N-oxyl Radical Research Articles

The N-Hydroxyphthalimide catalyzed oxidation of cyclohexene to cyclohexenyl hydroperoxide: Reasons for deactivation and stability of the catalyst

Selective oxidation of cyclohexene to cyclohexenyl hydroperoxide catalyzed by N-hydroxyphthalimide (NHPI) was studied. Kinetic observations and 13C and 1H NMR spectroscopy showed that accumulation of cyclohexenyl hydroperoxide was accompanied by deactivation of the catalyst. A mechanism of the deactivation through phthalimido N-oxyl radical (PINO) addition to vinyl position of olefin was suggested. Responsible for the deactivation, PINO-C6H10-OOH hydroperoxide adducts were detected in the reaction conditions, and their molecular structure was elucidated by DFT technique. The mechanism explained an unexpected experimental effect, that is, lowering the oxygen partial pressure improved the stability of NHPI without decrease in production of cyclohexenyl hydroperoxide.

Generation and Confinement of Long-Lived N-Oxyl Radical and Its Photocatalysis.

Generation of controllable carbon radical under the assistance of N-oxyl radical is an efficient method for the activation of C-H bonds in hydrocarbons. We herein report that irradiation of α-Fe2O3 and N-hydroxyphthalimide (NHPI) under 455 nm light generates phthalimide-N-oxyl radical (PINO*), which after being formed by oxidation with holes, is confined on α-Fe2O3 surface. The half-life time of the confined radical reaches 22 s as measured by in situ electron paramagnetic resonance (EPR) after the light being turned off. This allows the long-lived N-oxyl radical to abstract the H from C-H bond to form a carbon radical that reacts with molecular oxygen to form R3C-OO· species, decomposition of which leads to oxygenated products.

Distinguishing ionic and radical mechanisms of hydroxylamine mediated electrocatalytic alcohol oxidation using NO-H bond dissociation energies.

The mechanism of N-oxyl radical catalyzed oxidation is a long-standing scientific problem. In this work, radical or ionic mechanisms in electrocatalytic oxidation of alcohols are discussed on the NO-H bond dissociation energy (BDE) scale. A thermodynamic model was built to outline the range of BDEs for the catalysts that react via the two mechanisms. The N-oxyl radical catalyzed electrocatalytic benzyl alcohol oxidations with NO-H BDEs smaller than 74 kcal mol-1 reacted by an ionic mechanism, and with BDEs greater than 78 kcal mol-1 reacted by a radical mechanism. Oxidizing aliphatic alcohols via a radical mechanism requires catalysts with BDEs even greater than that of N-hydroxyphthalimide (NHPI), and the ionic mechanism requires catalysts with BDEs smaller than 74 kcal mol-1. With either the ionic or radical mechanism, catalysts with larger BDEs correspond to a smaller activation energy of the key step. Future design of N-oxyls with catalytic activity in alcohol oxidation can be streamlined by our efforts.

Hydrogen Atom Transfer (HAT) Processes Promoted by the Quinolinimide-N-oxyl Radical. A Kinetic and Theoretical Study.

A kinetic study of the hydrogen atom transfer (HAT) reactions from a series of organic compounds to the quinolinimide-N-oxyl radical (QINO) was performed in CH3CN. The HAT rate constants are significantly higher than those observed with the phthalimide-N-oxyl radical (PINO) as a result of enthalpic and polar effects due to the presence of the N-heteroaromatic ring in QINO. The relevance of polar effects is supported by theoretical calculations conducted for the reactions of the two N-oxyl radicals with toluene, which indicate that the HAT process is characterized by a significant degree of charge transfer permitted by the π-stacking that occurs between the toluene and the N-oxyl aromatic rings in the transition state structures. An increase in the HAT reactivity of QINO was observed in the presence of 0.15 M HClO4 and 0.15 M Mg(ClO4)2 due to the protonation or complexation with the Lewis acid of the pyridine nitrogen that leads to a further decrease in the electron density in the N-oxyl radical. These results fully support the use of N-hydroxyquinolinimide as a convenient substitute for N-hydroxyphthalimide in the catalytic aerobic oxidations of aliphatic hydrocarbons characterized by relatively high C-H bond dissociation energies.

Aerobic Oxidation of 4-Alkyl-N,N-dimethylbenzylamines Catalyzed by N-Hydroxyphthalimide: Protonation-Driven Control over Regioselectivity.

A change in regioselectivity has been observed in the hydrogen atom transfer (HAT) reactions from 4-alkyl-N,N-dimethylbenzylamines (alkyl = ethyl, isopropyl, and benzyl) to the phthalimide N-oxyl radical (PINO) by effect of protonation. This result can be rationalized on the basis of an acid-induced deactivation of the C-H bonds α to nitrogen toward HAT to PINO as evidenced by the 104-107-fold decrease in the HAT rate constants in acetonitrile following addition of 0.1 M HClO4. This acid-induced change in regioselectivity has been successfully applied for selective functionalization of the less activated benzylic C-H bonds para to the CH2N(CH3)2 group in the aerobic oxidation of 4-alkyl-N,N-dimethylbenzylamines catalyzed by N-hydroxyphthalimide in acetic acid.

フェントン試薬によるN－オキシル化合物の分解

2,2,6,6-Tetramethylpiperidine-1-oxyl radical (TEMPO) and their derivatives, 4-acetamide-TEMPO and 4-hydroxy-TEMPO, were dissolved in water, and their degradation behavior by Fenton reaction was studied under various conditions, considering the treatment of the N-oxyl radical-containing washing effluents formed during TEMPO-mediated oxidation of various celluloses. The N-oxyl radicals were treated with FeSO4 and H2O2 in water at pH 2.7 and 35 ̊C for various times, and time-dependent concentrations of the N-oxyl radicals were determined by electron spin resonance. When 0.29 mmol FeSO4 and 0.34 mmol H2O2 were used to the 100 mL solution containing 0.01 g N-oxyl radical (i.e., ~100 ppm), its concentration became below the detection limit (< 0.01 ppm) after Fenton reaction for 90 min. When 5% (v/v) ethanol, dimethylsulfoxide or acetone was present in the TEMPO-containing solution, similar degradation behavior by Fenton reaction was observed. The degradation products of TEMPO present in the supernatant and solid fractions formed during Fenton reaction were analyzed by gas-chromatography-mass spectroscopy, solid- and liquid-state 13C-NMR, ion chromatography and others. The results indicate that the N-oxyl radical compounds were mostly degraded to CO2, water and nitrate/nitrite ions by Fenton reaction. Thus, Fenton reaction is available for the treatment of washing effluents formed during TEMPO-mediated oxidation of celluloses.

Selective cross-dehydrogenative C–O coupling of N-hydroxy compounds with pyrazolones. Introduction of the diacetyliminoxyl radical into the practice of organic synthesis

Oxidative C–O coupling of oximes, N-hydroxyphthalimide, and N-hydroxybenzotriazole with pyrazolones via formation of N-oxyl radicals is described.

Structure–performance landscape of N-alkoxyphthalimides as organocatalysts in aerobic oxidation

N-Alkoxyphthalimides were studied to design new-type organocatalysts for aerobic oxidation that are capable of metal/initiator-freely forming both phthalimide N-oxyl radicals and alkyl radicals in situ via their light/heat-induced homolysis. Our results show that their >NO–C bond strengths and HOMO-LUMO gaps change greatly upon altering N-alkoxy groups, which greatly decrease when their N-alkoxy groups include steric fluorenyl, xanthenyloxy, or triphenylmethyl groups. The conventional substituents on the bilateral phenyl rings of N-benzyloxyphthalimide have negligible effects on their >NO–C bond strengths, but significantly tune their HOMO-LUMO gaps. The photochemical activity of N-benzyloxy-4-aminophthalimide and N-4-amino-benzyloxyphthalimide may be similar to that of known N-triphenylmethyloxyphthalimide and N-diphenylmethyloxyphthalimide. Both the thermal and photochemical stability of N-acetyloxyphthalimides are higher than those of N-alkoxyphthalimides, but their hydrolysis to form N-hydroxyphthalimide is more favorable. The present work allows a reasonable prediction of the catalytic performance of N-alkoxyphthalimides and provides a new perspective for the rational design of organocatalysts for industrial applications.

Nonheme iron complex-catalyzed efficient alcohol oxidation by t-BuOOH with N-hydroxyphthalimide (NHPI) as co-catalyst: Implication of high valent iron-oxo species

Two iron catalysts ([Fe(bpc)Cl2][Et4N] (1a) and [Fe(Me2bpb)Cl2][Et3NH] (1b)) displayed efficient catalysis in oxidation of various alcohols to the corresponding carbonyl products using t-BuOOH as an oxidant in the presence of N-hydroxyphthalimide (NHPI) under mild conditions. 1a having an electron-withdrawing group showed a little better catalytic activity than that of 1b with an electron-donating group. The mechanistic studies through Hammett plot, deuterium isotope effect, and the use of 2-methyl-1-phenylprop-2-yl hydroperoxide (MPPH) as a mechanistic probe suggested that the reactive oxidants responsible for the alcohol oxidation possibly involved FeIVO species, alkoxy radical (RO), and phthalimide N-oxyl radical (PINO). On the other hand, the presence of imidazole increased the heterolytic cleavage of Fe-OOR intermediate to form FeVO species and accelerated its OO bond cleavage rate. In particular, the formation of FeVO intermediate via the heterolytic cleavage of Fe-OOR species in the presence of imidazole in the catalytic oxidation systems of nonheme iron complexes with t-BuOOH was substantialized, for the first time, to the best of our knowledge.

Enhanced Structural Variety of Nonplanar N-Oxyl Radical Catalysts and Their Application to the Aerobic Oxidation of Benzylic C-H Bonds.

The design and synthesis of structurally variable, nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation, etherification, and acetoamidation of benzylic C-H bonds are described. The catalytic oxidation of C-H bonds represents a powerful tool to synthesize oxygenated functional molecules from simple hydrocarbons in a straightforward way. Electron-deficient N-oxyl radical catalysts, such as phthalimidoyl N-oxyl (PINO) radical, generated from N-hydroxyphthalimide (1), have attracted much attention because of their applications in the oxidation of C-H bonds with high bond dissociation energy (BDE). However, a few sites in 1 are available for structural modifications and improvements of the catalytic performance. By replacing one carbonyl group in 1 with a trifluoromethyl (CF3)-substituted sp(3)-carbon, we generated an additional tunable site and a nonplanar backbone, while retaining the desirable electron-withdrawing properties and increasing the lipophilicity with respect to 1. We synthesized a variety of N-hydroxy precatalysts containing such a CF3 moiety, and investigated their utility in the aerobic oxidation of benzylic C-H bonds. Precatalysts with electron-withdrawing substituents, such as trifluoroethoxy and the acetophenone moieties, afforded higher yields than a corresponding methoxy-substituted analogue. The introduction of substituents at the aromatic ring was also effective, as evident from the performance of 7-CF3 and 4,5,6,7-tetrafluoro precatalysts. Especially the combination of trifluoroethoxy- and 4,5,6,7-tetrafluoro substitution afforded a superior performance. These catalyst systems exhibited high functional group tolerance during the aerobic oxidation of C-H bonds, and benzylic etherification and Ritter-type reactions could be carried out at room temperature when a selected precatalyst and N-bromosuccinimide (NBS) were used.

Chemo- and regioselective oxygenation of C(sp3)-H bonds in aliphatic alcohols using a covalently bound directing activator and atmospheric oxygen.

Chemically reactive directing groups (directing activators) represent a promising strategy for mild and regioselective C(sp3)-H functionalization. The use of a radical N-oxyl directing activator promoted the aerobic oxygenation of benzylic, propargylic, tertiary, and unactivated acyclic methylene C(sp3)-H bonds in aliphatic alcohols with γ- (or δ-) selectivity under mild conditions (room temperature to 50 °C). The reaction was unaffected by the presence of various oxidation-sensitive functional groups, which proved to be problematic in previously reported studies on the oxidation of C(sp3)-H bonds. Structural modifications on the directing activator altered the regioselectivity, and thus provided an ultra-remote aerobic C(sp3)-H oxygenation. The observed reactivity and regioselectivity could be rationalized in terms of the intramolecular conformational accessibility of the N-oxyl radical and the electronic characteristics of C(sp3)-H bonds.

Well-Known Mediators of Selective Oxidation with Unknown Electronic Structure: Metal-Free Generation and EPR Study of Imide-N-oxyl Radicals.

Nitroxyl radicals are widely used in chemistry, materials sciences, and biology. Imide-N-oxyl radicals are subclass of unique nitroxyl radicals that proved to be useful catalysts and mediators of selective oxidation and CH-functionalization. An efficient metal-free method was developed for the generation of imide-N-oxyl radicals from N-hydroxyimides at room temperature by the reaction with (diacetoxyiodo)benzene. The method allows for the production of high concentrations of free radicals and provides high resolution of their EPR spectra exhibiting the superhyperfine structure from benzene ring protons distant from the radical center. An analysis of the spectra shows that, regardless of the electronic effects of the substituents in the benzene ring, the superhyperfine coupling constant of an unpaired electron with the distant protons at positions 4 and 5 of the aromatic system is substantially greater than that with the protons at positions 3 and 6 that are closer to the N-oxyl radical center. This is indicative of an unusual character of the spin density distribution of the unpaired electron in substituted phthalimide-N-oxyl radicals. Understanding of the nature of the electron density distribution in imide-N-oxyl radicals may be useful for the development of commercial mediators of oxidation based on N-hydroxyimides.

ChemInform Abstract: Organocatalytic Aerobic Oxidation of α‐Fluoroalkyl Alcohols to Fluoroalkyl Ketones at Room Temperature.

The organocatalytic aerobic oxidation of electron-deficient α-fluoroalkyl alcohols at room temperature is described. The resulting fluoroalkyl ketones are versatile synthetic intermediates for a variety of fluorine-containing molecules. This otherwise difficult transformation has now been accomplished by the reaction of α-fluoroalkyl alcohols with N-oxyl radicals, catalytically generated from 9-azabicyclo[3.3.1]nonan-3-one N-oxyl/nitrogen oxide (keto-ABNO/NOx) and oxygen in acetic acid (AcOH), affording the corresponding fluoroalkyl ketones in high yield. This operationally simple reaction can be performed under mild conditions, and was applied to a wide range of alcohols (20 examples), thus demonstrating a high functional group tolerance. Moreover, a modified one-pot protocol based on this method was able to convert an aldehyde to a trifluoromethyl ketone on a gram scale.

Selective aerobic oxidation of alcohols by a mesoporous graphitic carbon nitride/N-hydroxyphthalimide system under visible-light illumination at room temperature

By combination of photocatalysis and organocatalysis, a metal-free system composed of mesoporous graphitic carbon nitride (mpg-C3N4) and N-hydroxyphthalimide (NHPI) offers an efficient and environmentally friendly method for the oxidation of alcohols at room temperature. As a wide-band gap semiconductor, mpg-C3N4 absorbs visible light and uses the energy to activate NHPI, resulting in high catalytic activity in the subsequent oxidation of alcohols. Interestingly, the main oxidation product of benzyl alcohol can be tuned from benzoic acid to benzaldehyde by increasing the ratio of mpg-C3N4 in the catalyst system. To further understand the reaction route, electron spin resonance and Fourier transform infrared measurements were carried out, confirming that active oxygen and phthalimide N-oxyl radicals formed in the mpg-C3N4/NHPI system. Based on these results, a catalytic mechanism for the mpg-C3N4/NHPI system was proposed. Moreover, this metal-free system also works well for the oxidation of various aromatic alcohols with good selectivity for aldehydes or ketones.

Organocatalytic Aerobic Oxidation of α‐Fluoroalkyl Alcohols to Fluoroalkyl Ketones at Room Temperature

AbstractThe organocatalytic aerobic oxidation of electron‐deficient α‐fluoroalkyl alcohols at room temperature is described. The resulting fluoroalkyl ketones are versatile synthetic intermediates for a variety of fluorine‐containing molecules. This otherwise difficult transformation has now been accomplished by the reaction of α‐fluoroalkyl alcohols with N‐oxyl radicals, catalytically generated from 9‐azabicyclo[3.3.1]nonan‐3‐one N‐oxyl/nitrogen oxide (keto‐ABNO/NOx) and oxygen in acetic acid (AcOH), affording the corresponding fluoroalkyl ketones in high yield. This operationally simple reaction can be performed under mild conditions, and was applied to a wide range of alcohols (20 examples), thus demonstrating a high functional group tolerance. Moreover, a modified one‐pot protocol based on this method was able to convert an aldehyde to a trifluoromethyl ketone on a gram scale.magnified image

Copper-catalyzed aerobic C - C bond cleavage of lactols with N-hydroxy phthalimide for synthesis of lactones.

The transformation of cyclic hemiacetals (lactols) into lactones has been achieved by Cu-catalyzed aerobic CC bond cleavage in the presence of N-hydroxy phthalimide (NHPI). The present process is composed of a multistep sequence including a) formation of exo-cyclic enol ethers by dehydration; b) addition of phthalimide N-oxyl radical to the enol ethers followed by trapping of the resulting C-radicals with molecular oxygen to form peroxy radicals; c) reductive generation of oxy radicals and subsequent β-radical fragmentation to generate lactones.

ChemInform Abstract: Metal‐Free Aerobic Oxidations Mediated by N‐Hydroxyphthalimide. A Concise Review

AbstractReview: 73 refs.

Chiral N-hydroxybenzamides as potential catalysts for aerobic asymmetric oxidations.

Chiral N-hydroxybenzamides (1H-3H) have been synthesized as precursors of chiral short-lived N-oxyl radicals 1(•)-3(•). The latter species have been generated by oxidation of 1H-3H with Pb(OAc)4 or hydrogen abstraction from 1H-3H by the tert-butoxyl radical and characterized by UV-vis spectrophotometry and EPR spectroscopy. Through a kinetic study of the hydrogen atom transfer processes promoted by 1(•)-3(•) from three chiral benzylic substrates (1-phenylethylamine, 1-phenylethanol, and α-vinylbenzyl alcohol), a moderate chiral discrimination has been found, with selectivity factors 0.5 ≤ k(H)(S)/k(H)(R) ≤ 2.

Importance of π-stacking interactions in the hydrogen atom transfer reactions from activated phenols to short-lived N-oxyl radicals.

A kinetic study of the hydrogen atom transfer from activated phenols (2,6-dimethyl- and 2,6-di-tert-butyl-4-substituted phenols, 2,2,5,7,8-pentamethylchroman-6-ol, caffeic acid, and (+)-cathechin) to a series of N-oxyl radical (4-substituted phthalimide-N-oxyl radicals (4-X-PINO), 6-substituted benzotriazole-N-oxyl radicals (6-Y-BTNO), 3-quinazolin-4-one-N-oxyl radical (QONO), and 3-benzotriazin-4-one-N-oxyl radical (BONO)), was carried out by laser flash photolysis in CH3CN. A significant effect of the N-oxyl radical structure on the hydrogen transfer rate constants (kH) was observed with kH values that monotonically increase with increasing NO-H bond dissociation energy (BDENO-H) of the N-hydroxylamines. The analysis of the kinetic data coupled to the results of theoretical calculations indicates that these reactions proceed by a hydrogen atom transfer (HAT) mechanism where the N-oxyl radical and the phenolic aromatic rings adopt a π-stacked arrangement. Theoretical calculations also showed pronounced structural effects of the N-oxyl radicals on the charge transfer occurring in the π-stacked conformation. Comparison of the kH values measured in this study with those previously reported for hydrogen atom transfer to the cumylperoxyl radical indicates that 6-CH3-BTNO is the best N-oxyl radical to be used as a model for evaluating the radical scavenging ability of phenolic antioxidants.

Comparing the catalytic efficiency of ring substituted 1-hydroxybenzotriazoles as laccase mediators

A series of ring substituted 1-hydroxybenzotriazoles (6-X-HBTs) have been tested as mediators in the laccase-promoted oxidation of 4-methoxybenzyl alcohol, 3,4-dimethoxybenzyl alcohol, and the dimeric lignin model 1-(3,4-dimethoxyphenyl)-2-phenoxyethanol. The effect of the aryl substituents on the yields of oxidation products is remarkable. The catalytic mediation efficiency increases as the electron releasing (ER) properties of the substituent increases up to a maximum value for 6-CH3-HBT, which resulted a very efficient mediator. Both the oxidation of the 6-X-HBTs to the N-oxyl radicals (6-X-BTNO) by laccase and the hydrogen atom transfer (HAT) process from the benzylic C–H to the 6-X-BTNO contribute to the overall reactivity. The former process is favored by ER substituents that lower the mediator redox potentials. On the other hand, ER substituents decrease the 6-X-BTNO reactivity in the HAT process due to a decrease in the NO–H BDE value, as assessed in this study through a radical equilibration technique.