Thermal decomposition mechanisms of tert-alkyl peroxypivalates studied by the nitroxide radical trapping technique

The thermolysis of a series of tert-alkyl peroxypivalates 1 in cumene has been investigated by using the nitroxide radical-trapping technique. tert-Alkoxyl radicals generated from the thermolysis underwent the unimolecular reactions, beta-scission, and 1,5-H shift, competing with hydrogen abstraction from cumene. The absolute rate constants for beta-scission of tert-alkoxyl radicals, which vary over 4 orders of magnitude, indicate the vastly different behavior of alkoxyl radicals. However, the radical generation efficiencies of 1 varied only slightly, from 53 (R = Me) to 63% (R = Bu(t)()), supporting a mechanism involving concerted two-bond scission within the solvent cage to generate the tert-butyl radical, CO(2), and an alkoxyl radical. The thermolysis rate constants of tert-alkyl peroxypivalates 1 were influenced by both inductive and steric effects [Taft-Ingold equation, log(rel k(d)) = (0.97 +/- 0. 14)Sigmasigma - (0.31 +/- 0.04)SigmaE(s)(c), was obtained].     

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.     

Generation of Oxygen-Centered Radicals by Reaction of Nitrate Esters with Tri-n-Butyltin Hydride

Treatment of nitrate esters wilh tri-n-butyltin hydride and AIBN in benzene at reflux is a convenient way to generate oxygen-centered (alkoxyl) radicals.     

Generation of N-tert-butyl-α-phenylnitrone radical adducts in iron breakdown of tert-butyl-hydroperoxide

ESR spectroscopy coupled to the spin trapping technique was used to evaluate the generation of radical species arising from the ferrous ion induced decomposition of tert-butyl hydroperoxide (’BuOOH) in methylene chloride. We report here that N-tert-butyl-α-phenylinitrone (PBN) can trap peroxyl radicals generated in the ferrous ion induced breakdown of high concentration of ’BuOOH (IM) at room temperature, the radical adduct being stable under the light. The peroxyl radical formation was demonstrated by direct ESR measurements at 77K. In contrast, alkoxyl and methyl radicals were trapped only in the presence of low hydroperoxide concentration (ImM). In order to measure the hyperfine splitting constants (hfsc) of the PBN-methyl adduct spectra were obtained in the presence of diphenylamine (DPA) or 2,6-di-tert-butyl-4-methylphenol (BHT), which quenched the alkoxyl radical. For this latter radical, the hfsc were calculated by computer simulation. A mechanism for a direct interaction between DPA and the alkoxyl radical is presented. DPA quenched the peroxyl radical in the reaction of high hydroperoxide concentrations, with the concomitant generation of a DPA nitrogen-based radical.     

p-Nitrobenzenesulfenate esters as precursors for laser flash photolysis studies of alkyl radicals

A series of p-nitrobenzenesulfenate esters was used in laser flash photolysis (LFP) studies to generate alkoxyl radicals that fragmented to give the (2,2-diphenylcyclopropyl)methyl radical. Rate constants for the beta-scission reactions increased as a function of the carbonyl compound produced in the fragmentation reaction in the order CH2O < MeCHO < Me2CO < PhCHO < Ph2CO and increased with increasing solvent polarity. For alkoxyl radicals that fragment to produce benzaldehyde and benzophenone, the beta-scission reactions are faster than 1,5-hydrogen atom abstractions when the incipient carbon radical is as stable as a secondary alkyl radical, and this entry to carbon radicals can be used in LFP kinetic studies.     

On the mechanism and kinetics of radical reactions of epoxyketones and epoxynitriles induced by titanocene chloride

The reactions of a series of epoxynitriles and epoxyketones induced by titanocene chloride have been studied. The kinetics of the decyanogenation of beta,gamma-epoxynitriles with Ti(III) corresponds to a radical reaction (k25 approximately 106 s-1), as demonstrated by competition experiments with H-transfer from 1,4-cyclohexadiene (1,4-CHD) or PhSH or conjugate addition to acrylonitrile. The 5-exo cyclization onto nitrile induced by Ti(III) is a radical reaction (k25 approximately 107 s-1) as seen in competition experiments with H-transfer from PhSH or the titanocene-water complex. The iminyl or alkoxyl radicals generated by 5-exo cyclization onto nitriles or ketones only undergo a reduction with Ti(III). This reaction overwhelms any alternative process, such as tandem cyclization onto alkenes or beta-scission. Iminyl radicals generated by 4-exo cyclizations onto nitriles undergo reduction with Ti(III) and beta-scission reaction in a ratio of 96:4 when the alpha-substituent is CN. Alkoxyl radicals from 4-exo cyclizations onto ketone carbonyls undergo reduction with Ti(III) and beta-scission in a ratio of 60:40 when the alpha-substituent is COOR. In nearly all the reactions studied, the role of Ti(III) is triple: a radical initiator (homolytic cleavage of oxirane), a Lewis acid (coordination to CN or C=O), and a terminator (reduction of iminyl or alkoxyl radicals).     

Inter- and intramolecular pathways for the formation of tetrahydrofurans from beta-(Phosphatoxy)alkyl radicals. Evidence for a dissociative mechanism

beta-(Phosphatoxy)alkyl radicals generated by photolysis of Barton PTOC esters in the presence of allyl alcohol and tert-butyl mercaptan undergo nucleophilic substitution followed by 5-exo-trig radical ring closure leading to tetrahydrofurans in good yield and with high trans selectivity. beta-(Phosphatoxy)alkyl radicals obtained by intramolecular hydrogen 1,5-abstraction with an alkoxyl radical undergo nucleophilic displacement providing tetrahydrofurans. The ensemble of results, including the effects of leaving groups and substituents, strongly support a dissociative mechanism for these radical nucleophilic displacement reactions.     

Intramolecular reactions of free radicals formed from artemisinin

Two cyclic alkoxyl radicals are formed as a result of peroxide bridge scission in artemisinin. Intramolecular reactions of these radicals induce the cascade of reactions of isomerization, decyclization, and decomposition of formed free radicals. It includes 14 reactions of intramolecular free radical hydrogen transfer, 17 reactions of decyclization of alkoxyl and alkyl radicals, and 4 reactions of decomposition of alkoxyl, acyl, and carboxyl radicals. The enthalpies of these 35 reactions are calculated. Using intersection parabolas method, activation energies and rate constants of all these reactions are calculated. The most rapid reactions are selected for every intermediate free radical. © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 37: 554–565, 2005     

Synthesis and thermal decomposition of N,N-dialkoxyamides

N,N-dialkoxyamides 1c, a virtually unstudied member of the new class of anomeric amides, amides bearing two electronegative atoms at nitrogen, have been synthesised in useful yields directly from hydroxamic esters using phenyliodine(III)bis(trifluoroacetate) (PIFA). Infrared carbonyl stretch frequencies and carbonyl (13)C NMR properties have been reported, which support strong inhibition of amide resonance in these amides. Their thermal decomposition reactions in mesitylene at 155 °C proceed by homolysis to form alkoxyamidyl and alkoxyl free radicals in preference to HERON rearrangements to esters. The reactions follow first-order kinetics and for a series of N,N-dimethoxy-4-substituted benzamides, activation energies of 125-135 kJ mol(-1) have been determined together with weakly negative entropies of activation.     

Alkylation of Allyl/Alkenyl Sulfones by Deoxygenation of Alkoxyl Radicals

A challenging deoxygenation of alkoxyl radicals from readily accessible alcohol derivatives was developed, affording facile synthesis of functionalized alkenes with good functional group tolerance under mild reaction conditions. Because alkoxyl radicals can easily undergo β-fragmentations or hydrogen abstractions, this new strategy for deoxygenation of alkoxyl radicals is highly valuable. Moreover, mechanistic studies revealed that the electron-neutral phosphine acts as the deoxygenation reagent.     

Initiation of radical polymerization by peroxyacetates: Polymer end-group analysis by electrospray ionization mass spectrometry

End-groups of poly(methyl methacrylate) from radical solution polymerization of MMA using tert-butyl peroxyacetate (TBPA), tert-amyl peroxyacetate (TAPA), 1,1,2,2- tetramethylpropyl peroxyacetate (TMPPA), and 1,1,3,3-tetramethylbutyl peroxyacetate (TMBPA) as the initiators were analyzed via electrospray ionization mass spectrometry (ESI-MS). The type and the relative concentration of the radical species, which actually initiate macromolecular growth, are determined. In the majority of cases, these species differ from the primary radicals from thermal decomposition of the peroxyacetates. Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was applied for unambiguous peak assignment. The methylcarbonyloxyl radical, which is formed by the decomposition of all peroxyacetates, was found to undergo decarboxylation yielding an initiating methyl radical. TAPA- and TMPPA-derived alkoxyl radicals mainly show β-scission, TMBPA-derived alkoxyl radicals additionally undergo a 1,5-hydrogen-shift reaction. The tert-butoxyl radicals produced from TBPA undergo pronounced chain-transfer reaction prior to their decomposition into methyl radicals and acetone. In the case of using benzene as a relatively inert solvent, the tert-butoxyl radicals exhibit transfer to monomer yielding polymer molecules, which do not carry any initiator-derived end-groups. By using mesitylene as a cosolvent, small amounts of star polymer were generated via multiple hydrogen abstraction by tert-butoxyl radicals from the three individual methyl groups of mesitylene. This uncomplicated procedure of modification of end-group and polymer topology may be attractive for facile adjustment of polymer viscosity in technical processes. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2453–2467, 2007     

Mechanism of action of sensors for reactive oxygen species based on fluorescein-phenol coupling: the case of 2-[6-(4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid

We demonstrate the ability of a sensor containing a tethered fluorescein-phenol structure to react with peroxyl radicals and with an oxidizing agent such as potassium ferricyanide. This latter reaction yields the corresponding peroxyl radical as observed by EPR analysis. We propose that the reaction of the sensor with peroxyl and alkoxyl radicals is also initiated by the formation of the phenoxyl radicals, which is followed by radical-radical reactions and product hydrolysis responsible for the release of fluorescein. The proposed mechanism is based on results obtained by laser flash photolysis, HPLC and EPR studies of the reaction of peroxyl and alkoxyl radicals with 4-phenoxylphenol, a molecule used to mimic the behavior of the sensor.     

Antioxidant action of organic sulfites—II. Esters of sulfurous acid as primary antioxidants

The effect of esters of sulfurous acid as primary antioxidants was examined. Different aliphatic, aromatic, open-chain and cyclic sulfites were synthesized. The reactions of organic sulfites with RO₂ and RO radicals, the chain carriers of the autoxidation of hydrocarbons and polymers, were simulated by means of the thermal decomposition of azobisisobutyronitrile (AIBN) in the presence of oxygen and of di-tert-butylperoxalate (DTBPO). The reactivity of organic sulfites with 2-cyanoisopropylperoxyl radicals is low. Only aromatic sulfites are able to trap peroxyl radicals; however, they are not very effective primary antioxidants. The reactions of the organic sulfites with tert-butoxyl radicals generally lead to an increase in the rate of decomposition of DTBPO, as determined from rate constants measured at 50 °C. A decomposition of DTBPO induced by liberated tert-butyl radicals in the presence of alkyl sulfites is very probable. Alkyl sulfites and aromatic sulfites with aliphatic groups act mainly as hydrogen donors in reactions with alkoxyl and peroxyl radicals.     

Competition between mono-and bimolecular reactions of artemisinin alkoxyl radicals

The competition between intramolecular and bimolecular reactions of alkoxyl radicals formed from artemisinin was theoretically analyzed. The enthalpies of these reactions were calculated. The activation energies and rate constants of reactions of intramolecular hydrogen atom transfer, decyclization, and decomposition of alkoxyl radicals of artemisinin and several its derivatives, as well as the activation energies and rate constants of reactions of these radicals with the C-H, S-H, and O-H bonds in biological substrates and their analogs were calculated by the intersecting parabolas method The fastest reactions of artemisinin alkoxyl radicals were identified. The full kinetic scheme of transformation of these radicals was proposed. Artemisinin radicals with the free valence on the carbon atom are predominantly formed due to the transformation of the artemisininoxyl radicals. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1502–1510, September, 2006.     

Beneficial effect of internal hydrogen bonding interactions on the beta-fragmentation of primary alkoxyl radicals. Two-step conversion of D-xylo- and D-ribofuranoses into L-threose and D-erythrose, respectively

Primary alkoxyl free radicals were generated from their readily synthesized N-phthalimido derivatives under reductive conditions. Primary alkoxyl radicals derived from their corresponding xylo- and ribofuranose derivatives underwent, exclusively, an unusual beta-fragmentation affording L-threose and D-erythrose derivatives, respectively. This occurs because the alkoxyl radical is capable of achieving an internal hydrogen-bonding interaction leading to a stable six-membered ring intramolecular hydrogen-bonded structure. When the hydroxyl group is protected, the beta-fragmentation pathway is prevented and the hydrogen atom transfer (HAT) pathway occurs. Computational studies provided strong support for the experimental observations.     

On the synthesis of β-bromohydrine ethers via intermolecular alkoxyl radical addition to bicyclo[2.2.1]heptene

Primary, secondary, and tertiary alkoxyl radicals add exo-selectively to the olefinic π-bond in bicyclo[2.2.1]heptene to afford exo-2-alkoxybicyclo[2.2.1]hept-3-yl radicals, which are trapped with BrCCl₃ preferentially from the endo face to furnish β-bromohydrine ethers in 23-67% yield.     

4-Terf-Butylperoxymethyl-9-Methoxypsoralen as Intercalating Photochemical Alkoxyl-Radical Source for Oxidative DNA Damage

We describe the synthesis of a novel psoralen peroxide 1 that generates on irradiation (350 nml alkoxyl radicals, namely tert-butoxyl radicals, as confirmed by electron spin resonance studies with the spin trap 5,5-dimethyl-pyrroline-N-oxide. The radical source intercalates into the DNA, which has been demonstrated by linear-flow-dichroism measurements. Thus, the alkoxyl radicals are formed advantageously directly in the DNA matrix. In supercoiled pBR322 DNA, the generation of strand breaks by the photochemically or metal-catalyzed generated alkoxyl radicals is demonstrated. Photosensitization by the psoralen chromophore was excluded because similar substances that do not release radicals caused no DNA damage, nor were the photoproducts of the peroxide 1 active. With calf thymus DNA, 8-oxoGua and small amounts of guanidine-releasing products, e.g. oxazolone, were observed. However, in these reactions the photoproduct also displayed some DNA-oxidizing capacity.     

Oxidative free radical reactions of enamino esters

Oxidative free radical reactions of enamino esters are described. Electrophilic carbon-centered radicals produced by the cerium(IV) ammonium nitrate (CAN) oxidation of β-dicarbonyl compounds undergo efficient addition to the C-C double bond of enamino esters. This CAN mediated free radical reaction between enamino esters and β-dicarbonyl compounds provides a novel method for the synthesis of highly substituted pyrroles. The direct CAN oxidation of β-enaminocinnamates gave the dimerization products effectively.     

Synthesis of highly functionalized chiral nitriles by radical fragmentation of beta-hydroxy azides. Convenient transformation of aldononitriles into 1,4- and 1,5-iminoalditols

The synthesis of highly functionalized nitriles by an alkoxyl radical fragmentation of cyclic beta-hydroxy azides is described. The alkoxyl radicals were generated by reaction of the alcohols with (diacetoxyiodo)benzene and iodine under mild conditions compatible with the presence of sensitive substituents and the protective groups most frequently used in carbohydrate chemistry. To explore the scope and limitations of this methodology, experiments were carried out using a variety of beta-hydroxy azides of the carbohydrate (1-6, 33, and 41), monoterpenoid (21 and 22), and steroid (23-25) families of natural products. Of special interest are the aldopentonitriles (15-18, 34, and 42) and aldotetrononitriles (19 and 20) synthesized from the corresponding 2-azido-2-deoxycarbohydrates. To demonstrate the versatility of these aldononitriles as chiral synthons, 1,4-imino-1-deoxysugar (37) and 1,5-imino-1-deoxysugar (43) analogues of the polyhydroxypyrrolidine and -piperidine types were prepared.     

Synthesis of acyclic nucleosides and other C-1 substituted alditols from carbohydrates using a tandem alkoxyl radical β-fragmentation–nucleophilic addition

The oxidative β-fragmentation of alkoxyl radicals generated from easily available carbohydrates is an efficient methodology to obtain acyclic nucleosides and other C-1 substituted alditols. In the reaction conditions an oxycarbenium ion is generated, which can be trapped by a variety of oxygen, carbon and nitrogen nucleophiles, in good yields and stereoselectivities.