Alkoxyl Radical Intermediates Research Articles

Unpacking the diversity of monoterpene oxidation pathways via nitrooxy–alkyl radical ring-opening reactions and nitrooxy–alkoxyl radical bond scissions

Terrestrial vegetation emits vast quantities of monoterpenes to the atmosphere. These compounds, once oxidized, can contribute to the formation and growth of secondary organic aerosol (SOA) particles. However, studies report widely different SOA yields from atmospheric oxidation of different monoterpenes, despite their structural similarities. The NO3-radical-initiated oxidation of α-pinene for instance, leads to minimal SOA yields, whereas with Δ-carene a high SOA yield is observed. A previous study indicated that their oxidation mechanisms diverge after formation of a nitrooxy–alkoxyl radical intermediate, whose C–C bond scission reactions can either lead to early termination of the oxidative chain, thus limiting the yield of condensable vapors, or further propagate it, leading to low-volatility products. In this study, we employ computational methods to investigate these reactions in the NO3-radical oxidation of five other monoterpenes: limonene, sabinene, β-pinene, α-thujene and camphene. Additionally, we explore the possibility of rearrangement via ring-opening of the nitrooxy-alkyl radical adducts produced immediately after NO3 radical attack. Our calculations predict that alkyl radical rearrangement is dominant over O2-addition for sabinene, minor but competitive for α-thujene and β-pinene, and negligible for camphene. These rearrangements can induce further propagation of the oxidative chain, and thus higher SOA yields. Concerning alkoxyl radical C–C bond scissions, our results indicate that endocyclic nitrate species (derived from limonene and α-thujene) react preferentially via the channel leading to oxidative chain termination, whereas exocyclic nitrate species (sabinene, β-pinene, and camphene) react preferentially via channels leading to further propagation.

Intramolecular H-Atom Transfers in Alkoxyl Radical Intermediates Underlie the Apparent Oxidation of Lipid Hydroperoxides by Fe(II).

The one-electron reduction of lipid hydroperoxides by low-valent iron species is believed to be a driver of cellular lipid peroxidation and associated ferroptotic cell death. We investigated reactions of cholesterol 7α-OOH, the primary cholesterol autoxidation product, with Fe2+ to find that 7-ketocholesterol (7-KC, an oxidation product) is the major product under these (reducing) conditions. Mechanistic studies reveal the intervention of a 1,2-H-atom shift upon formation of the 7-alkoxyl radical to yield a ketyl radical that can be oxidized by either Fe3+ or O2 to give 7-KC, the most abundant oxysterol in vivo. We also investigated the corresponding reduction of the isomeric cholesterol 5α-OOH and again found that an oxidation product (5-hydroxycholesten-3-one) predominates under reducing conditions. An intramolecular H-atom shift (this time 1,4-) in the initially formed 5-alkoxyl radical is suggested to yield a ketyl radical that is oxidized to give the observed product. It would appear that a 1,2-H shift also accounts for the predominance of ketones over alcohols when unsaturated fatty acid hydroperoxides are exposed to iron-based reductants, which had previously been reported with hematin and demonstrated here with Fe2+. The predominance of 7-KC over the corresponding alcohol is maintained when cholesterol 7α-OOH embedded in phospholipid liposomes is treated with Fe2+ or when ferroptosis is induced in mouse embryonic fibroblasts. Our observation that 7-KC accumulates in ferroptotic cells suggests that it may be a good biomarker for ferroptosis.

Deconstructive Cyanomethylation Enabled by Radical Cross‐Coupling through Multiple C−C Bond and C−H Bond Cleavage

AbstractBeing in its infancy, radical cross‐coupling is highly efficient for C−C bond construction, though suffers from selectivity problems and limited reaction types. New methodologies to realize radical cross‐coupling selectively are highly desired. Herein, an iron catalyzed deconstructive cyanomethylation of unstrained cyclic and linear alcohols with acetonitrile has been developed through radical cross‐coupling. The unprecedented method enables a ring‐opening functionalization of cyclohexanols to produce α‐cyanomethyl ketones. Notably, the highly challenging reaction involves twice C−C single bond cleavage through β‐scission of alkoxyl radical intermediates, and twice C(sp3)−H bond transformation via hydrogen atom transfer (HAT) procedures, resulting in two carbon radical species that realize a radical cross‐coupling process to form a new C(sp3)−C(sp3) bond selectively. α‐arylketo and α‐aryl substituted tertiary alcohols can also be applied as substrates, leading to terminal cyano‐functionalized linear products, with ketone as the leaving fragment. Mechanistically, a new procedure to generate alkoxyl radical with chlorine radical through the in‐situ formed intermediate cycloalkyl hypochlorite was suggested.magnified image

Quantitative assessment of epoxide formation in oil and mayonnaise by 1H-13C HSQC NMR spectroscopy

Lipid oxidation is detrimental for the quality of oil-based foods. Historically, lipid oxidation research focussed on hydroperoxides and aldehydes, but a third class, the epoxides, have been proposed to resolve observed mechanistic anomalies. Here, we developed a 2D 1H-13C HSQC NMR spectroscopic method to quantify epoxides in food in a reproducible (relative standard deviation ≤11.6 %) and sensitive (LoQ 0.62 mmol/kg oil) manner. Lipid hydroperoxides, aldehydes, and epoxides generated in rapeseed oil and mayonnaise were quantified over time by NMR. Epoxides accounted at most for 10–40 % of the products. They were formed after hydroperoxide accumulation, most likely primarily via alkoxyl radical intermediates, which limits their potential as an early oxidation marker. As 99 % and ∼60 % of the epoxide signal intensities were assigned in a fatty acid and sub-structure specific manner, respectively, our quantitative HSQC method will enable unravelling and quantitative modelling of lipid oxidation mechanisms.

Photoinitiated Multicomponent Anti-Markovnikov Alkoxylation over Graphene Oxide.

The development of graphene oxide–based heterogeneous materials with an economical and environmentally–friendly manner has the potential to facilitate many important organic transformations but proves to have few relevant reported reactions. Herein, we explore the synergistic role of catalytic systems driven by graphene oxide and visible light that form nucleophilic alkoxyl radical intermediates, which enable an anti-Markovnikov addition exclusively to the terminal alkenes, and then the produced benzyl radicals are subsequently added with N–methylquinoxalones. This photoinduced cascade radical difunctionalization of olefins offers a concise and applicable protocol for constructing alkoxyl–substituted N–methylquinoxalones.

Oxidation of 4-substituted TEMPO derivatives reveals modifications at the 1- and 4-positions

Potenital pathways for the deactivation of hindered amine light stabilisers (HALS) have been investigated by observing reactions of model compounds--based on 4-substituted derivatives of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO)--with hydroxyl radicals. In these reactions, dilute aqueous suspensions of photocatalytic nanoparticulate titanium dioxide were irradiated with UV light in the presence of water-soluble TEMPO derivatives. Electron spin resonance (ESR) and electrospray ionisation mass-spectrometry (ESI-MS) data were acquired to provide complementary structural elucidation of the odd- and even-electron products of these reactions and both techniques show evidence for the formation of 4-oxo-TEMPO (TEMPONE). TEMPONE formation from the 4-substituted TEMPO compounds is proposed to be initiated by hydrogen abstraction at the 4-position by hydroxyl radical. High-level ab initio calculations reveal a thermodynamic preference for abstraction of this hydrogen but computed activation barriers indicate that, although viable, it is less favoured than hydrogen abstraction from elsewhere on the TEMPO scaffold. If a radical is formed at the 4-position however, calculations elucidate two reaction pathways leading to TEMPONE following combination with either a second hydroxyl radical or dioxygen. An alternate mechanism for conversion of TEMPOL to TEMPONE via an alkoxyl radical intermediate is also considered and found to be competitive with the other pathways. ESI-MS analysis also shows an increased abundance of analogous 4-substituted piperidines during the course of irradiation, suggesting competitive modification at the 1-position to produce a secondary amine. This modification is confirmed by characteristic fragmentation patterns of the ionised piperidines obtained by tandem mass spectrometry. The conclusions describe how reaction at the 4-position could be responsible for the gradual depletion of HALS in pigmented surface coatings and secondly, that modification at nitrogen to form the corresponding secondary amine species may play a greater role in the stabilisation mechanisms of HALS than previously considered.

The mechanism of the reaction of intradiol dioxygenase with hydroperoxy probe: A DFT study

The mechanism for the reaction between an intradiol dioxygenase and a hydroperoxy probe was modeled with the DFT method – B3LYP. Five models of the iron cofactor – probe complexes differing in the total charge and the number of ligands bound to iron were considered. The most important conclusion from the study described in this contribution is that the critical O–O bond cleavage, leading to the alkoxyl radical intermediate, most likely does not yield the reactive oxoferryl species. Instead, in the preferred reaction channel the peroxo group is protonated and the O–O cleavage leads to the ferrous complex with one of the tyrosine ligands oxidized to the tyrosinate radical. The factors affecting the product specificity are also discussed in the paper.

ChemInform Abstract: Radical Species Produced from the Photolytic and Pulse-Radiolytic Degradation of tert-Butyl Hydroperoxide. An EPR Spin Trapping Investigation.

The radicals generated during the photolysis of tert-butyl hydroperoxide have been identified by comparison with those generated by reductive pulse radiolysis of the same compound, by photolysis of di-tert-butyl peroxide, and by oxidative degradation of dimethyl sulfoxide. While ButO˙ can definitely be identified as the primary alkoxyl radical intermediate, the identify of the predominantly-formed peroxyl radical is dependent on the generation system.

AAPH-mediated antioxidant reactions of secoisolariciresinol and SDG

Secoisolariciresinol (SECO ) is the major lignan found in flaxseed (Linum usitatissimum L.) and is present in a polymer that contains secoisolariciresinol diglucoside (SDG ). SECO, SDG and the polymer are known to have a number of health benefits, including reduction of serum cholesterol levels, delay in the onset of type II diabetes and decreased formation of breast, prostate and colon cancers. The health benefits of SECO and SDG may be partially attributed to their antioxidant properties. To better understand their antioxidant properties, SECO and SDG were oxidized using 2,2'-azobis(2-amidinopropane), an in vitro model of radical scavenging. The major lignan radical-scavenging oxidation products and their formation over time were determined. SDG was converted to four major products, which were the result of a phenoxyl radical intermediate. One of these products, a dimer of SDG, decomposed under the reaction conditions to form two of the other major products, and . SECO was converted to five major products, two of which were also the result of a phenoxyl radical intermediate. The remaining products were the result of an unexpected alkoxyl radical intermediate. The phenol oxidation products were stable under the reaction conditions, whereas two of the alcohol oxidation products decomposed. In general, only one phenol group on the lignans was oxidized, suggesting that the number of phenols per molecule may not predict radical scavenging antioxidant ability of lignans. Finally, SECO is a superior antioxidant to SDG, and it may be that the additional alcohol oxidation pathway contributes to its greater antioxidant ability.

Involvement of alkoxyl radical intermediates in the photolysis of 1-alkylcycloalkanols in the presence of bis(pyridine)iodonium tetrafluoroborate: Comparison with the (diacetoxyiodo)benzene/I 2 system

The product distributions observed after visible light irradiation of a series of 1-alkylcycloalkanols ( 1– 3) and bis(pyridine)iodonium tetrafluoroborate (IPy 2BF 4), have been compared with those observed after irradiation of the same substrates in the presence of (diacetoxy)iodobenzene (DIB) and I 2, i.e. under bona fide conditions for alkoxyl radical generation. The observation of very similar product distributions with the two systems strongly supports the previous hypothesis that alkoxyl radical intermediates are formed after photolysis of substrates 1– 3 in the presence of IPy 2BF 4.

4+2] Cyclohexane Ring Formation by a Tandem of a Free Radical Alkylation of a Non-Activated δ-Carbon Atom and Intramolecular Carbanion Cyclo­alkylation

A[4+2] cyclohexane ring formation was achieved by the combination of free radical and ionic reaction sequences. Free radical alkylation of the remote non-activated δ-carbon atom involves addition of 8-carbon radicals, generated by 1,5-hydrogen transfer in alkoxyl radical intermediates, to the radicophilic olefins, while the polar sequence involves the enolate anions as intermediates which undergo a cycloalkylation reaction. The cyclohexane rings were constructed using diverse acyclic compounds 15 and 18 as well as cyclic alkyl arenesulfenates (e.g., 5, 24, 27) as the precursors of alkoxyl radicals (four-carbon atom fragment) and methyl vinyl ketone or other activated olefins as two-carbon atom fragments. Annulation of the cyclohexane ring was applied for the synthesis of a variety of cyclic systems including monocyclic (17 and 20), fused-rings (e.g. 23, 26, 29) and spirocyclic systems (7).

A New, Convenient, Highly Selective Free-Radical Hydroxymethylation of Heteroaromatic Bases by Persulfate Oxidation of Ethylene Glycol and Glycerol, Catalysed by AgNO3

A new, convenient and selective source of hydroxymethyl ( . CH 2 OH) radical has been developed by persulfate oxidation of ethylene glycol with AgNO 3 catalysis. The . CH 2 OH radical is selectively trapped by protonated heteroaromatic bases, providing a new, general process of hydroxymethylation; the importance of the β-scission of the alkoxyl radical intermediate is emphasised.

On the radical brook rearrangement. Reactivity of alpha-silyl alcohols, alpha-silyl alcohol nitrite esters, and beta-haloacylsilanes under radical-forming conditions

Two alkoxyl radical generation methods, lead tetraacetate treatment of alcohols and photolysis of nitrites, were applied to alpha-silyl alcohols 21 and to the corresponding nitrites 25 with a view to forming alpha-silyl alkoxyl radicals 23 and studying their possible radical Brook rearrangement to alpha-silyloxy carbon radicals 24. LTA treatment of 21 led to their quick and efficient conversion into mixed acetyl-silyl acetals 33 under very mild conditions. Photolysis of alpha-alkylmonosubstituted alpha-silyl nitrites 25 to the corresponding aldehydes is considered to proceed through alpha-silyl alkoxyl radical intermediates 23. A concerted process is, however, proposed for the case of the benzyl nitrites analogues. On the basis of these results, it is postulated that resonance stabilization can have a major influence on the evolution of alpha-silyl alkoxyl radicals: should this stabilization be possible, they quickly evolve by alpha-silyl fragmentation; otherwise, they tend to undergo radical Brook rearrangement. It was also found that the radical Brook rearrangement of alpha-silyl cyclopropyloxyl radicals generated from beta-bromoacylsilanes under standard tin-radical conditions is too slow to compete with beta-fragmentation.

An Efficient Aerobic Oxidation of Isobutane to t-Butyl Alcohol by N-Hydroxyphthalimide Combined with Co(II) Species

Abstract Highly selective aerobic oxidation of isobutane to t-butyl alcohol was successfully achieved by the use of a radical catalyst, N-hydroxyphthalimide (NHPI) in the presence of Co(II) salt under relatively mild conditions. The oxidation of isobutane by NHPI combined with Co(acac)2 under a pressure of air (10 atm) in benzonitrile at 100 °C gave t-butyl alcohol in high yield (84%) along with acetone (13%). The reaction is thought to proceed via hydrogen abstraction from isobutane by the phthalimidooxyl radical (PINO), which seems to be a key active species. The formation of acetone can be explained by a partial β-scission of the t-butoxy radical, generated from the redox decomposition of t-butyl hydroperoxide by cobalt ion. Alkyl-substituted butanes and pentanes were difficult to be oxidized selectively under these conditions because of easy degradation to smaller fragments of the resulting alkoxyl radical intermediates.

Mechanism of hydroperoxide reduction by mangano-prostaglandin endoperoxide synthase.

Reaction of manganese-reconstituted prostaglandin endoperoxide synthase (Mn-PGHS) with 15-hydroperoxyeicosatetraenoic acid (15-HPETE) generates two products in nearly equal amounts: 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-ketoeicosatetraenoic acid (15-KETE) [Kulmacz et al. (1994) Biochemistry 33, 5428-5439]. Their proposed mechanism to explain 15-KETE formation, namely oxidation of 15-HETE by the peroxidase activity of MnPGHS, was tested and found not to occur. Instead, 15-KETE may arise by one-electron reduction of 15-HPETE followed by oxidation of an intermediate alkoxyl radical. The mechanism of hydroperoxide reduction by Mn-PGHS was investigated using 10-hydroperoxyoctadeca-8,12-dienoic acid (10-OOH-18:2), a diagnostic probe of hydroperoxide reduction pathways. Reaction of Mn-PGHS with 10-OOH-18:2 generated the two-electron reduced product, 10-hydroxyoctadeca-8,12-dienoic acid (10-OH-18:2), as well as the one-electron reduction products, 10-oxooctadeca-8,12 dienoic acid (10-oxo-18:2) and 10-oxodec-8-enoic acid (10-oxo-10:1) in relative yields of 82, 10, and 7%, respectively. The identity of the one-electron reduction products was confirmed by electrospray ionization mass spectrometry. The detection of 10-oxo-10:1 provides strong evidence for the production of an alkoxyl radical during 10-OOH-18:2 reduction by Mn-PGHS. Like 15-HPETE, reaction of Mn-PGHS with 13-hydroperoxyoctadeca-8,12-dienoic acid (13-OOH-18:2) generated two products in equal amounts: 13-hydroxyoctadeca-8,12-dienoic acid (13-OH-18:2) and the keto fatty acid 13-oxooctadeca-8,12-dienoic acid (13-oxo-18:2). Comparison of the three hydroperoxides demonstrates that 15-HPETE is a much better substrate for Mn-PGHS than 10-OOH-18:2 or 13-OOH-18:2 with 10-fold greater turnovers. The results show that Mn-PGHS catalyzes both one- and two-electron hydroperoxide reduction and that the pathway of alkoxyl radical decomposition is influenced by the protein component of Mn-PGHS and the structure of the alkoxyl radical intermediate.

Reactions of γ-arylalkanols via aryl radical cation and alkoxyl radical intermediates. Part 3. Reactions of 3-arylprop-1-yl hydroperoxides with iron(II) in the presence of copper(II)

A strategy for comparing the 1,5- and 1,6-cyclisation reactions of 3-phenylpropan-1-oxyl radicals is described. Iron(II)-catalysed reduction of 3-(p-methylphenyl)prop-1-yl hydroperoxide and its para-chloro and para-methoxy-substituted analogues, carried out in the presence of copper(II), has been found to give in each case the appropriate para-substituted 3-phenylpropan-1-ol, 3-phenylpropanal and a low yield of a mixture of isomeric 6- and 7-substituted chromans. The alcohols are proposed to form via reduction of either the hydroperoxide or the resulting alkoxyl radical or its cyclised intermediates, and the aldehydes as a result of rearrangement of the alkoxyl radical to an α-hydroxy alkyl radical which subsequently undergoes oxidation. The 7-substituted chromans, which arise directly from 1,6-cyclisation of the alkoxyl radical, were found to dominate the 6-substituted isomers which result from rearrangement of 1,5-cyclised intermediates. This effect is attributed to inefficient interception of the 1,5-cyclised radical intermediate which permits equilibration to the thermodynamically more stable 1,6-cyclised radical isomer to occur. The effect of pH on the reactions has been investigated and although no products typical of the intermediary of aryl radical rations were detected (even under highly acidic conditions), the formation of such intermediates cannot be excluded. Semiempirical MO calculations have been carried out (at the PM3 level of approximation) on a series of model compounds, yielding results which have clarified our understanding of the effect of substituents on the stabilities of the various intermediates arising from the cyclisation reactions of 3-phenylpropan-1-oxyl radicals. Furthermore, these calculations have supported our assumptions regarding the probability and specificity of rearrangements of the spirodienyl intermediates.

Oxidation of a macrocyclic nickel(II) complex by alkyl hydroperoxides

Oxidation of NiL[sup 2+] (L = 1,4,8,11-tetraazacyclotetradecane) by alkyl hydroperoxides in acidic aqueous solutions produces NiL[sup 3+]. Kinetic measurements by the initial-rate method yielded rate constants that were ionic strength dependent. The yields of NiL[sup 3+] depend on the relative concentrations of the reactants and improve in the presence of oxygen. Possible causes for these observations are discussed. Bromide ions alter the stoichiometry and products of the reaction with tert-butyl hydroperoxide but have no effect on the reaction with tert-amyl hydroperoxide. This difference is rationalized in terms of the relative reactivities of the intermediate alkoxyl radicals toward [beta]-scission versus bromide oxidation. The addition of alcohols containing [alpha]-hydrogens (CH[sub 3]OH and (CH[sub 3])[sub 2]CHOH) decreases substantially the yield of NiL[sup 3+] for reactions with both hydroperoxides. Evidence is presented to attribute this effect to the reduction of NiL[sup 3+] by the [alpha]-hydroxyalkyl radicals formed in the reactions of alcohols with alkyl and alkoxyl radical intermediates. 30 refs., 2 figs., 1 tab.