A theoretical study on the decomposition mechanism of artemisinin

A theoretical study on the artemisinin decomposition mechanism is reported. The suggested pathways have been reproduced and the appearance of the final products can be explained in a satisfactory way. In addition, several intermediates and radicals have been found as relatively stable species, thus giving support to the current hypothesis that some of these species can be responsible for the antimalarial action of artemisinin and its derivatives.     

Theoretical study of radical and neutral intermediates of artemisinin decomposition

Four artemisinin reductive decomposition routes A, B1, B2, and B3 with 13 species (QHS, 1/2, 3, 4, 5, 5a, 6, 7, 18, 18a, 19, 20, and 21) were studied at the B3LYP/6-31G** level. Structures of the species were analyzed in terms of geometrical parameters, L?wdin bond orders, partial atomic charges and spin densities, electronic and free energies, and entropy. Searches in the Cambridge Structural Database for high-level quality artemisinin-related structures were also performed. Principal Component and Hierarchical Cluster analyses were performed on selected electronic and structural variables to rationalize relationships between the routes. The A and B1 routes are possibly interconnected. Structural and electronic features of all species show that there are two clusters: A-B1 and B2-B3. The latter cluster is thermodynamically more favorable (DeltaDeltaG is -64 to -88 kcal mol(-1)) than the former (DeltaDeltaG is -58 to -59 kcal mol(-1)), but kinetical preference may be the opposite. Along the artemisinin decomposition routes, especially B2 and B3, larger structural changes including formation of branched structures and CO2 release are related to increased exothermicity of the conversions, weakened attractive oxygen-oxygen interactions, and increased entropy of the formed species. The intermediate 4 definitely belongs to some minor artemisinin decomposition route.     

Hydroxyl mechanism of the antimalarial action of dimeric analogues of artemisinin

Kinetic schemes of intramolecular oxidation have been constructed for four model compounds containing two artemisinin residues. Each step of the kinetic scheme has been characterized by an enthalpy of reaction. The activation energy and rate constant have been calculated using the intersecting-parabolas model. The competition between unimolecular and bimolecular reactions has been taken into account in constructing the kinetic scheme. In the case of H atom abstraction from the C-H bond in the α-position with respect to the hydroperoxyl group, the fragmentation of the molecule concerted with H abstraction has been taken into consideration. The intramolecular oxidation of the model compounds yields hydroperoxide groups, which, reacting with Fe(II), generate free radicals. Among the latter, hydroxyl radicals play the key role, as in the case of artemisinin. It is the number of hydroxyl radicals generated by the artemisinin analogues (n _OH) that correlates with their antimalarial activity. The relationship between the effectiveness of the dimeric analogues, which is characterized by IC ₅₀, and n _OH is linear and, in the n _OH = 3–7 range, is given by the formula IC ₅₀(artemisinin)/IC ₅₀(analogue) = 1 + 0.27/(n _OH ? 3.17).     

Hydroxyl mechanism of the antimalarial effect of artemisinin and its analogs

Kinetic schemes for the intramolecular oxidation of four artemisinin analogs, which are used as drugs against malaria, were developed. Each stage of the kinetic scheme is characterized by the enthalpy, activation energy, and rate constant calculated using the model of intersecting parabolas. The competition of mono- and bimolecular radical reactions was taken into account when developing the schemes. The hydroperoxide groups are formed as a result of the intramolecular oxidation of these compounds and generate free radicals in the reaction with Fe^II. Among these free radicals, hydroxyl radicals play the key role, since their yield (n _OH) correlates with the antimalarial activity of the peroxide compound. The efficiency of the drug (index IC₅₀) exponentially depends on n _OH and is expressed by the formula IC₅₀(Artemisinin)/IC₅₀(Compound) = 1.54·10⁻⁶exp(3.9n _OH). The elementary reactions resulting in the generation of hydroxyl radicals are considered. It is supposed that DNA of a malaria parasite is the main biological target for hydroxyl radicals.     

The role of C-centered radicals on the mechanism of action of artemisinin

Artemisinin is a sesquiterpene lactone with an endoperoxide function that is essential for its antimalarial activity. Endoperoxides are supposed to act on heme leading to the reduction of the peroxide bond and production of radicals, which can be responsible for killing the parasite. The geometries of artemisinin, radical anions and neutral species generated by rearrangement after reduction of the peroxide bond were fully optimized with the AM1 and PM3 semi-empirical methods, in order to characterize the intermediates formed during the process. Among the radicals calculated along the pathway for reductive decomposition of artemisinin, the secondary radical centered on carbon C₄ has the highest stability when compared to other radicals that can be achieved either by hydrogen migration to the original O-centered radical or by homolytic break of C–C bond. This suggests that the C₄-centered radical may be the species responsible for killing the parasite, as has been indicated previously in experimental studies.     

Kinetics and mechanism of the silane decomposition

The homogeneous gas-phase decomposition kinetics of silane has been investigated using the single-pulse shock tube comparative rate technique (T = 1035–1184?K, P_total ≈? 4000 Torr). The initial reaction of the decomposition SiH₄ \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm SiH}_{\rm 4} \mathop \to \limits^1 {\rm SiH}_{\rm 2} + {\rm H}_{\rm 2} $\end{document} SiH₂ + H₂ is a unimolecular process in its pressure fall-off regime with experimental Arrhenius parameters of logk₁ (sec^?1) = 13.33 ± 0.28–52,700 ± 1400/2.303RT. The decomposition has also been studied at lower temperatures by conventional methods. The results confirm the total pressure effect, indicate a small but not negligible extent of induced reaction, and show that the decomposition is first order in silane at constant total pressures. RRKM-pressure fall-off calculations for four different transition-state models are reported, and good agreement with all the data is obtained with a model whose high-pressure parameters are logA₁ (sec^?1) = 15.5, E_1(∞) = 56.9 kcal, and ΔE^0±₀(1) = 55.9 kcal. The mechanism of the decomposition is discussed, and it is concluded that hydrogen atoms are not involved. It is further suggested that silylene in the pure silane pyrolysis ultimately reacts with itself to give hydrogen: 2SiH₂ → (Si₂H₄)* → (SiH₃SiH)* → Si₂H₂ + H₂. The mechanism of H ? D exchange absorbed in the pyrolysis of SiD₄-hydrocarbon systems is also discussed.     

Kinetics and mechanism of the germane decomposition

The homogeneous gas-phase thermal decomposition kinetics of germane have been measured in a single-pulse shock tube between 950 and 1060 K at pressures around 4000 torr. The initial decomposition is GeH₄ → GeH₂ + H₂ in its pressure-dependent regime, with log k = 13.83 ± 0.78 – 50,750 ± 3570 cal/2.303RT. RRKM calculations suggest that the high-pressure Arrhenius parameters are log k GeH₄(M → ∞) = 15.5 – 54,300 cal/2.303RT. Extrapolations to static system pyrolysis conditions (T ～ 600 K, P ～ 200 torr) give homogeneous reaction rates which are much slower than those observed, hence the static system pyrolysis of germane must be predominantly heterogeneous. Shock-initiated pyrolysis reaction stoichiometry is 2 mol H₂ per mole GeH₄, suggesting that the subsequent decomposition of germylene is essentially quantitative. Investigations of the hydrogen product yields for pyrolysis of GeD₄ in øCH₃ further indicate that the germylene decomposition reaction is mainly GeH₂ → H₂ + Ge, but that a small amount of reaction to H atoms may also occur.     

Reactions of alkoxy and peroxy radicals formed upon the decomposition of hydroxyperoxide groups in the artemisinin derivatives

The enthalpies of intramolecular reactions of alkoxy and peroxy radicals formed from polyatomic artemisinin hydroperoxides and of their bimolecular reactions with C—H, S—H, and O—H bonds of biological substrates were calculated. The activation energies and rate constants of these reactions were calculated using the intersecting parabolas method. The decomposition of artemisinin hydroperoxides can initiate the cascade of intramolecular oxidation reactions involving radicals R·, RO·, HO·, HO₂·, and RO₂·. The main sequences of transformation of these radicals were established. The oxidative destruction of the artemisinin peroxy derivatives generates radicals RO₂·, HO·, and HO₂· in an amount of 4.5 radicals per peroxide derivative molecule on the average. The kinetic scheme of oxidative transformations of the hydroperoxide with four OOH groups and radicals formed from it was constructed using this radical as an example.     

Thermal decomposition mechanism of disilane

Thermal decomposition of disilane was investigated using time-of-flight (TOF) mass spectrometry coupled with vacuum ultraviolet single-photon ionization (VUV-SPI) at a temperature range of 675-740 K and total pressure of 20-40 Torr. Si(n)H(m) species were photoionized by VUV radiation at 10.5 eV (118 nm). Concentrations of disilane and trisilane during thermal decomposition of disilane were quantitatively measured using the VUV-SPI method. Formation of Si(2)H(4) species was also examined. On the basis of pressure-dependent rate constants of disilane dissociation reported by Matsumoto et al. [J. Phys. Chem. A 2005, 109, 4911], kinetic simulation including gas-phase and surface reactions was performed to analyze thermal decomposition mechanisms of disilane. The branching ratio for (R1) Si(2)H(6) --> SiH(4) + SiH(2)/(R2) Si(2)H(6) --> H(2) + H(3)SiSiH was derived by the pressure-dependent rate constants. Temperature and reaction time dependences of disilane loss and formation of trisilane were well represented by the kinetic simulation. Comparison between the experimental results and the kinetic simulation results suggested that about 70% of consumed disilane was converted to trisilane, which was observed as one of the main reaction products under the present experimental conditions.     

Energetics and mechanism of the decomposition of trifluoromethanol

The thermal instability of alpha-fluoroalcohols is generally attributed to a unimolecular 1,2-elimination of HF, but the barrier to intramolecular HF elimination from CF3OH is predicted to be 45.1 +/- 2 kcal/mol. The thermochemical parameters of trifluoromethanol were calculated using coupled-cluster theory (CCSD(T)) extrapolated to the complete basis set limit. High barriers of 42.9, 43.1, and 45.0 kcal/mol were predicted for the unimolecular decompositions of CH2FOH, CHF2OH, and CF3OH, respectively. These barriers are lowered substantially if cyclic H-bonded dimers of CF3OH with complexation energies of approximately 5 kcal/mol are involved. A six-membered ring dimer has an energy barrier of 28.7 kcal/mol and an eight-membered dimer has an energy barrier of 32.9 kcal/mol. Complexes of CF3OH with HF lead to strong H-bonded dimers, trimers and tetramers with complexation energies of approximately 6, 11, and 16 kcal/mol, respectively. The dimer, CH3OH:HF, and the trimers, CF3OH:2HF and (CH3OH)2:HF, have decomposition energy barriers of 26.7, 20.3, and 22.8 kcal/mol, respectively. The tetramer (CH3OH:HF)2 gives rise to elimination of two HF molecules with a barrier of 32.5 kcal/mol. Either CF3OH or HF can act as catalysts for HF-elimination via an H-transfer relay. Because HF is one of the decomposition products, the decomposition reactions become autocatalytic. If the energies due to complexation for the CF3OH-HF adducts are not dissipated, the effective barriers to HF elimination are lowered from approximately 20 to approximately 9 kcal/mol, which reconciles the computational results with the experimentally observed stabilities.     

Primary mechanism of the thermal decomposition of tricyclodecane

To better understand the thermal decomposition of polycyclanes, the pyrolysis of tricyclodecane has been studied in a jet-stirred reactor at temperatures from 848 to 933 K, for residence times between 0.5 and 6 s and at atmospheric pressure, corresponding to a conversion between 0.01% and 25%. The main products of the reaction are hydrogen, methane, ethylene, ethane, propene, 1,3-cyclopentadiene, cyclopentene, benzene, 1,5-hexadiene, toluene, and 3-cyclopentylcyclopentene. A primary mechanism containing all the possible initiation steps, including those involving diradicals, as well as propagation reactions has been developed and allows experimental results to be satisfactorily modeled. The main reaction pathways of consumption of tricyclodecane and of formation of the main products have been derived from flow rate and sensitivity analyses.     

Kinetic mechanism of the thermal decomposition of tobacco

Equations have been derived to describe the chemical kinetic factors that affect the rate of formation of products when a mixture of solid components (tobacco) decomposes on heating. Using these equations, a computer model of tobacco pyrolysis has been constructed which can calculate the gas formation rate/temperature profile from a given set of reaction parameters. By comparing the predictions of the model with experimental results at heating rates between 0.8 and 25 deg C s^?1, a generalised kinetic mechanism for the thermal decomposition of tobacco has been developed. For carbon monoxide and other low molecular weight gases, the mechanism is an independent formation of each gas from one solid tobacco component in each temperature region. Pyrolysis of some individual tobacco components in other studies suggests that each gas is actually produced from many components in each temperature region. This more complex mechanism is kinetically equivalent to the deduced mechanism of independent formation from one component.The region in which a given decomposition reaction takes place moves to higher temperatures as the heating rate increases. The amounts of gases formed over any temperature region from 200 to 900°C can be calculated for a given heating rate using the mechanism and the kinetic constants. The present results imply that 75–90% of the carbon monoxide produced by tobacco decomposition at temperatures up to 900°C during a puff on a cigarette corresponds to that formed in the “low temperature region” (200–450°C) defined for pyrolysis experiments at the lower heating rates of 1–10 deg C s^?1.     

Elucidation of the natural artemisinin decomposition route upon iron interaction: a fine electronic redistribution promotes reactivity

The conformational analysis of artemisinin by molecular dynamics and quantum chemistry calculations revealed the existence of seven energy minima with specific interconversion pathways. Among the seven conformers, only , and were able to undergo bond rearrangements upon Fe(2+) interaction. These rearrangements were due to a peculiar puckering of the trioxane ring that brings its three oxygen atoms in an ideal geometrical position for interacting with Fe(2+) ions, promoting an electronic redistribution in the molecule. A rapid molecule rearrangement led to a stable energy minimum structure with an additional ring that is similar to a plant metabolite. Our results suggest an alternative pathway for generating toxic radical chemical species for the malaria parasite, where artemisinin is not toxic by itself but rather is an intermediate for molecular partners that generate radical structures deleterious for the parasite proteins, after electron transfers from the Fe(2+)/artemisinin complex.     

The formaldehyde decomposition chain mechanism

A kinetic mechanism for the chain decomposition of formaldehyde consistent with recent theoretical and experimental results is presented. This includes new calculations and measurements of the rate constant for the abstraction reaction The calculation uses a multi-reference configuration interaction wavefunction to construct the potential energy surface which is used in a tunneling-corrected TST calculation of the rate constant. The rate constant for the bond fission at high temperatures was determined by an RRKM extrapolation of direct low temperature measurements. This mechanism has been successfully tested against laser-schlieren measurements covering the temperature range 2200–3200 K. These measurements are insensitive to all but the above two reactions and they confirm the large, non-Arrhenius rate for the abstraction reaction derived here from theory. Modeling of previous experiments using IR emission, ARAS, and CO laser absorption with this mechanism is quite satisfactory. The branching ratio of the rate of the faster molecular dissociation (CH₂O + (M) → CO + H₂ + (M)), to that of the bond fission reaction, was estimated to be no more than 2 or 3 over 2000 to 3000 K. Such a ratio is consistent with one recent theoretical estimate and most of the experimental observations. © 1993 John Wiley & Sons, Inc.     

A mechanism for the decomposition of dinitropropyl compounds

A decomposition mechanism is proposed for 2,2-dinitro-1-methoxypropane, a compound whose structure resembles the nitroplasticizer (NP) component of plastic-bonded explosive PBX 9501. A library of key reactions is presented and is based on the results of NP aging studies and existing decomposition mechanisms for similar nitro compounds. Density functional electronic structure calculations on these reactions were used to develop a decomposition mechanism at lower temperatures, which begins with HONO elimination and leads to intermediates that can produce CO, CO(2), NO, and N(2)O gases. These gases were observed in low temperature (48 to 64 degrees C) aging studies of NP. A high temperature mechanism involving NO(2) scission is compared to a thermal decomposition mechanism determined by simultaneous thermogravimetric modulated beam mass spectrometry. The calculated energy barriers for HONO elimination and NO(2) scission in the gas phase are reported and compared to experimental results.     

Studying of silane thermal decomposition mechanism

The mechanism of silane thermal decomposition is investigated in a flow reactor. The time dependencies of silane consumption and disilane formation were compared with those parameters of solid product (aerosol particles) such as concentration, total hydrogen content in solid product, and fraction of hydrogen contained in solid product as polyhydride groups (SiH₂)_n. Silane loss and gaseous product formation were analyzed using a mass spectrometer. The hydrogen content in solid product was analyzed by the methods of IR-spectroscopy and hydrogen evolution. Based on a simple kinetic scheme we qualitatively explained the experimental dependencies of silane conversion and disilane formation, the effective activation energy of the decomposition process, and the amount of polyhydride groups in the solid product on reaction time and initial silane concentration. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 99–110, 1998.     

The kinetics and mechanism of the decomposition of N-chloroleucine

At 298 K the rate constant for the decomposition of N-chloroleucine has the constant value 3.20 × 10⁻⁴ s⁻¹ over the range pH 5–12, increases with increasing acidity at pH < 5, and increases with pH at pH > 12. A mechanism is put forward which explains these results.     

The mechanism of the acid-catalyzed decomposition of the farnesyl phosphates

The rates and (in some cases) products of the acid-catalyzed decomposition of (Z,E)- and (E,E)-farnesyl phosphate, (Z,E)- and (E,E) - 1,1 - dideutereofarnesyl phosphate, (Z)- and (E) - 6,7,10,11 - tetrahydrofarnesyl phosphate, and t-butyl phosphate have been studied in an attempt to determine whether (Z,E)-farnesyl phosphate ionizes with intramolecular assistance from the C-6/C-7 double bond or via an unassisted process leading to a simple allylic cation. Data in support of both possibilities are adduced, but it is concluded, primarily on the basis of the secondary deuterium kinetic isotope effects, that the ionization involves little, if any, assistance from the double bond.