Ring opening versus ring expansion in rearrangement of bicyclic cyclobutylcarbinyl radicals

Ring opening and expansion of multicyclic cyclobutylcarbinyl radicals provides an appealing method for the construction of heavily substituted ring systems in a stereocontrollable fashion. Here we conducted the first, systematic study on the regioselectivity in the rearrangement of various synthetically relevant cyclobutylcarbinyl radicals. It was found that a two-layer ONIOM method, namely ONIOM(QCISD(T)/6-311+G(2d,2p):B3LYP/6-311+G(2df,2p)), could accurately predict the free energy barriers of the ring openings of cyclobutylcarbinyl radicals with a precision of 0.3 kcal/mol. By using this powerful tool we found that the regiochemistry for the ring opening of monocyclic cyclobutylcarbinyl radicals could be easily predicted by the relative stability of the two possible carbon radical products. A linear correlation was found between the activation and reaction free energies. This observation indicated that the ring opening of cyclobutylcarbinyl radicals was strongly affected by the thermodynamic factors. On the basis of the above results we extended our study to the rearrangement of bicyclic cyclobutylcarbinyl radicals that could undergo both ring opening and expansion. It was found that for bicyclic cyclobutylcarbinyl radicals whose radical center was located at the bridge methyl group, ring expansion was the favored rearrangement pathway unless a strongly radical-stabilizing substituent was placed in the cyclobutyl ring adjacent to the bridge methyl group. On the other hand, for bicyclic cyclobutylcarbinyl radicals whose radical center was located at the 2-position, ring opening was the favored rearrangement pathway unless a strongly radical-stabilizing substituent was placed in the cyclobutyl ring at the bridge position.     

Relative rates and approximate rate constants for inter- and intramolecular hydrogen transfer reactions of polymer-bound radicals

Measurements of relative rates and rate constants for inter- and intramolecular hydrogen transfer reactions of polymer-bound radicals are reported. The relative rate of reaction of resin-bound primary alkyl radical with tributyltin hydride is about 2 times slower than that of the benchmark reaction in solution. The data do not reveal whether this is due to a reduced rate constant or a lower concentration of tin hydride in the resin phase. Yet the difference between solid and solution reactions is small enough to be neglected, and it appears that rate constants measured in solution can be applied directly to resin-bound radicals. A resin-bound aryl radical abstracts a hydrogen atom rapidly (k = 3 x 10(6) s(-1)) from its own polymer backbone and linker, and a simplified view of the resin as a "solvent" is suggested for predicting such effects with other polymers and linkers. Rapid cyclizations of resin-bound aryl radicals will be possible, but slower cyclizations and most bimolecular reactions will be difficult due to the competing polymer/linker hydrogen transfer.     

Photolysis of 1-alkylcycloalkanols in the presence of (diacetoxyiodo)benzene and I2. Intramolecular selectivity in the beta-scission reactions of the intermediate 1-alkylcycloalkoxyl radicals

The C-C beta-scission reactions of 1-alkylcycloalkoxyl radicals, generated photochemically by visible light irradiation of CH2Cl2 solutions containing the parent 1-alkylcycloalkanols, (diacetoxy)iodobenzene (DIB), and I2, have been investigated through the analysis of the reaction products. The 1-alkylcycloalkoxyl radicals undergo competition between ring opening and C-alkyl bond cleavage as a function of ring size and of the nature of the alkyl substituent. With the 1-propylcycloheptoxyl, 1-propylcyclooctoxyl,and 1-phenylcyclooctoxyl radicals, formation of products deriving from an intramolecular 1,5-hydrogen atom abstraction reaction from the cycloalkane ring has also been observed. The results are discussed in terms of release of ring strain associated to ring opening, stability of the alkyl radical formed by C-alkyl cleavage, and with cycloheptoxyl and cyclooctoxyl radicals, also in terms of the possibility of achieving a favorable geometry for intramolecular hydrogen atom abstraction.     

Electron Spin Resonance of Oxiranyl Radicals in Solution: Configurational Stabilities and Rearrangement Reactions

Several alkyl substituted oxiranyl radicals derived by hydrogen abstraction from oxiranes are observed in solution by ESR.-spectroscopy. The ESR.-spectra demonstrate that oxiranyl radicals have pyramidal configurations at the radical carbon atom and undergo inversion. Alkyl substituted oxiranyls rearrange by ring opening to α-keto alkyl radicals. The rates of inversion decrease and the rates of rearrangement increase with alkyl substitution. The activation parameters of these processes are given for several cases and are related to radical structure. Line broadening effects caused by inversion allow the determination of relative signs of γ-CH₃-coupling constants.     

Competition of monomolecular and bimolecular reactions of the alkyl radicals of artemisinin

The competition between monomolecular and bimolecular reactions of alkyl radicals of artemisinin is considered theoretically. The enthalpies of these reactions are calculated. The activation energies and rate constants of intramolecular hydrogen atom transfer, of the decyclization of the alkyl radicals of artemisinin, and of the bimolecular reactions of these radicals with C-H, S-H, and O-H bonds of biological substrates and their analogues are calculated in the framework of the parabolic model. The intramolecular hydrogen transfer reactions proceed at the highest rate. The bimolecular reactions occur somewhat less rapidly. The fastest of them are the reactions of the alkyl radicals with the thio groups of cysteine. The decyclization reactions of all artemisinin alkyl radicals are very slow.     

Rate constants and Arrhenius functions for ring opening of a cyclobutylcarbinyl radical clock and for hydrogen atom transfer from the Et(3)B-MeOH complex

Kinetics of ring opening of the 1-cyclobutyldodecyl radical (1) were studied, and an Arrhenius function over the temperature range -20 to 47 degrees C was determined. The radical clock reaction has kinetics described by log k = 13.2 - 13.5/2.313 RT (in kcal/mol), and k = 1.5 x 10(3) s(-1) at 20 degrees C. Previous kinetic studies of hydrogen atom transfer trapping of radical 1 by the triethylborane-methanol complex at variable temperatures (J. Org. Chem. 2007, 72, 5098) were analyzed with the newly obtained kinetic data.     

Rate constants for cyclizations of α-hydroxy radical clocks

The 1-hydroxy-1-methyl-6,6-diphenyl-5-hexenyl radical (4a) and the 1-hydroxy-1-methyl-7,7-diphenyl-6-heptenyl radical (4b) were prepared from the corresponding PTOC esters (anhydrides of a carboxylic acid and N-hydroxypyridine-2-thione). The key step in the synthetic method for the precursors was a coupling reaction of the respective carboxylic acids with the thiohydroxamic acid, which was conducted for ca. 5 min and followed rapidly by chromatography. Rate constants for cyclizations of radicals 4a and 4b in acetonitrile and in THF were measured directly between -30 and 60 °C by laser flash photolysis methods. The Arrhenius functions in acetonitrile are log k = 9.9-2.6/2.303RT and log k = 8.9-4.4/2.303RT (kcal mol(-1)) for 4a and 4b, respectively. Rate constants for cyclizations at room temperature of 9 × 10(7) s(-1) and 4 × 10(5) s(-1) are somewhat larger than the rate constants for cyclizations of analogous alkyl radicals. Crude rate constants at room temperature for H-atom trapping of 4a by thiophenol and 4b by t-butylthiol were k(T) = 1.2 × 10(9) M(-1) s(-1) and k(T) = 2 × 10(7) M(-1) s(-1), respectively, which are modestly larger than rate constants for reactions of alkyl radicals with the same trapping agents.     

Structural effects on the beta-scission reaction of alkoxyl radicals. Direct measurement of the absolute rate constants for ring opening of benzocycloalken-1-oxyl radicals

[reaction: see text] The absolute rate constants for beta-scission of a series of benzocycloalken-1-oxyl radicals and of the 2-(4-methylphenyl)-2-butoxyl radical have been measured directly by laser flash photolysis. The benzocycloalken-1-oxyl radicals undergo ring opening with rates which parallel the ring strain of the corresponding cycloalkanes. In the 1-X-indan-1-oxyl radical series, ring opening is observed when X = H, Me, whereas exclusive C-X bond cleavage occurs when X = Et. The factors governing the fragmentation regioselectivity are discussed.     

The Tris(trimethylsilyl)silane/Thiol Reducing System: A Tool for Measuring Rate Constants for Reactions of Carbon‐Centered Radicals with Thiols

An extension of the well‐known ‘free‐radical‐clock’ methodology is described that allows one to determine the rate constants of carbon‐centered radicals with a variety of thiols by using the tris(trimethylsilyl)silane/thiol couple as a reducing system. A total of 20 rate constants for the hydrogen abstraction from a variety of alkyl‐, silyl‐, and aryl‐substituted thiols by the primary‐alkyl radical 2 in toluene at 80° were determined with the aid of the 5‐exo‐trig cyclization as a timing device. Further, seven rate constants for the hydrogen abstraction from a variety of alkyl‐ and silyl‐substituted thiols by the acyl radical 9 in benzene at 80° were measured using the decarbonylation process as a timing device. The rate constants varied over two orders of magnitude from 10⁶ to 10⁸ M ^?1 s^?1. Substituent effects were rationalized. The radical‐trapping abilities of these reducing systems and those of other common hydrogen donors were compared.     

Addition of electrophilic and heterocyclic carbon-centered radicals to glyoxylic oxime ethers

[reaction: see text] Stabilized primary radicals can be formed from alkyl halides in an atom transfer process with Et(3)B. This process depends on the strength of the carbon-halogen bond and the stability of the resulting primary radical. Radicals formed from benzyl iodide and ethyl iodoacetate add to glyoxylic oxime ethers; however, more electrophilic radicals do not. Glyoxylic oxime ethers are also good radical acceptors for heterocyclic carbon-centered secondary radicals, giving novel alpha-amino acid derivatives.     

Photoinduced Electron and H-atom Transfer Reactions of Xanthone by Laser Flash Photolysis

The property of the lowest excited triplet states of xanthone in acetonitrile was investigated using time-resolved laser °ash photolysis at 355 nm. The transient absorption spectra and the quenching rate constants(kq) of the excited xanthone with several amines were determined. Good correlation between lgkq and the driving force of the reactions suggests the electron transfer mechanism, except aniline and 3-nitroaniline (3-NO2-A) which showed energy transfer mechanism. With the appearance of ketyl radical, hydrogen atom transfer also happened between xanthone and dimethyl-p-toluidine, 3,5,N,N-tetramethylaniline, N,N-dimethylaniline, and triethylamine. Therefore, both electron transfer and H-atom transfer occured in these systems. Great discrepancies of kq values were discovered in H-atom abstraction reactions for alcohols and phenols, which can be explained by di?erent abstraction mechanisms. The quenching rate constants between xanthone and alcohols correlate well with the ?-C?H bonding energy of alcohols.     

Radical heterolysis reactions. Dynamics of formation, collapse, and solvation of ion pairs determined by a competition kinetic method

The kinetics of radical heterolysis reactions, including rate constants for radical cation-anion contact ion pair formation, collapse of the contact pair back to the parent radical, and separation of the contact pair to a solvent-separated ion pair or free ions were obtained in several solvents for a beta-mesyloxy radical. Rate constants were determined from indirect kinetic studies using thiophenol as both a radical trapping agent via H-atom transfer and an alkene radical cation trapping agent via electron transfer. [reaction: see text].     

Multi‐faceted Reactivity of Alkyltellurophenols Towards Peroxyl Radicals: Catalytic Antioxidant Versus Thiol‐Depletion Effect

Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO^. radicals with rate constants as high as 10⁷ M ^?1 s^?1 at 303 K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO^. radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro‐oxidative (thiol depletion) when thiol concentrations are low.     

Rate constants for 1,5- and 1,6-hydrogen atom transfer reactions of mono-, di-, and tri-aryl-substituted donors, models for hydrogen atom transfers in polyunsaturated fatty acid radicals

Rate constants for 1,5- and 1,6-hydrogen atom transfer reactions in models of polyunsaturated fatty acid radicals were measured via laser flash photolysis methods. Photolyses of PTOC (pyridine-2-thioneoxycarbonyl) ester derivatives of carboxylic acids gave primary alkyl radicals that reacted by 1,5-hydrogen transfer from mono-, di-, and tri-aryl-substituted positions or 1,6-hydrogen transfer from di- and tri-aryl-substituted positions to give UV-detectable products. Rate constants for reactions in acetonitrile at room temperature ranged from 1 x 10(4) to 4 x 10(6) s(-1). The activation energies for a matched pair of 1,5- and 1,6-hydrogen atom transfers giving tri-aryl-substituted radicals were approximately equal, as were the primary kinetic isotope effects, but the 1,5-hydrogen atom transfer reaction was 1 order of magnitude faster at room temperature than the 1,6-hydrogen atom transfer reaction due to a less favorable entropy of activation for the 1,6-transfer reaction. Solvent effects on the rate constants for the 1,5-hydrogen atom transfer reaction of the 2-[2-(diphenylmethyl)phenyl]ethyl radical at ambient temperature were as large as a factor of 2 with the reaction increasing in rate in lower polarity solvents. Hybrid density functional theory computations for the 1,5- and 1,6-hydrogen atom transfers of the tri-aryl-substituted donors were in qualitative agreement with the experimental results.     

Mutual Effect of Functional Groups and the Radical Center on the Reactivity of Nitroxyl Radicals

This review considers the correlation between the reactivity of nitroxyl radicals (piperidine, pyrroline, pyrrolidine, imidazoline, dihydroquinoline, tetrahydroquinoline, diphenyl nitroxide, etc.) and their chemical structure in terms of the rate constants of reactions between these radicals and hydrazobenzene. 4,4′-Di(tert-butyl)diphenyl nitroxyl has the highest reactivity, and the nitroxyl radical of benzoindolopyrrolidine is the least reactive (the difference is a factor of ∼10⁴). The effects of the metal atom in stable organometallic nitroxyl radicals and of the halogen atom in halogenated nitroxyl radicals on the reactivity of the nitroxyl center are considered. Data on the effect of the nitroxyl center on the reactivity of functional groups in the piperidine nitroxyl radical are generalized. Nitroxyl radicals with an activated double bond are shown by quantum chemical calculations to form cyclic transition complexes with amines, involving both the paramagnetic center and a double bond. This explains why the activated double bond in nitroxyl radicals is more reactive in nucleophilic additions of amines than the same bond in their diamagnetic analogues. The rate constants of nitroxyl reduction with hydrazobenzene and of nitroxyl oxidation with tetranitromethane are related to the σ_ESR constant derived from isotropic hyperfine coupling constants HFC_(aN), and their correlation with Hammett constants is demonstrated. The role of solvents in the reduction and oxidation of the nitroxyl radicals is considered. The influence of hydroxyl radical-polar solvent complexes and hydroxylamine-polar solvent H complexes on the course of reactions is considered for hydrogen atom transfer in systems of a sterically hindered nitroxyl radical and hydroxylamine.__________Translated from Kinetika i Kataliz, Vol. 46, No. 4, 2005, pp. 506–528.Original Russian Text Copyright © 2005 by Malievskii, Shapiro.     

Rate constants for hydrogen atom transfer reactions from bis(cyclopentadienyl)titanium(III) chloride-complexed water and methanol to an alkyl radical

Rate constants for hydrogen atom transfer reactions of the water, deuterium oxide, and methanol complexes of bis(cyclopentadienyl)titanium(III) chloride with the secondary alkyl radical 1-cyclobutyldodecyl (2) were determined using indirect kinetic methods. The rate constant for reaction of Cp2Ti(III)Cl-H2O in THF at ambient temperature was 1.0 x 10(5) M(-1) s(-1), and the kinetic isotope effect was kH/kD = 4.4. In benzene containing 0.95 M methanol, the rate constant for reaction of the Cp2Ti(III)Cl-MeOH at ambient temperature was 7.5 x 10(4) M(-1) s(-1). An Arrhenius function for reaction of the Cp2Ti(III)Cl-H2O complex in THF was log k = 9.1 - 5.5/2.3 RT (kcal/mol). The entropic term for reaction of Cp2Ti(III)Cl-H2O was normal, whereas the entropic term previously found for reaction of the Et3B-H2O complex with radical 2 was unusually small (Jin, J.; Newcomb, M. J. Org. Chem. 2007, 72, 5098).     

An ab initio and DFT study of some halogen atom transfer reactions from alkyl groups to acyl radical

Ab initio calculations using the 6-311G**, cc-pVDZ, and (valence) double-zeta pseudopotential (DZP) basis sets, with (MP2, QCISD, CCSD(T)) and without (HF) the inclusion of electron correlation, and density functional (BHandHLYP, B3LYP) calculations predict that the transition states for the reaction of acetyl radical with several alkyl halides adopt an almost collinear arrangement of attacking and leaving radicals at the halogen atom. Energy barriers (DeltaE(double dagger)) for these halogen transfer reactions of between 89.2 (chlorine transfer from methyl group) and 25.3 kJ mol(-1) (iodine transfer from tert-butyl group) are calculated at the BHandHLYP/DZP level of theory. While the difference in forward and reverse energy barriers for iodine transfer to acetyl radical is predicted to be 15.1 kJ mol(-1) for primary alkyl iodide, these values are calculated to be 6.7 and -4.2 kJ mol(-1) for secondary and tertiary alkyl iodide respectively. These data are in good agreement with available experimental data in that atom transfer radical carbonylation reactions are sluggish with primary alkyl iodides, but proceed smoothly with secondary and tertiary alkyl iodides. These calculations also predict that bromine transfer reactions involving acyl radical are also feasible at moderately high temperature.     

Addition of radicals to quinones—II. ESR spectra of radicals derived from fluoranil

In systems consisting of thermally decomposing benzoyl peroxide in alkylbenzenes, fluoranil behaves as a selective spin trap. As a result of charge transfer (CT) complex formation between alkylbenzenes and fluoranil, the latter traps secondary radicals formed via H-atom abstraction by phenyl radicals from the alkyl group of the aromatic solvents. Weaker CT interaction leads to the trapping of phenyl radicals. The kinetic isotope effect in H-atom abstraction leads to the same result.     

Oxidation of C-H bonds by [(bpy)2(py)RuIVO]2+ occurs by hydrogen atom abstraction

Anaerobic oxidations of 9,10-dihydroanthracene (DHA), xanthene, and fluorene by [(bpy)(2)(py)Ru(IV)O](2+) in acetonitrile solution give mixtures of products including oxygenated and non-oxygenated compounds. The products include those formed by organic radical dimerization, such as 9,9'-bixanthene, as well as by oxygen-atom transfer (e.g., xanthone). The kinetics of these reactions have been measured. The kinetic isotope effect for oxidation of DHA vs DHA-d(4) gives k(H)/k(D) > or = 35 +/- 1. The data indicate a mechanism of initial hydrogen-atom abstraction forming radicals that dimerize, disproportionate and are trapped by the oxidant. This mechanism also appears to apply to the oxidations of toluene, ethylbenzene, cumene, indene, and cyclohexene. The rate constants for H-atom abstraction from these substrates correlate well with the strength of the C-H bond that is cleaved. Rate constants for abstraction from DHA and toluene also correlate with those for oxygen radicals and other oxidants. The rate constant for H-atom transfer from toluene to [(bpy)(2)(py)Ru(IV)O](2+) appears to be close to that predicted by the Marcus cross relation, using a tentative rate constant for hydrogen atom self-exchange between [(bpy)(2)(py)Ru(III)OH](2+) and [(bpy)(2)(py)Ru(IV)O](2+).     

Peroxyesters as precursors to peroxyl radical clocks

The reactions of peroxyl radicals are at the center of the oxidative degradation of essentially all petroleum-derived hydrocarbons and biological lipids and consequently, the inhibition of these processes by radical-trapping antioxidants. Recently described peroxyl radical clocks offer a simple, convenient, and inexpensive method of determining rate constants for H-atom transfer reactions to peroxyl radicals, greatly enabling the kinetic and mechanistic characterization of compounds with antioxidant properties. We follow up our preliminary communication on the development of a methodology utilizing tert-butyl styrylperacetate as a precursor to a versatile peroxyl radical clock with the present paper, wherein we describe a novel naphthyl analogue, which provides for much improved product resolution for analysis, and provide the complete details associated with its development and application. Using this new precursor, and with consideration of the expanded set of reaction products, inhibition rate constants were measured for a variety of representative phenolic and diarylamine radical-trapping antioxidants. We also provide details for the use of this methodology for the determination of mechanistic information, such as kinetic solvent effects, Arrhenius parameters, and kinetic isotope effects.