N-oxyl Radical Research Articles

Hydrogen-Bond-Assisted Electrocatalytic Semi-Oxidation of 5-Hydroxymethylfurfural into 2,5-Diformylfuran by Operando Dissociated N-Oxyl Mediator.

The conversion of 5-hydroxymethylfurfural (HMF) to 2,5-diformylfuran (DFF) is a promising approach for enhancing biomass utilization. Nevertheless, traditional methods using noble metal catalysts face challenges due to high costs and poor selectivity towards DFF. Herein, we developed a novel catalytic electrode integrating N-hydroxyphthalimide (NHPI) into a metal-organic framework on a hydrophilic carbon cloth. This design significantly enhances the selective adsorption of HMF due to stronger hydrogen-bond interaction between the electrode's hydrophilic surface and the C(sp3)-OH group in HMF compared to the C(sp2)=O in DFF. Additionally, the electro-driven dissociation of the NHPI-linker generates stabilized N-Oxyl radicals that promote selective semi-oxidation of HMF under neutral conditions. As a result, this approach achieves a high yield rate of 138.2 mol molcat-1 h-1 with a selectivity of 96.7% for the HMF-to-DFF conversion. This work introduces a novel strategy for designing catalytic electrodes with stabilized N-Oxyl radicals, and offers a promising method for electrocatalytic DFF synthesis, leveraging hydrogen-bond interaction between electrode surface and HMF.

Revisiting the Reactivity of the Dismissed Hydrogen Atom Transfer Catalyst Succinimide-N-oxyl.

Phthalimide-N-oxyl (PINO) and related radicals are promising catalysts for C-H functionalization reactions. To date, only a small number of N-oxyl derivatives have demonstrated improved activities over PINO. We postulate that the lack of success in identifying superior catalysts is associated not only with challenges in the design and synthesis of new structures, but also the way catalysts are evaluated and utilized. Catalyst evaluation typically relies on the use of chemical oxidants to generate N-oxyl radicals from their parent N-hydroxy compounds. Herein we provide an example where a potential-controlled electrochemical analysis reveals that succinimide-N-oxyl (SINO) compares favorably to PINO as a hydrogen atom transfer (HAT) catalyst-in contrast to previous claims based on other approaches. Our efforts to understand the basis for the greater reactivity of SINO relative to PINO have underscored that the HAT kinetics are significantly influenced by factors beyond changes in thermodynamics. This is perhaps best illustrated by the similar reactivity of tetrachloro-PINO and SINO despite the latter engaging in substantially more exergonic reactions. The key role of HAT transition state (TS) polarization prompted the design and initial characterization of a chlorinated SINO derivative, which we found to be the most reactive N-oxyl HAT catalyst reported to date.

Synthesis of ω-functionalized ketones from strained cyclic alcohols by ring-opening and cross-recombination between alkyl and N-oxyl radicals.

Radical ring-opening oxyimidation of cyclobutanols and cyclopropanols with the formation of ω-functionalized ketones was discovered. The oxidative C-O coupling proceeds via the interception of a primary alkyl radical generated from a cyclic alcohol with a reactive radical generated in situ, which is an electron-deficient N-oxyl radical. The developed conditions allow for the balanced generation rates of carbon- and N-oxyl radicals, which are necessary for their selective cross-recombination. Thus, typical competitive dimerization processes of carbon-centered radicals, their intermolecular cyclization, and N-oxyl radical self-decay are suppressed. The method is applicable to a wide range of cyclobutanols and results in oxyimidated ketones in yields of up to 82%.

A simple reaction pathway allowing easy EPR characterization of N-oxyl radicals

Mixing a dinuclear CuII complex with a primary or secondary amine in excess in the presence of dioxygen with or without toluene yields N-oxyls radicals, here (CH3)2CHNHO·, and CuI entities.

Spirobifluorene-based conjugated microporous polymer embedded with N-hydroxyphthalimide as a synergistic photocatalyst for selective solvent-dependent aerobic oxidations

N-Hydroxyphthalimide organocatalytic sites are embedded into a spirobifluorene-based conjugated microporous polymer for developing a synergistic green and selective photocatalytic system governed by O2˙−, 1O2, and phthalimide N-oxyl radicals.

C-H Fluorination Promoted by Pyridine N-Oxyl Radical

Inspired by C-H hydroxylation by cytochrome P450 enzymes (P450s), we report here a method for preparing organofluorides through single-electron transfer (SET) process, in which the pyridine N-oxyl radical greatly promotes...

Aerobic oxidation of alkyl aromatics to ketones catalyzed by biomimetic copper complex and N-hydroxyphthalimide (NHPI) under mild conditions

A galactose oxidase-like copper complex (CuIIL) (Ligand: N, N′-bis(2-hydroxy-3,5-di-tert-butylphenyl)-2,2′-diaminobiphenyl) was synthesized and used to catalyze the aerobic oxidation of alkyl aromatics to ketones in presence of N-hydroxyphthalimide (NHPI). The catalytic system exhibited excellent performance and tolerance under mild conditions. Mechanistic studies indicated that NHPI could be activated smoothly to generate phthalimide N-oxyl (PINO) radical in the presence of CuIIL. The kinetic isotope effect (KIE) studies showed that the generation of PINO radical was the rate-determining step.

Matching the metal oxides with a conjugated and confined N-oxyl radical for the photocatalytic C(sp3)–H bond activation

Generating controllable N-oxyl radicals is an efficient method for the C–H bonds activation. Here the promotion effect of N-hydroxyphthalimide (NHPI) on the photocatalytic C(sp3)–H bond activation over various metal oxides was systemically studied with control experiments, UV-Vis DRS, FT-IR, ESR, and PCR. Two photocatalytic mechanisms were highlighted for the generation of critical PINO radical from NHPI: (1) The hole oxidation mechanism, the photo-induced hole (h+) of metal oxides directly oxidize the adsorbed NHPI* to a confined PINO*; (2) Ligand-to-metal charge transfer (LMCT) mechanism, the light induces the electron transfer from adsorbed NHPI* to oxides with a wide-band gap and provides a confined PINO*. Furthermore, this work also highlights a lattice-molecular structure matching effect to explain the success of certain oxides in building the h+ oxidation or LMCT systems with NHPI. The corresponding results can inspire further photocatalysis of semiconductors in C–H bond activation with versatile N-oxyl radicals.

Fabrication of micro-reactors by a self-assembly of cationic surfactants to mediate NHPI/Co catalyzed selective aerobic oxidation of cumene to cumyl hydroperoxide

A highly efficient transformation from cumene to cumyl hydroperoxide (CHP) is pursued industrially. Herein, didodecyl dimethyl ammonium bromide (DDAB) as a phase transfer catalyst was found an outstanding role for aerobic oxidation of cumene to CHP with a conversion of 99.5 % and a selectivity of 83.5 % at near room temperature. The promotion can partially be attributed to the formation of the reversed multilamellar vesicles (MLVs) as micro-reactors via a self-assembly. The vesicles promoted the enrichments of cumene on the outer surface due to their outward hydrophobic chains (didodecyl), and enhanced the concentrations of NHPI and cobaltous ions in the MLVs malls for the inward head groups, leading to close contacts between the catalyst and the substrate and a highly efficient transformation from cumene to CHP. Cumyl, cumyl oxyl, cumyl peroxyl, methyl, phthalimide N-oxyl (PINO) radicals and dicumyl, dicumyl peroxide (DCP) were well confirmed, demonstrating an intact propagation chain of from cumene to CHP.

Catalytic oxidation of hydrocarbon with the organic metal-free system of N-hydroxyphthalimide/tert‑butyl nitrite at room temperature

Catalytic oxidation of hydrocarbons under mild conditions is a meaningful and challenging process. N-hydroxyphthalimide (NHPI) combining with tert‑butyl nitrite (TBN) as the promoter was used in 1,2-dichloroethane (DCE) to efficiently catalyzed the oxidation of fluorene to fluorenone. At room temperature, both conversion of fluorene and selectivity of fluorenone reached 96%. The presence of TBN facilitated the dissolution of NHPI in the weakly polar solvent of DCE, and then the active phthalimide N-oxyl radical (PINO) was efficiently generated under the synergistic action of TBN and DCE. With the present NHPI/TBN system, the efficient oxidation of a series of hydrocarbons under mild conditions was also realized.

Free Radicals in the Queue: Selective Successive Addition of Azide and N-Oxyl Radicals to Alkenes.

The selective successive addition of azide (•N3) and N-oxyl radicals to alkenes is demonstrated, despite each of the two radicals being known to attack C═C bonds and the mixture of radical adducts possibly being expected. The proposed radical mechanism was supported by density functional theory calculations, electron paramagnetic resonance, and radical trapping experiments. The reaction proceeds at room temperature with the available reagents: NaN3, N-hydroxy compounds, and PhI(OAc)2 as the oxidant. The method can be applied for N-hydroxyimides, N-hydroxyamides, N-hydroxybenzotriazole, and oximes as N-oxyl radical precursors. Vinylarenes, aliphatic alkenes, and even electron-deficient methyl methacrylate were successfully functionalized.

Redox properties of N-hydroxyimides in sulfuric acid-acetonitrile mixed solution as a HAT mediator for alcohol oxidation

Two hydroxyimides, N-hydroxysuccinimide and N-hydroxy-1,8-naphthalimide, showed chemically reversible redox responses in a sulfuric acid-acetonitrile mixture. In the mixed solution containing benzyl alcohol, catalytic oxidation of alcohol using N-oxyl radicals generated by the oxidation of hydroxyimide as a mediator was observed. The reaction between the mediator and alcohol was quantitatively evaluated from measurements by rotating disk electrode voltammetry.

Synthesis of phenyliodine(III) bis(3-bromopropionate) for an organocatalyzed Markovnikov-type bromo-aminoxidation of vinylarenes

An organocatalytic Markovnikov-type bromo-aminoxidation of styrene derivatives was achieved by using in-situ-generated bromine and N-oxyl radicals, and the desired products were obtained in moderate to good yields. The bromine radical was generated from phenyliodine(III) bis(3-bromopropionate) through consecutive decarboxylation and deethylenation reactions via an organocatalytic SET process. Phenyliodine(III) bis(3-bromopropionate) also served as the oxidant for the generation of the N-oxyl radicals, while the N-oxyl radical was also crucial for the generation of the key β-enaminyl radical intermediate that was required for the SET process.

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

Diisopropylcarbodiimide (DIC) constitutes one of the most widely used coupling reagents for amide bond formation in peptide synthesis. We have previously reported that DIC contains a varying amount of sulfur (61–2030 ppm), and that the main S-containing impurity in DIC is the thiourea DITU, which exhibits an excellent ability to suppress side reactions caused by N-oxyl radicals formed from common N-hydroxyl-coupling additives such as HOBt and Oxyma (Green Chem. 2019, 21, 5990). Aiming to understand how the quality of DIC impacts peptide synthesis, here, we report an evaluation of 14 batches of GMP-grade DIC from seven different vendors. With the evaluation by elemental analysis (S), gas chromatography–mass spectrometry, high-performance liquid chromatography, liquid chromatography-mass spectrometry, and nuclear magnetic resonance, we determined that the main S-containing impurity in DIC currently in use is not DITU, but rather the diazetidine-2-thione [1,3-diisopropyl-4-(isopropylimino)-1,3-diazetidine-2-thione, DIDT], formed by a 2 + 2 cycloaddition between DIC and iPr-NCS. The identity of DIDT was confirmed by a synthesis from DIC and iPr-NCS, followed by spiking a batch of DIC with the synthesized DIDT material. In a comparative evaluation of DITU and DIDT aimed at determining their ability to suppress breakdown of Fmoc-Cys(Trt)-OH caused by N-oxyl radicals formed from Oxyma, DITU completely prevented the Cys decomposition, whereas DIDT had no effect on the suppression of the breakdown of the amino acid. Finally, catalytic amounts of DITU as well as thiols DTT and NAC had a positive effect on minimization of the HOBt-induced breakdown of Fmoc-Trp(Boc)-OH, whereas the urea DIU, formed in every DIC-mediated peptide coupling reaction, accelerated the breakdown of the Trp substrate.

Bioconjugation of Au25 Nanocluster to Monoclonal Antibody at Tryptophan.

We report the first bioconjugation of Au25 nanocluster to a monoclonal antibody at scarcely exposed tryptophan (Trp) residues toward the development of high-resolution probes for cryogenic electron microscopy (cryo-EM) and tomography (cryo-ET). To achieve this, we improved the Trp-selective bioconjugation using hydroxylamine (ABNOH) reagents instead of previously developed N-oxyl radicals (ABNO). This new protocol allowed for the application of Trp-selective bioconjugation to acid-sensitive proteins such as antibodies. We found that a two-step procedure utilizing first Trp-selective bioconjugation for the introduction of azide groups to the protein and then strain-promoted azide-alkyne cycloaddition (SPAAC) to attach a bicyclononyne (BCN)-presenting redox-sensitive Au25 nanocluster was essential for a scalable procedure. Covalent labeling of the antibody with gold nanoclusters was confirmed by various analytical methods, including cryo-EM analysis of the Au25 nanocluster conjugates.

Oxidations of aromatic sulfides promoted by the phthalimide N-oxyl radical (PINO)

The oxidation of a series of alkyl aryl sulfides promoted by the phthalimide N-oxyl radical (PINO) has been investigated by kinetic and product analysis. Sulfoxides are formed as major reaction products in the oxidation of thioanisoles and benzyl phenyl sulfides. The observation of fragmentation products in the oxidation of 2-phenyl-2-propyl phenyl sulfide and diphenylmethyl phenyl sulfide indicates that the reaction involves an initial electron transfer reaction from the sulfide to PINO with the formation of aryl sulfide radical cations and the anion PINO-. Combination of the species then leads to a radical adduct precursor of sulfoxides while the rapid C–S cleavage occurs with aryl sulfide radical cations that can form the stable 2-phenyl-2-propyl or diphenylmethyl carbocation.

Building N-hydroxyphthalimide organocatalytic sites into a covalent organic framework for metal-free and selective oxidation of silanes.

A novel crystalline covalent organic framework COF-NHPI was built by a bottom-up strategy to guarantee highly ordered embedment of the N-hydroxyphthalimide (NHPI) units as nitroxyl radical organocatalytic sites. The COF-NHPI was demonstrated to be a metal-free, highly selective and heterogeneous catalyst for the efficient oxidation of various silanes to the corresponding silanols. Mechanistic studies revealed that the critical phthalimido N-oxyl radical was generated in situ to govern the catalysis.

Redox-active molecules as organocatalysts for selective oxidative transformations - an unperceived organocatalysis field.

Organocatalysis is widely recognized as a key synthetic methodology in organic chemistry. It allows chemists to avoid the use of precious and (or) toxic metals by taking advantage of the catalytic activity of small and synthetically available molecules. Today, the term organocatalysis is mainly associated with redox-neutral asymmetric catalysis of C-C bond-forming processes, such as aldol reactions, Michael reactions, cycloaddition reactions, etc. Organophotoredox catalysis has emerged recently as another important catalysis type which has gained much attention and has been quite well-reviewed. At the same time, there are a significant number of other processes, especially oxidative, catalyzed by redox-active organic molecules in the ground state (without light excitation). Unfortunately, many of such processes are not associated in the literature with the organocatalysis field and thus many achievements are not fully consolidated and systematized. The present article is aimed at overviewing the current state-of-art and perspectives of oxidative organocatalysis by redox-active molecules with the emphasis on challenging chemo-, regio- and stereoselective CH-functionalization processes. The catalytic systems based on N-oxyl radicals, amines, thiols, oxaziridines, ketone/peroxide, quinones, and iodine(I/III) compounds are the most developed catalyst types which are covered here.

Catalytic Ammonia Oxidation to Dinitrogen by a Nickel Complex.

We report a nickel complex for catalytic oxidation of ammonia to dinitrogen under ambient conditions. Using the aryloxyl radical 2,4,6-tri-tert-butylphenoxyl (t Bu3 ArO⋅) as a H atom acceptor to cleave the N-H bond of a coordinated NH3 ligand up to 56 equiv of N2 per Ni center can be generated. Employing the N-oxyl radical 2,2,6,6-(tetramethylpiperidin-1-yl)oxyl (TEMPO⋅) as the H-atom acceptor, up to 15 equiv of N2 per Ni center are formed. A bridging Ni-hydrazine product identified by isotopic nitrogen (15 N) studies and supported by computational models indicates the N-N bond forming step occurs by bimetallic homocoupling of two paramagnetic [Ni]-NH2 fragments. Ni-mediated hydrazine disproportionation to N2 and NH3 completes the catalytic cycle.

Non-metal-mediated N-oxyl radical (TEMPO)-induced acceptorless dehydrogenation of N-heterocycles via electrocatalysis.

The development of protocols for direct catalytic acceptorless dehydrogenation of N-heterocycles with metal-free catalysts holds the key to difficulties in green and sustainable chemistry. Herein, an N-oxyl radical (TEMPO) acting as an oxidant in combination with electrochemistry is used as a synthesis system under neutral conditions to produce N-heterocycles such as benzimidazole and quinazolinone. The key feature of this protocol is the utilization of the TEMPO system as an inexpensive and easy to handle radical surrogate that can effectively promote the dehydrogenation reaction. Mechanistic studies also suggest that oxidative TEMPOs redox catalytic cycle participates in the dehydrogenation of 2,3-dihydro heteroarenes.