T. G. Denisova

Influence of the size of the formed cycle on the reactivity of free radicals in cyclization reactions

Numerous experimental data for the cyclization of free radicals C·H2(CH2)nCH=CH2 → cyclo-[(CH2)n+1CH(C·H2)], and C·H2(CH2)nCH=CHR → cyclo-[(CH2)n+1C·HCHR] were analyzed in the framework of the parabolic model. The activation energy of thermoneutral (ΔHe = 0) cyclization Ee0 decreases linearly with an increase in the energy of cycle strain Ersc: Ee0(n) (kJ mol–1) = 85.5 – 0.44Ersc(n) (n is the number of atoms in the cycle). The activation entropy of cyclization ΔS# also depends on the cycle size: the larger the cycle, the lower ΔS#. A linear dependence of ΔS# on the difference between the entropies of formation S° of cyclic hydrocarbon and the corresponding paraffin was found: ΔS# = 1.00[S°(cycle) – S°(CnH2n+2)]. The Ee0 values coincide for cyclization reactions with the formation of the six-membered cycle and the bimolecular addition of alkyl radicals to olefins.

Polar and solvation effects in reactions of oxygen atoms and hydroxyl and alkoxyl radicals with oxygen-containing compounds

Experimental data on the activation energies of reactions of H-abstraction from oxygencontaining compounds by oxygen atoms and hydroxyl and alkoxyl radicals in the gas and liquid phases have been analyzed by means of the parabolic model of the transition state. The contribution of polar interaction to the activation energies of the reactions has been calculated. The contribution of solvation to the activation energy has been calculated by comparison of the reaction parameters of the respective reaction in the liquid and gas phases.

The energy and geometric characteristics of the transition state in reactions of RO2• with carbonyl compound C-H bonds

The energy and geometry of the transition state in reactions of the ethyl peroxyl radical with ethane, ethanol (its α and β C-H bonds), acetone, butanone-2, and acetaldehyde were calculated by the density functional theory method. In all these reactions (except EtO2/• + ethanol α C-H bond), the C…H…O reaction center has an almost linear configuration (φ = 176° ± 2°); polar interaction only influences the r≠ (C…O) interatomic bond. In the reaction of EtO2/• with the ethanol α C-H bond, it is the O-H…O H-bond formed in the transition state that determines the configuration of the reaction center with the angle φ(C…H…O) = 160°. The results were used to estimate the r≠ (C…H) and r≠ (O…H) interatomic bonds in the transition state by the method of intersecting parabolas and the contribution of polar interaction to the activation energy of reactions between peroxyl radicals and aldehydes and ketones.

Reactions of mono- and bimolecular hydrogen transfer in alkyl radicals: analysis using the parabolic model and density functional calculations

Experimental data on monomolecular hydrogen transfer in the reactions of the type RC·H(CH2)nCH2R1 → RCH2(CH2)nC·HR1 (n = 2—4, R and R1 are alkyl substituents) were analyzed using the parabolic model (PM). The parameters characterizing this class of reactions were calculated. Isomerization of alkyl radicals via cyclic transition states (TS) is characterized by the following energy barriers to thermoneutral reaction Ee0: 53.5, 65.4, and 63.2 kJ mol–1 for the six-, five-, and seven-membered TS, respectively. The Ee0 energy and the strain energy change in parallel in the series of cycloparaffins CnH2n. Density functional calculations of intramolecular hydrogen transfer in the n-butyl and n-pentyl radicals and of the bimolecular hydrogen abstraction from the ethane molecule by the ethyl radical were performed. The activation energies of the intra- and intermolecular hydrogen transfer were compared. The parameters of the PM were compared with the interatomic distances in the reaction center of the TS calculated by the density functional method.

Energy of N-H-bond dissociation in phenothiazines and diphenylamines

Energies of the dissociation of N-H-bonds (DN-H) in 3 phenothiazines, phenoxazine, phenoselenoazine, and 9 diphenylamines (AmH) are determined. The DN-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: RO2· + AmiH, R· + AmiH, Ami· + PhMe2CH, and Ami· + 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.

Generation of radicals and antimalarial activity of dispiro-1,2,4-trioxolanes

The kinetic schemes of the intramolecular oxidation of radicals generated from substituted dispiro-1,2,4-trioxolanes (seven compounds) in the presence of Fe2+ and oxygen were built. Each radical reaction was defined in terms of enthalpy, activation energy, and rate constant. The kinetic characteristics were calculated by the intersecting parabolas method. The competition between the radical reactions was considered. The entry of radicals generated by each compound into the volume was calculated. High antimalarial activity was found for 1,2,4-trioxolanes, which generated hydroxyl radicals. The structural features of trioxolanes responsible for the generation of hydroxyl radicals were determined.

Mechanism of hydroxyl radical induced antimalarial action of hybrid analogues of 10-dihydroartemisinin

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.

Kinetic analysis of free radical generation by peroxy, hydroxy, and alkoxy derivatives of 10-dihydroartemisinin

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 nOH was obtained for a series of peroxy, hydroxy, and alkoxy derivatives of 10-dihydroartemisinin (11 compounds): ln(IC50)rel =–13.51 + 3.76•nOH.

Geometric parameters of transition states of radical abstraction reactions with C...H...C reaction center

An algorithm of calculations of interatomic distances in the transition states (TS) of reactions of hydrogen abstraction by alkyl, allyl, and benzyl radicals from C—H bonds of organic molecules using the enthalpies of the corresponding reactions is proposed. The geometric parameters of the TS of the reactions involving carbon-centered radicals with the C...H...C reaction center, calculated using experimental data, are compared with other characteristics of the reactions and reactants. The r(C...H...C) distance in the TS of the reactions of alkyl radicals with alkanes remains unchanged as the enthalpies of reactions vary, being a characteristic parameter of a given class of reactions. π-Bonds adjacent to the reaction center are responsible for an increase in the parameter r(C...H...C) in the TS.