Allylic Hydroperoxides Research Articles

ChemInform Abstract: Photooxygenation of Chiral Dienol Ethers: Asymmetric Synthesis of Alkoxydioxines.

The addition of 1O2 to chiral dienol ethers provides a new route to alkoxydioxines (alkoxyendoperoxides). Depending upon substitution and geometry, the [4+2] cycloaddition is accompanied or even supplanted by [2+2] cycloaddition leading to alkene cleavage and/or ene-like reaction leading to allylic hydroperoxides. The diastereoselectivity of cycloaddition is ultimately limited by the conformational freedom of the dienol ether substrates.

Photoinduced azidohydroperoxidation of myrtenyl hydroperoxide with semiconductor particles and lucigenin as PET-catalysts

The allylic hydroperoxide 2 (myrtenyl hydroperoxide), available from singlet oxygen photooxygenation of beta-pinene (1), is converted into the azido bis-hydroperoxide 3 by an electron-transfer induced azidyl radical formation and trapping of the initial tertiary carbon radical by triplet oxygen. The azido bis-hydroperoxide 3 is reduced to the azido 1,2-diol 4 or the amino diol 5, respectively. Beside classical fluorescent PET sensitizers such as rhodamines, also nanosized semiconductor particles as well as lucigenin were applied as catalysts. The electron transfer rate of azide oxidation was determined for lucigenin by fluorescence quenching analysis.

Recent Mechanistic Insights in the Singlet Oxygen Ene Reaction

Singlet oxygen reacts with alkenes, which bear allylic hydrogens,in an ene fashion to afford allylic hydroperoxides. This reaction,apart from its synthetic usefulness, has received extensive mechanisticattention. Numerous experimental studies (e.g., trapping of intermediates,deuterium kinetic isotope effects, regio- or stereoselectivity studiesetc.) and to a lesser extend computational work, support a stepwisemechanism with the formation of a three-membered ring (perepoxide-like)intermediate. This Account mainly highlights our group’searlier and recent experimental efforts to ascertain facts relatingto this concept. 1 Introduction 2 Theoretical Calculations 3 Kinetic Isotope Effects 4 Regioselectivity 4.1 ‘ CIS Effect’ Selectivity 4.2 ANTI ‘ CIS Effect’ Selectivity 4.3 The Large Group Nonbonding Effect 4.4 GEMINAL Selectivity with Respectto Allylic or Vinyl Substituent 4.5 Electron-Withdrawing Group at the α- and β-Position 4.6 Regioselective Self-Sensitized Oxygenation of Fullerene Derivatives 4.7 Solvent and Electronic Effects 4.7.1 Site Selectivity in the ¹ O 2 EneReaction of α,β-Unsaturated Esters and Acids 4.7.2 Site Selectivity in the ¹ O 2 EneReaction of Allylic Alcohols 4.7.3 SYN Selectivity of β,β-Dimethylstyrene 4.7.4 Site Selectivity of Isobutenylarenes 4.7.5 ‘Push-Pull’ Electronic Effect 5 Studies on Diastereoselectivity 5.1 Diastereoselectivity in Self-Sensitized Oxygenation of a FullereneDerivative 5.2 Diastereoselectivity in the ¹ O 2 EneReaction of Chiral Functionalized Alkenes 6 Stereochemistry 7 Hypersensitive Probes in the ¹ O 2 EneReaction 8 The ¹ O 2 Ene Reaction in ConfinedMedia 9 Concluding Remarks

ChemInform Abstract: One‐Pot Synthesis of 1,2,3‐Triols from Allylic Hydroperoxides and a Catalytic Amount of OsO4 in Aqueous Acetone.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The effectiveness of ruthenium(II) complexes and ruthenium trichloride as pre-catalysts in solvent-free isomerization of model alkyl allyl ether

The isomerization of readily available allyl ethers catalyzed by soluble ruthenium complexes is an extremely versatile methodology for synthesis of O-1-propenyl systems—attractive monomers in cationic UV-radiation curing technology. From the process development perspective, the effectiveness of selected simple ruthenium catalyst precursors, mainly [RuClH(CO)(PPh 3) 3], [RuCl 2(PPh 3) 3] and RuCl 3· xH 2O in the solvent-free isomerization of 1,4-bisallyloxybutane has been examined. The relationship between basic reaction parameters such as the reaction temperature, the amount of catalyst precursor, the promoters of non-hydride complexes (bases or alcohols), the ambient gas atmosphere and the reaction time allowing to achieve quantitative conversion of the model bisallyl ether to its 1-propenyl derivatives ( τ 100%) has been presented. Particular attention has been paid to the use of lower loadings of [Ru] complex required for the completion of the reaction within the reasonable times. For the first time a detailed study on the effect of the presence and amount of allyl hydroperoxides on the course of isomerization has been done.

Theoretical study of the peroxidation of chlorophenols in gas phase and aqueous solutions

Theoretical study of the reactions between singlet oxygen and chlorophenols is an important aspect in understanding the reaction mechanism of the dye-sensitized photodegradation. With the intention of finding certain predictors to be used for the determination of the most probable reaction path and estimating the dye-sensitized photodegradation rates of chlorophenols, the reactions of 1O 2 with six chlorophenols (CPs), including 2-chlorophenol (2-CP), 3-CP, 4-CP, 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP) and pentachlorophenol (PCP), were investigated by using the density functional theory. Results suggested that 1,3-addition to a double bond connected to a hydrogen-carrying group, resulting in the formation of allylic hydroperoxides, and 1,4-addition to chlorophenols to form of hydroperoxide ketones are thermodynamically more likely to take place. Furthermore the reaction barrier of the former one is lower than that of later one, which tends to conclude that 1,3-addition to a double bond connected to a hydrogen-carrying group to form allylic hydroperoxides is the most likely route both in gas phase and aqueous solution. Those reactions are thermodynamically more likely to take place in presence of water, but the reaction barriers increased. Also it was observed that with the increase of chlorine substitutions, the reactions become less exergonic and kinetically less favorable due to the increase in reaction barriers.

One-Pot Synthesis of 1,2,3-Triols from Allylic Hydroperoxides and a Catalytic Amount of OsO4 in Aqueous Acetone

Allylic hydroperoxides were converted into the corresponding triols in the presence of a catalytic amount of O S O 4 . The present reaction involves regeneration of active osmium species by the hydroperoxide functionality and occurs in a diastereoselective manner to form triols in high yields. A plausible mechanism for the formation of 1,2,3-triols from allylic hydroperoxide is presented.

The Schenck Rearrangement of Allylic Hydroperoxides

It is 50 years since Schenck's discovery of the ubiquitous rearrangement of allylic hydroperoxides, and its unique homolytic mechanism has now been clarified by a combination of experimental and computational methods. The recognised examples of the reaction are surveyed and the way in which the present mechanistic picture has emerged is reviewed. A brief account is given of the closely related Smith epimerisation of allylic hydroperoxides.

Evidence for Singlet-Oxygen Generation and Biocidal Activity in Photoresponsive Metallic Nitride Fullerene−Polymer Adhesive Films

The adhesive properties, as measured by bulk tack analysis, are found to decrease in blends of isomerically pure Sc3N@I(h)-C80 metallic nitride fullerene (MNF) and polystyrene-block-polyisoprene-block-polystyrene (SIS) copolymer pressure-sensitive adhesive under white light irradiation in air. The reduction of tack is attributed to the in situ generation of 1O2 and subsequent photooxidative cross-linking of the adhesive film. Comparisons are drawn to classical fullerenes C60 and C70 for this process. This work represents the first demonstration of 1O2 generating ability in the general class of MNFs (M3N@C80). Additional support is provided for the sensitizing ability of Sc3N@I(h)-C80 through the successful photooxygenation of 2-methyl-2-butene to its allylic hydroperoxides in benzene-d(6) under irradiation at 420 nm, a process that occurs at a rate comparable to that of C(60). Photooxygenation of 2-methyl-2-butene is found to be influenced by the fullerene sensitizer concentration and O2 flow rate. Molar extinction coefficients are reported for Sc3N@I(h)-C80 at 420 and 536 nm. Evaluation of the potential antimicrobial activity of films prepared in this study stemming from the in situ generation of 1O2 led to an observed 1 log kill for select Gram-positive and Gram-negative bacteria.

Singlet oxygen addition to homoallylic substrates in solution and microemulsion: novel secondary reactions

The photooxygenation of three homoallylic substrates, the γ,δ-unsaturated ketone 1a, nitrile 2a, and the γ,δ-unsaturated ester 3a was investigated in homogeneous solution and in microemulsion (for 1a). Two secondary reaction pathways were detected for the allylic hydroperoxides of type b and c, respectively. The cyclization reactions of 1b and 2b to the 1,2-dioxanes 1d and 2d followed well-known reaction patterns, whereas the base-catalyzed epoxide ( 1e– 3e) formation from the tertiary allylic hydroperoxides 1c– 3c is a unprecedented reaction type.

Photooxygenation Catalysis with a Polyol‐Decorated Disc‐Shaped Porphyrin Sensitizer: Shell‐Recognition Effects

AbstractPolar meso‐tetraarylporphyrins 2–4 were synthesized from tetrakis‐4‐hydroxyphenylporphyrin 1 as the central building block by consecutive base‐induced reactions with glycidol. The decorating units form a polar hydrogen‐bonded shell around the sensitizer core which is proposed as the binding site for polar substrates in photocatalyzed oxygenation reactions. As substrate, the polarity‐sensor mesitylol (5) was applied and the reaction constrained in a polystyrene matrix. Increasing shell dimensions lead to increased diastereoselectivities for the allylic hydroperoxides 6 and thus clearly demonstrate the concept of shell‐induced substrate stereoselectivity in singlet oxygen reactions.

1,2,5,10,11,14-Hexaoxadispiro[5.2.5.2]hexadecanes: Novel Spirofused Bis-Trioxane Peroxides

A set of new bis-spirofused 1,2,4-trioxanes 4a-d was obtained from the reaction of cyclohexane-1,4-dione with allylic hydroperoxides 2a-d, bearing an additional hydroxy group in the homoallylic position, by diastereoselective photooxygenation of allylic alcohols 1a-d and subsequent BF3-catalyzed peroxyacetalization with the diketone. From the reaction of a monoprotected cyclohexane-1,4-dione 5 with the allylic hydroperoxide 6 derived from the singlet oxygenation of methyl hydroxytiglate, one monospiro compound was obtained, the 1,2,4-trioxane ketone 7, as well as a mixture of the diastereoisomeric syn- and anti bis-1,2,4-trioxanes 8. The structures of bis-1,2,4-trioxanes were examined theoretically by DFT methods and compared with X-ray structural data in order to evaluate the preferential trioxane ring conformational orientation.

Carbon- and Oxygen-Centered Radicals Are Equally Important Haptens of Allylic Hydroperoxides in Allergic Contact Dermatitis

Limonene is one of the most commonly used fragrance compounds in western countries today. When exposed to air, it autoxidises, forming hydroperoxides that are strong contact allergens. To cause allergic contact dermatitis (ACD), the hydroperoxides are considered to bind covalently to proteins in the skin via a radical pathway. Consequently, the nature and reactions of the radicals formed from the hydroperoxides are important. We have examined the radical formation from, and sensitizing potential of, three allylic hydroperoxides. Two of these are found in the oxidation mixture of limonene, while the third is a synthetic structural analogue. The identity of the radicals formed from these hydroperoxides has been studied in radical trapping experiments. Chemical trapping experiments were performed using 5,10,15,20-tetraphenyl-21 H,23 H-porphine iron(III) chloride [Fe(III)TPPCl 3] as an initiator and 1,1,3,3-tetramethylisoindolin-2-yloxyl as a radical trapper. Electron paramagnetic resonance experiments using photolysis for initiation were performed with and without 5-diethoxy-phosphoryl-5-methyl-1-pyrroline N-oxide. Our results demonstrate the ability of the studied hydroperoxides to form peroxyl, allyloxyl, and oxiranylcarbinyl radicals. These radicals can potentially react with proteins to form immunogenic hapten-protein complexes relevant for ACD. The sensitizing potency of the hydroperoxides was studied in the murine local lymph node assay. All three hydroperoxides were found to be potent sensitizers with some variations, which can be related to the identity and quantity of the radicals formed. The results indicate that both carbon- and oxygen-centered radicals are important intermediates in the formation of hapten-protein complexes and that the sensitizing potency of the hydroperoxides is related to their structures.

The Cyclopropyl Group as a Hypersensitive Probe in the Singlet Oxygen Ene Reaction Mechanism

Cyclopropyl-substituted olefins are employed as mechanistic probes in the singlet oxygen-alkene ene reaction. In MeOH and aprotic solvents [CHCl(3), (CH(3))(2)CO, CH(3)CN], only the allylic hydroperoxides bearing an intact cyclopropyl group are detected. The reaction mechanism is independent of solvent polarity. Our findings, to a certain experimental limit, exclude a biradical or dipolar intermediate.

Theoretical study of the reaction of 2,4-dichlorophenol with 1O 2

The dye sensitized photodegradation of chlorophenols has attracted a great deal of attentions recently because of its high efficiency, low cost and the convenience in utilizing solar energy directly. Much experimental evidences suggest that singlet oxygen, a very active oxygen species formed in the photosensitized process, is responsible for the photooxidation of the chlorophenols. However, the theoretical aspects of the detailed mechanism of the reaction between chlorophenols and singlet oxygen have been less frequently addressed. 2,4-dichlorophenol is used as a model chlorophenol in this work and four types of reactions between 2,4-dichlorophenol and singlet oxygen were investigated at the density functional theory level (functional B3LYP): (1)1,3-addition to a double bond connected to a hydrogen-carrying group, resulting in the formation of allylic hydroperoxides; (2)1,4-cycloaddition to a system containing at least two conjugated double bonds, resulting in the formation of the 1,4-peroxides; (3)[π2+π2] 1,2-cycloaddition to an isolated double bond, resulting in the formation of 1,2-peroxides; (4)1,4-addition to chlorophenols with the formation of hydroperoxide ketones. The type (1) and type (4) reactions are the most exergonic ones, (−17.5 to −20.0 kcal mol −1) and type (1) also has the lowest reaction barrier, therefore is predicted to be the most likely route.

Identification of radical species derived from allergenic 15-hydroperoxyabietic acid and insights into the behaviour of cyclic tertiary allylic hydroperoxides in Fe(II)/Fe(III) systems

Abstract To understand the skin sensitization mechanism of 15-hydroperoxyabietic acid, the major allergen in colophony, we first examined the formation of potential reactive radicals derived from its reaction with light, heat and TPP-Fe 3+ . Trapping with 1,1,3,3-tetramethylisoindolin-2-yloxyl nitroxide confirmed the formation of carbon-centred radicals derived from allyloxyl/allylperoxyl radicals as a consequence of the hydroperoxide scission. Particular interest was further given to the reactivity with Fe(II)/Fe(III) due to the biological importance of haem containing enzymes. Using a monocyclic 15-hydroperoxyabietic acid-like compound as a model of allergenic allylic hydroperoxides, we evidenced, by the ESR spin-trapping technique, the competition between carbon and oxygen-centred radicals formed in the presence of Fe(II)/Fe(III) in organic/aqueous media. We complemented the study by showing the possibility of formation, via a radical mechanism induced by ferric chloride, of an adduct between the allylic hydroperoxide and N -acetyl-cysteine ethyl ester. The results gave new knowledge on the possible generation of highly reactive radicals that could lead to the formation of antigenic structures.

Factors influencing the rearrangement of bis-allylic hydroperoxides by manganese lipoxygenase

Manganese lipoxygenase (Mn-LOX) catalyzes the rearrangement of bis-allylic S-hydroperoxides to allylic R-hydroperoxides, but little is known about the reaction mechanism. 1-Linoleoyl-lysoglycerophosphatidylcholine was oxidized in analogy with 18:2n-6 at the bis-allylic carbon with rearrangement to C-13 at the end of lipoxygenation, suggesting a "tail-first" model. The rearrangement of bis-allylic hydroperoxides was influenced by double bond configuration and the chain length of fatty acids. The Gly316Ala mutant changed the position of lipoxygenation toward the carboxyl group of 20:2n-6 and 20:3n-3 and prevented the bis-allylic hydroperoxide of 20:3n-3 but not 20:2n-6 to interact with the catalytic metal. The oxidized form, Mn(III)-LOX, likely accepts an electron from the bis-allylic hydroperoxide anion with the formation of the peroxyl radical, but rearrangement of 11-hydroperoxyoctadecatrienoic acid by Mn-LOX was not reduced in D(2)O (pD 7.5), and aqueous Fe(3+) did not transfer 11S-hydroperoxy-9Z,12Z,15Z-octadecatrienoic acid to allylic hydroperoxides. Mutants in the vicinity of the catalytic metal, Asn466Leu and Ser469Ala, had little influence on bis-allylic hydroperoxide rearrangement. In conclusion, Mn-LOX transforms bis-allylic hydroperoxides to allylic by a reaction likely based on the positioning of the hydroperoxide close to Mn(3+) and electron transfer to the metal, with the formation of a bis-allylic peroxyl radical, beta-fragmentation, and oxygenation under steric control by the protein.

Corrugoside, a new immunostimulatory α-galactoglycosphingolipid from the marine sponge Axinella corrugata

Corrugoside ( 1a), a new immunostimulatory triglycosilated α-galactoglycosphingolipid, was isolated from the marine sponge Axinella corrugata, and its structure determined by spectral analysis and chemical degradation. Compound 1a activated murine NKT cells in vitro, with a potency of about 2 logs lower than that of αGalCer. Four stereoisomeric glycosphingolipids ( 2a– 2d) were also obtained, β-glucosylceramides bearing unusual endoperoxide and allylic hydroperoxide functionalities on the sphinganine chain. They were shown to be photooxidation artifacts of the known glycosphingolipids 3, also present in the sponge. A possible role of compound 3 as a singlet oxygen scavenger to protect the organism from oxidative damage is proposed.

Biomarkers derived from heterolytic and homolytic cleavage of allylic hydroperoxides resulting from alkenone autoxidation

Laboratory incubation of alkenone mixtures with tert-butyl hydroperoxide and di- tert-butyl nitroxide (radical initiator) in hexane, as a means to simulate alkenone autoxidation processes, rapidly led to the formation of allylic hydroperoxides, whose presence was recently demonstrated in Emiliania huxleyi cells. After incubation in seawater and subsequent reduction with NaBH 4 (to reduce residual hydroperoxides before analysis), these reaction products quickly disappeared and were replaced by complex mixtures of n-alcohols, fatty acids, alkyldiols and hydroxyacids. Methyl alkenones produced saturated n-alkan-1-ols and fatty acids ranging from C 13 to C 16 and two series of C 13−C 16 (ω-1)-hydroxyacids and (1,ω-1)-diols. Ethyl alkenones also afforded C 13−C 16 saturated n-alkan-1-ols and fatty acids, accompanied by the production of C 14−C 17 (ω-2)-hydroxyacids and (1,ω-2)-diols. Deuterium labelling allowed us to show that most of the n-alkan-1-ols, hydroxyacids and alkyldiols resulted from the reduction during the NaBH 4 treatment of the corresponding aldehydes, ketoxyacids and ketoxyaldehydes formed from heterolytic or homolytic cleavages of allylic hydroperoxyl groups resulting from the oxidation of the double bonds of di- and triunsaturated alkenones. Amongst these products, the (ω-1)- and (ω-2)-hydroxyacids formed after NaBH 4 reduction of the (ω-1)- and (ω-2)-ketoxyacids were selected as potential biomarkers for alkenone autoxidation. Re-examination of lipid extracts of post-bloom seawater particulate matter samples from the DYFAMED station in the Ligurian Sea (where strong autoxidative alteration of the lipid distributions had previously been detected) showed the presence of significant amounts of 12-hydroxytetradecanoic, 13-hydroxytetradecanoic, 14-hydroxyhexadecanoic and 15-hydroxyhexadecanoic acids thus providing good evidence that these autoxidative processes occur in natural samples.

In vivo transformations of artemisinic acid in Artemisia annua plants

Artemisinic acid labeled with both 13C and 2H at the 15-position has been fed to intact plants of Artemisia annua via the cut stem, and its in vivo transformations studied by 1D- and 2D-NMR spectroscopy. Seven labeled metabolites have been isolated, all of which are known as natural products from this species. The transformations of artemisinic acid—as observed both for a group of plants, which was kept alive by hydroponic administration of water and for a group, which was allowed to die by desiccation—closely paralleled those, which have been recently described for its 11,13-dihydro analog, dihydroartemisinic acid. It seems likely therefore that similar mechanisms, involving spontaneous autoxidation of the Δ 4,5 double bond in both artemisinic acid and dihydroartemisinic acid and subsequent rearrangements of the resultant allylic hydroperoxides, may be involved in the biological transformations, which are undergone by both compounds. All of the sesquiterpene metabolites, which were obtained from in vivo transformations of artemisinic acid retained their unsaturation at the 11,13-position, and there was no evidence for conversion into any 11,13-dihydro metabolite, including artemisinin, the antimalarial drug, which is produced by A. annua. This observation led to the proposal of a unified biosynthetic scheme, which accounts for the biogenesis of many of the amorphane and cadinane sesquiterpenes that have been isolated as natural products from A. annua. In this scheme, there is a bifurcation in the biosynthetic pathway starting from amorpha-4,11-diene leading to either artemisinic acid or dihydroartemisinic acid; these two committed precursors are then, respectively, the parents for the two large families of highly oxygenated 11,13-dehydro and 11,13-dihydro sesquiterpene metabolites, which are known from this species.