Simple Hydroperoxides Research Articles

The Fe2+‐Mediated Decomposition, PfATP6 Binding, and Antimalarial Activities of Artemisone and Other Artemisinins: The Unlikelihood of C‐Centered Radicals as Bioactive Intermediates

The results of Fe(2+)-induced decomposition of the clinically used artemisinins, artemisone, other aminoartemisinins, 10-deoxoartemisinin, and the 4-fluorophenyl derivative have been compared with their antimalarial activities and their ability to inhibit the parasite SERCA PfATP6. The clinical artemisinins and artemisone decompose under aqueous conditions to give mixtures of C radical marker products, carbonyl compounds, and reduction products. The 4-fluorophenyl derivative and aminoartemisinins tend to be inert to aqueous iron(II) sulfate and anhydrous iron(II) acetate. Anhydrous iron(II) bromide enhances formation of the carbonyl compounds and provides a deoxyglycal from DHA and enamines from the aminoartemisinins. Ascorbic acid (AA) accelerates the aqueous Fe(2+)-mediated decompositions, but does not alter product distribution. 4-Oxo-TEMPO intercepts C radicals from a mixture of an antimalaria-active trioxolane, 10-deoxoartemisinin, and anhydrous iron(II) acetate to give trapped products in 73 % yield from the trioxolane, and 3 % from the artemisinin. Artemisone provides a trapped product in 10 % yield. Thus, in line with its structural rigidity, only the trioxolane provides a C radical eminently suited for intermolecular trapping. In contrast, the structural flexibility of the C radicals from the artemisinins allows facile extrusion of Fe(2+) and collapse to benign isomerization products. The propensity towards the formation of radical marker products and intermolecular radical trapping have no relationship with the in vitro antimalarial activities of the artemisinins and trioxolane. Desferrioxamine (DFO) attenuates inhibition of PfATP6 by, and antagonizes antimalarial activity of, the aqueous Fe(2+)-susceptible artemisinins, but has no overt effect on the aqueous Fe(2+)-inert artemisinins. It is concluded that the C radicals cannot be responsible for antimalarial activity and that the Fe(2+)-susceptible artemisinins may be competitively decomposed in aqueous extra- and intracellular compartments by labile Fe(2+), resulting in some attenuation of their antimalarial activities. Interpretations of the roles of DFO and AA in modulating antimalarial activities of the artemisinins, and a comparison with antimalarial properties of simple hydroperoxides and their behavior towards thapsigargin-sensitive SERCA ATPases are presented. The general basis for the exceptional antimalarial activities of artemisinins in relation to the intrinsic activity of the peroxide within the uniquely stressed environment of the malaria parasite is thereby adumbrated.

Hydroperoxides with zero, one, two or more carbonyl groups formed during the oxidation of n-dodecane

Experimental investigations and kinetic interpretation indicate the presence of several peroxidic species during the oxidation of n-dodecane. The oxidation was performed either in the gaseous phase in a flow system, or with a liquid/gas interaction in a bulb, because in many combustion processes liquid and gas coexist during preignition. The different peroxides were identified by mass spectrometry. Simple hydroperoxides with two oxygen atoms per molecule were observed at relatively low temperatures above 370 K with liquid and gas present. Ketohydroperoxides with three oxygen atoms per molecules are formed at ∼500 K. Di-, and even tri-, ketohydroperoxides with four or five oxygen atoms per molecule are also present under these experimental conditions at 518 K. Their formation is explained by isomerization reactions of alkoxy radicals OR −2HO bearing a carbonyl group; these stem from the decomposition of carbonyl-hydroperoxides. Depending on the experimental conditions, the nature of the hydroperoxides is different and the respective reactions of these species should be introduced in low temperature oxidation mechanisms. These reaction schemes should include the isomerization of peroxy radicals RO 2 and of ketoalkoxy radicals OR −2HO, leading to the formation of peroxides with several carbonyl groups.

Synthesis and oxygen‐atom transfer reactions of 3‐hydroperoxy‐3,4,4,5,5‐pentasubstituted‐1,2‐dioxolanes

AbstractA series of 3‐hydroperoxy‐3,4,4,5,5‐pentasubstituted‐1,2‐dioxolanes 2a‐d were synthesized in good yield from the corresponding 3‐hydroxy‐1,2‐dioxolanes by reaction with concentrated hydrogen peroxide in acetonitrile with p‐toluenesulfonic acid as catalyst. The 3‐hydroperoxy‐1,2‐dioxolanes were effective oxygen‐atom transfer reagents for the oxidation of thioanisole, triethylamine and 2,3‐dimethyl‐2‐butene to the sulfoxide, N‐oxide and epoxide, respectively. The reactions occurred under mild conditions and were found to be of the second order overall. The second order rate constants (k2) were determined for oxidation of thioanisole by 2a‐d in deuteriochloroform. For 2a, k2 values for N‐oxidation and epoxidation were also measured. The 3‐hydroperoxy‐1,2‐dioxolanes were found to be less reactive than the structurally similar cyclic α‐azohydroperoxides but much more reactive than simple hydroperoxides. The mechanism of oxygen‐atom transfer is postulated to occur via nucleophilic attack of the substrate on the terminal oxygen of the hydroperoxide. Intramolecular hydrogen bonding of the hydroperoxy proton to a dioxolane oxygen appears to account for the reaction order in aprotic media.

Stabilization mechanisms of hindered amines

AbstractAs a result of studying the interaction of hindered amine stabilizers (2, 2, 6, 6‐tetramethylpiperidines) with simple hydroperoxides, peroxy radicals, and acylperoxy radicals, the last two in AIBN‐initiated oxidation experiments in chlorobenzene, the following conclusions have been reached: Hindered amines have multiple mechanisms of functioning as photostabilizers of polymers. Reactions between tetramethylpiperidines and simple hydroperoxides are too slow at moderate temperatures to make a significant contribution to polymer stabilization. Reactions between tetramethylpiperidines and alkylperoxy radicals at moderate temperatures occur at varying rates with varying effectiveness for stabilization. With favorable alignment among reaction rates for oxidation propagation and termination, reactions between tetramethylpiperidines and alkylperoxy radicals can play a significant role in oxidation inhibition. Hydrocarbon polymer photooxidation proceeds by two major paths ‐ the usually accepted alkyl radical/alkylperoxy radical/hydroperoxide route and the usually neglected aldehyde/acyl radical/acylperoxy radical/peracid route. Hindered amine stabilizers are able to participate in inhibiting both photooxidation reactions ‐ they trap acylperoxy radicals, converting them to carboxylic acids and are converted to nitroxyl radicals in the process; the nitroxyl radicals trap alkyl radicals and the hindered amines trap alkylperoxy radicals to inhibit the other oxidation pathway. Nitroxyls are regenerated from N‐alkyloxy hindered amines in a fast, efficient reactions with acylperoxy radicals and in slow reactions with alkylperoxy radicals. We postulate neither reaction yields peroxides: carboxylic acids and oxidized alkyloxy substituents are obtained from the first reaction; alcohols and oxidized alkyloxy substituents are obtained from the second reaction.

Stabilization mechanisms of hindered amines

As a result of studying the interaction of hindered amine stabilizers (2,2,6,6-tetramethylpiperidines) with simple hydroperoxides, peroxy radicals, and acylperoxy radicals, the last two in AIBN-initiated oxidation experiments in chlorobenzene, the following conclusions have been reached: 1. 1. Hindered amines have multiple mechanisms of functioning as photo-stabilizers of polymers. 2. 2. Reactions between tetramethylpiperidines and simple hydroperoxides are too slow at moderate temperatures to make a significant contribution to polymer stabilization. 3. 3. Reactions between tetramethylpiperidines and alkylperoxy radicals at moderate temperatures are very likely too slow and too inefficient for these to be important polymer photo-stabilizing reactions. 4. 4. Hydrocarbon polymer photo-oxidation proceeds by two major paths—the usually accepted alkyl radical/alkylperoxy radical/hydroperoxide route and the usually neglected aldehyde/acyl radical/acylperoxy radical/peracid route. 5. 5. Hindered amine stabilizers are able to participate in inhibiting both photo-oxidation reactions—they trap acylperoxy radicals, converting them to carboxylic acids and are converted to nitroxyl radicals in the process; the nitroxyl radicals trap alkyl radicals and the hindered amines trap alkylperoxy radicals to inhibit the other oxidation pathway. 6. 6. Nitroxyls are regenerated from N-alkyloxy hindered amines in a fast, efficient reaction with acylperoxy radicals and in a slow, inefficient reaction with alkylperoxy radicals. We postulate that neither reaction yields peroxides: carboxylic acids and oxidized alkyloxy substituents are obtained from the first reaction; alcohols and oxidized alkyloxy substituents are obtained from the second reaction.