Для 13 производных 10-дигидроартемизинина, содержащих фторзаместители (F и CF3), построены кинетические схемы внутримолекулярного окисления. Каждая стадия кинетической схемы охарактеризована энтальпией, с использованием модели пересекающихся парабол вычислены ее энергия активации и константа скорости. Учтена конкуренция моно- и бимолекулярных радикальных реакций, а в случае отрыва Н от -гидроперокси-С–Н-связи – согласованная с отрывом фрагментация молекулы с образованием гидроксильных радикалов. По эмпирической зависимости антималярийной активности IC50 от числа гидроксильных радикалов nOH, генерируемых соединением, вычислена антималярийная эффективность каждого препарата, обусловленная только гидроксильными радикалами. Выявлены соединения, антималярийная активность которых дополнительно обусловлена иными факторами.

The experimental data on the reactions of iodine atoms with olefins, alkyl halides, and oxygencontaining compounds (20 reactions) are analyzed under the model of intersecting parabolas (MIPs). The effect of the following factors on the activation energy of these reactions is found: the enthalpy of the reaction, triplet repulsion, and dipole–dipole interaction of the reaction site with the polar groups and π electrons of the neighboring double bonds. The increments characterizing the contribution from each factor to the activation energy are calculated.

Experimental data concerning reactions of the bromine atoms with haloalkanes and carbonyl compounds (25 reactions) have been analyzed within the intersecting parabolas model. The following factors have an effect on the activation energy of these reactions: enthalpy of reaction, triplet repulsion, electronegativity of reaction center atoms, dipole–dipole and multidipole interactions of the reaction center with polar groups, and the interaction of π electrons with electrons of the reaction center. The increments characterizing the contribution from each factor to the activation energy of the reaction have been calculated. The increment ΔEμ, which characterizes the dipole–dipole interaction in the transition state, and the dipole moment of the polar group (μ) are correlated by the following empirical equation: ln(ΔE μ/Σμ) = −0.14 + 0.47(ΔE μ/Σμ) − 0.024(ΔE μ/Σμ)2.

Experimental kinetic data on reactions of the chlorine atom with halogenated derivatives of methane and ethane (37 reactions) have been analyzed by the intersecting-parabolas method. The following five factors have an effect on the activation energy of these reactions: the enthalpy of reaction, triplet repulsion, the electronegativities of the reaction center atoms, the dipole–dipole and multidipole interactions between the reaction center and polar groups, and the effect of π electrons in the vicinity of the reaction center. The increments characterizing the contribution from each factor to the activation energy of the reaction have been calculated. The contribution from the polar interaction, Δ E μ , to the activation energy depends on the dipole moment of the polar group and obeys the following empirical equation: ln(Δ E μ /Σμ) = −0.74 + 0.87(Δ E μ /Σμ) − 0.084(Δ E μ /Σμ) 2 .

The O−H bond dissociation energy (D O−H) has been determined for eight alkylseleno-substituted phenols, one alkyltelluro-substituted phenol, and one alkyltelluro-substituted pyridinol. D O−H has been estimated by the intersecting-parabolas method from kinetic data using five reference compounds: α-tocopherol (D O−H = 330.0 kJ/mol), 3,5-di-tert-butyl-4-methoxyphenol (D O−H = 347.6 kJ/mol), 4-methylphenol (D O−H = 361.6 kJ/mol), 2,6-di-tert-butyl-4-methylthiophenol (D O−H = 336.3 kJ/mol), and 2,6-di-ter-tbutyl-4-methylphenol (D O−H = 338.0 kJ/mol). The following D O−H values (kJ/mol) have been obtained: 335.9 for 2,5,7,8-tetramethyl-2-phytyl-6-hydroxy-3,4-dihydro-2H-1-benzoselenopyran, 342.6 for 2-methyl-5-hydroxy-2,3-dihydrobenzoselenophene, 333.5 for 2,4,6,7-tetramethyl-5-hydroxy-2,3-dihydrobenzoselenophene, 339.4 for 2-tert-butyl-4-methoxy-6-octylselenophenol, 357.9 for dodecyl 3-(4-hydroxyphenyl) propyl selenide, 348.5 for dodecyl 3-(3,5-dimethyl-4-hydroxyphenyl)propyl selenide, 350.9 for dodecyl 3-(3-tert-butyl-4-hydroxyphenyl)propyl selenide, 338.0 for dodecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propyl selenide, 343.0 for 2,6-di-tert-butyl-4-(tellurobutyl-4′-phenoxy)phenol, and 338.8 for 6-octyltelluro-3-pyridinol. The stabilization energies of phenoxyl radicals containing R substituents (X = O, S, Se, Te) have been compared.

The O−H bond dissociation energy ( D O−H ) has been estimated for 20 substituted 3-pyridinols and a substituted 3-pyrimidinol from experimental kinetic data by the intersecting parabolas method using α-tocopherol and 4-methoxyphenol as reference compounds. The following D O−H values (kJ/mol) have been obtained: 363.7 for 3-pyridinol, 365.3 for 2-alkyl-3-pyridinols (five compounds), 358.8 for 2-alkyl-6-methyl-3-pyridinols (six compounds), 378.1 for 5-benzyl-3-pyridinol, 353.2 for 2,4,6-trimethyl-3-pyridinol, 340.9 for 2-benzyl-6-methoxy-3-pyridinol, 345.8 for 2,6-dimethoxy-5-benzyl-3-pyridinol, 381.7 for 2-ethyl-4-nitro-6-methyl-3-pyridinol, 376.8 for 2-isopropyl-4-nitro-6-methyl-3-pyridinol, 318.3 for 2,4-dimethyl-6-dimethylamino-3-pyridinol, 357.3 for mexidol, and 322.2 for 2,4-dimethyl-6-dimethylamino-3-pyrimidinol. The substituent effect on the O−H bond dissociation energy in 3-pyridinols is considered. The stabilization energies of pyridinoxyl and phenoxyl radicals are compared. The activation energies and rate constants have been calculated for a series of reactions of various radicals with 3-pyridinols.

The kinetics of 1,1-dimethylpropyl peroxy radicals recombination in polar solvents—water, methanol, and their mixtures—was studied by EPR spectroscopy in combination with the stopped-flow method, and the rate constants of this reaction were determined. Peroxyl radicals were generated by mixing solutions of Ce4+ sulfate and 1,1-dimethylpropyl hydroperoxide. The observed EPR signal of the peroxyl radical is a singlet with a g-factor of 2.015 ± 0.001, and a line width of ΔH = (1.36 ± 0.02) × 10−3 T for methanol and ΔH = (9.7 ± 0.2) × 10−4 T for water. The measured rate constants of (CH3)2C(O2 ·)CH2CH3 radical recombination at 298 K are 2k t = (3.9 ± 0.4) × 104 L mol−1 s−1 for water and 2k t = (5.2 ± 0.5) × 103 L mol−1 s−1 for methanol. A linear relationship between ln(2k t ) and the Kirkwood function (ε−1)/(2ε + 1), where e is the dielectric constant of the medium, has been established, indicating an important role of nonspecific solvation in the recombination of tertiary peroxyl radicals.

Kinetic schemes for the intermolecular oxidation of four analogs of 10-dihydroartemisinin with peroxide substituents were developed. Each step of the kinetic scheme was characterized by the enthalpy, and its activation energy and rate constant were calculated using the model of intersecting parabolas. The antimalarial activity of these derivatives is proved to depend on the number of hydroxyl radicals generated by the compound upon oxidation rather than on the number of peroxide groups. An empirical dependence between the antimalarial efficiency relative to artemisinin (IC50)rel and the number of generated hydroxyl radicals n OH was obtained for a series of peroxy, hydroxy, and alkoxy derivatives of 10-dihydroartemisinin (11 compounds): ln(IC50)rel =–13.51 + 3.76•n OH.

The review discusses compiled data on the N-H bond dissociation energies of 108 aromatic amines of various structures. A brief description of experimental methods for their determination has been given, and the results obtained by different methods have been compared. Stabilization energies of structurally different aminyl radicals (Δ E RS ) have been calculated, and this structural energy has been compared with Δ E RS of phenylaminyl and phenoxyl radicals. Values of D N-H , D O-H , and D S-H for a series of hybrid antioxidants (19 compounds) are reported. Bibliography: 42 references.

Kinetic schemes of intramolecular oxidation are constructed for 13 derivatives of 10-dihydroartemisinin containing fluorine substituents (F and CF 3 ). Each step of the kinetic scheme is characterized by its enthalpy. The activation energy and rate constant of each step are calculated using the intersecting parabolas model. The competition between mono- and bimolecular radical reactions is taken into account. In the case of H abstraction from the α-hydroperoxy-C-H bond, the fragmentation of the molecule with the formation of hydroxyl radicals concerted with the abstraction is taken into account. The antimalarial efficiency of each drug due to the hydroxyl radicals only is calculated from the empirical dependence of the antimalarial activity IC 50 on the number of hydroxyl radicals n OH generated by the compound. The compounds whose antimalarial activity is additionally caused by other factors are revealed.

Energies of the dissociation of N-H-bonds (D N-H) in 3 phenothiazines, phenoxazine, phenoselenoazine, and 9 diphenylamines (AmH) are determined. The D N-H values are calculated from kinetic data by means of intersecting parabolas. The rate constants of the following types of reaction are used in calculations: RO 2 · + Am i H, R· + Am i H, Am i · + PhMe2CH, and Am i · + ROOH. As a rule, the results obtained for the reactions of different types are in good agreement with each other and with the results obtained using other methods.

The dissociation energies of N-H bonds ( D , kJ/mol) were calculated by the intersecting parabolas method using the kinetic data for the following aromatic diamines: para -phenylenediamine (359.8), N , N ′-dimethyl- para -phenylenediamine (348.9), N -dimethyl- N ′-methyl- para -phenylenediamine (342.4), N , N ′-diphenyl- para -phenylenediamine (352.8), N , N ′-diphenylethylenediamine (372.7), N , N ′-diheptylethylenediamine (373.3), N , N ′-di-(4,4′-ethoxyphenyl)ethylenediamine (363.3), N , N ′-di-(4,4′-diisopropylphenyl)- para -phenylenediamine (344.6), 4-{[dimethyl(4-phenylamino)phenoxy)silyl]oxy}- N -phenylaniline (353.4), N , N ′-di-β-naphthyl- para -phenylenediamine (354.6), N , N ′-di-β-naphthoxy- para -phenylenediamine (353.7), 1,1′-dinaphthyl-2,2′-bis- N , N ′-phenyldiamine (372.9), 1,1′-dinaphthyl-2,2′-bis- N , N ′-β-naphthyldiamine (384.2), and 2,6-bis[(1E)-1-(2-phenylhydrazin-1-ylidene)ethyl]pyridine (367.9). Individual dissociation energies for the two N-H bonds were determined in N -phenyl- N ′-isopropyl- para -phenylenediamine: D (PhN-H) = 352.5 and D (Me 2 CHN-H) = 348.7 kJ/mol.

By the dissociation energies of N-H-bonds we calculated stabilization energy of aromatic aminyl radicals of different structure. We have established the rules of additivity for the influence of substituents on the energy of stabilization of mono and bis-substituted diphenylamines and linear correlation between stabilization energies of phenylaminyl and diphenylaminyl radicals. Comparison has been carried out of stabilization for aminyl, benzyl and phenoxyl radicals of similar structure. Linear correlation has been established between stabilization energies of aminyl (XC6H4N  H) and phenoxyl (XC6H4O  ) radicals. Bibliography - 17 references.

Kinetic schemes of intramolecular oxidation were constructed for ten hybrid analogues of 10-dihydroartemisinin with heteroatom-containing substituents (N, F, Cl). All steps of the kinetic scheme were characterized by the enthalpy of the reaction. The activation energies and rate constants were calculated using the intersecting parabolas model. During intramolecular oxidation of the model compounds, free radicals are generated, and the key role belongs to hydroxyl radicals. The kinetic method was developed, which provides the possibility to differentiate the therapeutic effect of hybrid compounds induced by the hydroxyl radicals alone from that induced in addition by the presence of substituents. Some compounds showed therapeutic effect which exceeds the effect caused by generation of the hydroxyl radicals alone. Several compounds bear substituents, which decrease the action induced by generation of the hydroxyl radicals. Substituents were identified, which made additional contribution to the therapeutic effect of the substance, thus providing the complex action.

The dissociation energies of O-H and N-H bonds have been determined for ten aminophenoltype (HOArAmH) hybrid antioxidants. The bond dissociation energies D O-H and D N-H have been estimated from experimental kinetic data (rate constants of the reactions of peroxyl radicals with these antioxidants and their alkyl-substituted derivatives) by the intersecting-parabolas method. Kinetic data for the reactions of peroxyl radicals with HOArAmH, ROArAmH, and HOArAmR compounds were used. The following D O-H and D N-H values (kJ/mol) were obtained: for 4-hydroxydiphenylamine, D O-H = 338.8 and D N-H = 355.9; for 4-hydroxyphenyl-2-naphthylamine, D O-H = 335.4 and D N-H = 353.6; for 6-hydroxy-1,2-dihydro-2,2,4-tri-methylquinoline, D O-H = 338.0 and D N-H = 348.2; for 9-hydroxy-1,2-dihydro-2,3,4-trimethylquinoline, D O-H = 329.7 and D N-H = 383.3; for 6-hydroxy-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, D O-H = 324.4 and D N-H = 345.3; for 8-hydroxy-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, D O-H = 329.4 and D N-H = 380.6; for 5-hydroxyimidazole, D O-H = 356.4 and D N-H = 368.4; for 5-hydroxy-2-methylimidazole, D O-H = 351.3 and D N-H = 362.6; for 5-hydroxy-4,6-dimethylimidazole, D O-H = 346.7 and D N-H = 357.3; for 5-hydroxy-2,4,6-trimethylimidazole, D O-H = 347.7 and D N-H = 358.7.