the same, then electron-donating groups will increase the rate, while electron-withdrawing groups will decrease the rate. Correlations between the vibronic coupling and physical properties of the phenol are also analyzed. Negative Hammett constants correspond to higher vibronic couplings, while positive Hammett constants correspond to similar or slightly lower vibronic couplings relative to the unsubstituted phenoxyl/phenol system. In addition, lower bond dissociation enthalpies, ionization potentials, and redox potentials, as well as higher pKa values, tend to correspond to higher vibronic couplings relative to the unsubstituted phenoxyl/phenol system. The observed trends enable the prediction of the impact of general substituents on the vibronic coupling, and hence the rate, for the phenoxyl/phenol self-exchange reaction. The fundamental physical insights obtained from these studies are applicable to other proton-coupled electron transfer systems.

Kinetics of dissociative electron transfer to ascaridole and dihydroascaridole-model bicyclic endoperoxides of biological relevance.

The homogeneous and heterogeneous electron transfer (ET) reduction of ascaridole (ASC) and dihydroascaridole (DASC), two bicyclic endoperoxides, chosen as convenient models of the bridged bicyclic endoperoxides found in biologically relevant systems, were studied in aprotic media by using electrochemical methods. ET is shown to follow a concerted dissociative mechanism that leads to the distonic radical anion, which is itself reduced in a second step by an overall two-electron process. The kinetics of homogeneous ET to these endoperoxides from an extensive series of radical anion electron donors were measured as a function of the driving force of electron transfer (deltaG(o)ET). The kinetics of heterogeneous ET were also studied by convolution analysis. Together, the heterogeneous and homogeneous ET kinetic data provide the best example of the parabolic nature of the activation-driving force relationship for a concerted dissociative ET described by Savéant; the data is particularly illustrative due to the low bond-dissociation enthalpy (BDE) of the O-O bond and hence small intrinsic barriers. Analysis of the data allowed the dissociative reduction potentials (E(o)diss) to be determined as -1.2 and -1.1 Vagainst SCE for ASC and DASC, respectively. Unusually low pre-exponential factors measured in temperature-dependent kinetic studies suggest that ET to these O-O bonded systems is nonadiabatic. Analysis of ET kinetics for ASC and DASC by the Savéant model with a modification for nonadiabaticity allowed the intrinsic free energy for ET to be determined. The use of this approach and estimates for the BDE provide approximations of the reorganization energies. We suggest the methodology described herein can be used to evaluate the extent of ET to other endoperoxides of biological relevance and to provide thermochemical data not otherwise available.

Photodissociation of N-(Triphenylmethyl)anilines: A Laser Flash Photolysis, ESR, and Product Analysis Study1

N−(Triphenylmethyl)anilines (Ph3C-NHPh-R, R = H, o-Me, m-Me, p-Me, p-CPh3), upon photolysis with 248- and 308-nm laser light, as well as by lamp irradiation with 254-nm light in acetonitrile and hexane solutions, undergo exclusively C−N bond homolysis to give the triphenylmethyl radical in a monophotonic process. Product analysis gives as main products Ph3CH, 9-Ph-fluorene, and PhNH2. The quantum yields for the formation of Ph3C• are high (0.6−0.8, 248-nm excitation) and independent of the solvent. This effective homolytic dissociation results from the low electronegativity difference between the carbon and nitrogen atoms constituting the bond to be broken, the low bond dissociation enthalpy of the C−N bond, the high excitation energy of the local chromophore (aniline), and probably from a favorable alignment of the C−N bond in a plane perpendicular to the anilino chromophore (due to the large steric requirements of the trityl group), thus enabling an effective hyperconjugative interaction with it. The above dissociation competes effectively with heterolytic cleavage, which is the pathway dominating, e.g., in the photolysis of Ph3C−Cl in MeCN under the same conditions. At high pulse intensities the trityl radicals formed above are excited by a second photon leading to either electrocyclization to 4a,4b-dihydro-9-phenylfluorenyl radical (DHPF•), or photoionization to Ph3C+, the latter only in MeCN and only on 248-nm photolysis. A new intermediate (9-Ph-4aH-fluorene) on the way to the final product 9-Ph-fluorene is identified resulting from electrocyclization, supporting a mechanism proposed earlier. The optical measurements are supported by ESR studies (irradiation with 254-nm light).

Free-Radical Polymerization for Narrow-Polydispersity Resins. Semiempirical Molecular Orbital Calculations as a Criterion for Selecting Stable Free-Radical Reversible Terminators

Semiempirical molecular orbital calculations at the AM1 and PM3 levels have been used to model stable free-radical-mediated living polymerization reactions. These calculations predict that in the living free-radical polymerization, the reversible terminator of the growing polymer radical must have a calculated bond dissociation enthalpy of less than 35 kcal/mol in order to achieve reasonable rates of chain propagation. Furthermore, the calculations also correctly predict that reversible terminators such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) have an endothermic enthalpy of reaction with styrene monomer and, therefore, are not able to initiate new chains, a prerequisite for narrow polydispersity in these systems. Calculations have been performed on 21 possible reversible terminator structures. One of these reversible terminators, di-tert-butyl nitroxide, was predicted to have a lower bond dissociation enthalpy than the benchmark TEMPO reversible terminator. Experiments have confirmed that under comparable reaction conditions, the di-tert-butyl nitroxide-mediated reaction proceeds to completion more rapidly than the comparable TEMPO reaction, consistent with the predictions of the molecular orbital calculations

Using thermodynamic cycles to study reactive intermediates

Abstract

Diphenylpyridylmethyl radicals. Part 1. Synthesis, dimerization and ENDOR spectroscopy of diphenyl(2-, 3- or 4-pyridyl)methyl radicals; bond dissociation enthalpies of their dimers

ortho–ortho hydrogen van der Waals repulsions are the origin of the propeller shape of the triphenylmethyl radical and the main reason for the low bond dissociation enthalpy (BDH) of its dimer 1(44.8 J mol–1). In order to reduce these steric repulsions (eliminating some aromatic hydrogens), diphenyl(2-, 3- or 4-pyridyl)methyl radicals 2–4 were prepared through reductive dehalogenation of the corresponding triarylchloromethanes 2–4a with silver in benzene. They form α,p-dimers 2–4e exclusively through the pyridine ring. ENDOR spectroscopy shows that the structure of the radicals, does not deviate substantially from that of the parent radical, Ph3C˙. In contrast, the BDH values of the dimers (measured using EPR spectroscopy) show strengthening of the central C–C bond in 2e(88.7 kJ mol–1) and 3e(90.0 kJ mol–1) and a similar value for 4e(46.4 kJ mol–1) with respect to the trityl dimer 1. This is a consequence of the ground state stabilization of the dimers 2–4e due to relief of strain (elimination of ring hydrogens), whereas in the case of 4e, this stabilization is probably compensated by the formation of a weaker C–N bond with respect to the C–C bond. The above dimers undergo easy 1,5-H-rearrangement, autocatalysed by the basic pyridyl groups themselves.