Phthalimide N-oxyl Research Articles

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.

Overlooked interaction between redox-mediator and bisphenol-A in permanganate oxidation

Research efforts on permanganate (Mn(VII)) combined with redox-mediator (RM), have received increasing attention due to their significant performance for bisphenol-A (BPA) removal. However, the mechanisms underpinning BPA degradation remain underexplored. Here we show the overlooked interactions between RM and BPA during permanganate oxidation by introducing an RM—N-hydroxyphthalimide (NHPI). We discovered that the concurrent generation of MnO2 and phthalimide-N-oxyl (PINO) radical significantly enhances BPA oxidation within the pH range of 5.0–6.0. The detection of radical cross-coupling products between PINO radicals and BPA or its derivatives corroborates the pivotal role of radical cross-coupling in BPA oxidation. Intriguingly, we observed the formation of an NHPI-BPA complex, which undergoes preferential oxidation by Mn(VII), marked by the emergence of an electron-rich domain in NHPI. These findings unveil the underlying mechanisms in the Mn(VII)/RM system and bridge the knowledge gap concerning BPA transformation via complexation. This research paves the way for further exploration into optimizing complexation sites and RM dosage, significantly enhancing the system's efficiency in water treatment applications.

Constructing Cu+ and Lewis acid sites enabling the generation of highly reactive N‑oxyl radical for the efficient aerobic oxidation of alkylarenes

Developing heterogeneous catalytic systems with high performance for the oxygenation of C(sp3)–H bonds to carbonyls using molecular oxygen as the oxidant is highly desirable. In the present research, active Cu+ sites have been efficiently constructed based on layered double hydroxides (LDHs) through in-situ reduction during the coprecipitation. Simultaneously, the formed CuZn(Mg)Al-LDH(R) catalysts demonstrated the characters of increased amount of oxygen vacancy and surface Lewis acid site. The newly synthesized catalysts exhibited higher catalytic performance than the samples prepared via conventional method, and up to 49.4% improvement in specific activity was observed in the aerobic oxidation of ethylbenzene. The mechanism study including a series of control experiments, semi-in-situ FT-IR analysis, and EPR analysis, demonstrated that reactive •O2– species generated via the acceleration of Cu+ species, and activated the NHPI (N-hydroxyphthalimide) molecule to form active PINO (phthalimide N-oxyl) species. The oxygen vacancy was verified to be able to activate O2 molecule and promote the formation of active 1O2 species. The surface Lewis acid site was proposed to interact with NHPI molecule, enabling the generation of highly active PINO species. The catalytic system also has the advantages of catalytical and structural stability, recyclability, and tolerance of wide substrate scope. We believe that the synergistic effect between the highly active sites and Lewis acid sites in catalyst can open up new opportunities for the activation of inert C–H bonds via O2/NHPI system.

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.

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.

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.

The design of PINO-like hydrogen-atom-transfer catalysts.

Phthalimide-N-oxyl (PINO) is a valuable hydrogen-atom-transfer (HAT) catalyst for selective C-H functionalization. To advance and optimize PINO-catalysed HAT reactions, researchers have been focused on modifying the phthalimide core structure. Despite much effort and some notable advances, the modifications to date have centred on optimization ofa single parameter of the catalyst, such as reactivity, solubility or stability. Unfortunately, theoptimization with respect to one parameter is often associated with a worsening of the others. The derivation of a singlecatalyst structure with optimal performance across multiple parameters has therefore remained elusive. Here we present an analysis of the structure-activity relationships of PINO and its derivatives as HAT catalysts, which we hope will stimulate further development of PINO-catalysed HAT reactions and, ultimately, lead to much improved catalysts for real-world applications.

Electrochemical Decarboxylative Silylation of α,β-Unsaturated Carboxylic Acids.

An electrochemical method for the decarboxylative silylation of α,β-unsaturated carboxylic acids was developed. A variety of alkenylsilanes could be obtained in satisfactory yields and excellent selectivities under external oxidant- and metal-free conditions. Mechanistic studies showed that the formation of the silyl radical was mediated by NHPI, which produces the hydrogen atom transfer (HAT) reagent phthalimide N-oxyl (PINO) via multiple-site concerted proton-electron transfer (MS-CPET).

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.

Heterogeneous Photocatalysis as a Potent Tool for Organic Synthesis: Cross-Dehydrogenative C-C Coupling of N-Heterocycles with Ethers Employing TiO2/N-Hydroxyphthalimide System under Visible Light.

Despite the obvious advantages of heterogeneous photocatalysts (availability, stability, recyclability, the ease of separation from products and safety) their application in organic synthesis faces serious challenges: generally low efficiency and selectivity compared to homogeneous photocatalytic systems. The development of strategies for improving the catalytic properties of semiconductor materials is the key to their introduction into organic synthesis. In the present work, a hybrid photocatalytic system involving both heterogeneous catalyst (TiO2) and homogeneous organocatalyst (N-hydroxyphthalimide, NHPI) was proposed for the cross-dehydrogenative C-C coupling of electron-deficient N-heterocycles with ethers employing t-BuOOH as the terminal oxidant. It should be noted that each of the catalysts is completely ineffective when used separately under visible light in this transformation. The occurrence of visible light absorption upon the interaction of NHPI with the TiO2 surface and the generation of reactive phthalimide-N-oxyl (PINO) radicals upon irradiation with visible light are considered to be the main factors determining the high catalytic efficiency. The proposed method is suitable for the coupling of π-deficient pyridine, quinoline, pyrazine, and quinoxaline heteroarenes with various non-activated ethers.

Electrochemical PINOylation of Methylarenes: Improving the Scope and Utility of Benzylic Oxidation through Mediated Electrolysis.

A mediated electrosynthetic method has been developed for selective benzylic oxidation of methylarenes. Phthalimide-N-oxyl (PINO) radical generated by proton-coupled electrochemical oxidation of N-hydroxypthalimide serves as a hydrogen atom-transfer (HAT) mediator and as a radical trap for the benzylic radicals generated in situ. This mediated electrolysis method operates at much lower anode potentials relative to direct electrolysis methods for benzylic oxidation initiated by single-electron transfer (SET). A direct comparison of SET and mediated-HAT electrolysis methods with a common set of substrates shows that the HAT reaction exhibits a significantly improved substrate scope and functional group compatibility. The PINOylated products are readily converted into the corresponding benzylic alcohol or benzaldehyde derivative under photochemical conditions, and the synthetic utility of this method is highlighted by the late-stage functionalization of the non-steroidal anti-inflammatory drug celecoxib.

Aminoxyl Catalyzed Electrochemical Ethanol Detection: Development of a New Breathalyzer Using Molecular Catalysis

Blood alcohol concentration (BAC) is the indicator of alcohol intoxication, and its measurement has emerged as the most common analytical procedure requested by law enforcement. Due to its volatility, ethanol vapor can be detected in breath, and its vapor concentration is proportional to BAC. Currently available instrumentation used for breath alcohol content (BrAC) analysis include gas chromatography (GC) and GC coupled with mass spectrometry, infrared (IR) spectroscopy, and fuel cell based electrochemical sensors. GC and IR spectroscopy devices have some drawbacks such as size, initial cost, and operational expense. Electrochemical sensors are capable of miniaturization and are available as portable and handheld breathalyzers. However, the lack of a single use and disposable sensing element, resulting memory effect and the need for frequent recalibration is the main drawback of currently available electrochemical breathalyzers. There have been few attempts at designing a sensing element to improve the current methods of alcohol detection by electrochemical techniques, all relying on enzymatic alcohol oxidation.1 Herein, we report a proof-of-concept non-enzymatic breathalyzer, harnessing the unique catalytic activity of the aminoxyl radical/oxoammonium redox couple toward alcohol oxidation.2 The relatively low redox potentials of aminoxyls, the mild conditions required for use, and their selective interactions with ethanol are their advantages compared to currently available Pt based breathalyzers. Our functional sensing element consists of a screen-printed electrode in which the graphene oxide-based working electrode is modified with aminoxyl derivatives, of which 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate (TMB) was the most efficient derivative. Exposing this modified electrode to simulated breath that contains ethanol, while applying the required potential for oxidation of the aminoxyl radical, generates an electrocatalytic current proportional to the ethanol concentration in the breath. These simple, sensitive, durable, and inexpensive electrodes may contribute to the development of a single-use reliable ethanol sensor for personal or law enforcement applications. Heikenfeld, J.; Jajack, A.; Rogers, J.; Gutruf, P.; Tian, L.; Pan, T.; Li, R.; Khine, M.; Kim, J.; Wang, J.; Kim, J. Wearable Sensors: Modalities, Challenges, and Prospects. Lab Chip 2018, 18, 217.Nutting, J. E.; Rafiee, M.; Stahl, S. S. Tetramethylpiperidine N-Oxyl (TEMPO), Phthalimide N-Oxyl (PINO), and Related N-Oxyl Species: Electrochemical Properties and Their Use in Electrocatalytic Reactions. Chem. Rev. 2018, 118, 4834.

Unveiling the highly disordered NbO6 units as electron-transfer sites in Nb2O5 photocatalysis with N-hydroxyphthalimide under visible light irradiation

Although different NbOx units are present in Nb2O5-based catalysts, the correlations between these structures and activity remain unclear, which considerably hinders the further development of Nb2O5 photocatalysis. Herein, we utilized N-hydroxyphthalimide (NHPI) as the probe molecule to distinguish the role of different NbOx units in the activation of C–H bond under visible light irradiation. With the addition of NHPI, Nb2O5 catalysts with highly disordered NbO6 units exhibited higher activities than that with slightly disordered NbO6 units (419–495 vs. 82 μmol·g−1·h−1) in photocatalytic selective oxidation of ethylbenzene. Revealed by Raman spectra, electron paramagnetic resonance spectra, and transmission-electron-microscopy images, highly disordered NbO6 units were confirmed to act as the active sites for the transfer of photogenerated electrons from NHPI, promoting the generation of phthalimide-N-oxyl (PINO) radicals for the enhanced conversion of ethylbenzene under visible light irradiation. This study provides guidance on the role of local NbOx units in Nb2O5 photocatalysis.

Electrochemical Activation of C-C Bonds through Mediated Hydrogen Atom Transfer Reactions.

Activating inert sp3 -sp3 carbon-carbon (C-C) bonds remains a major bottleneck in the chemical upcycling of recalcitrant polyolefin waste. In this study, redox mediators are used to activate the inert C-C bonds. Specifically, N-hydroxyphthalimide (NHPI) is used as the redox mediator, which is oxidized to phthalimide-N-oxyl (PINO) radical to initiate hydrogen atom transfer (HAT) reactions with benzylic C-H bonds. The resulting carbon radical is readily captured by molecular oxygen to form a peroxide that decomposes into oxygenated C-C bond-scission fragments. This indirect approach reduces the oxidation potential by >1.2 V compared to the direct oxidation of the substrate. Studies with model compounds reveal that the selectivity of C-C bond cleavage increases with decreasing C-C bond dissociation energy. With NHPI-mediated oxidation, oligomeric styrene (OS510 ; Mn =510 Da) and polystyrene (PS; Mn ≈10 000 Da) are converted into oxygenated monomers, dimers, and oligomers.

Biomimetic catalytic aerobic oxidation of C-sp(3)-H bonds under mild conditions using galactose oxidase model compound CuIIL.

Developing highly efficient catalytic protocols for C–sp(3)–H bond aerobic oxidation under mild conditions is a long-desired goal of chemists. Inspired by nature, a biomimetic approach for the aerobic oxidation of C–sp(3)–H by galactose oxidase model compound CuIIL and NHPI (N-hydroxyphthalimide) was developed. The CuIIL–NHPI system exhibited excellent performance in the oxidation of C–sp(3)–H bonds to ketones, especially for light alkanes. The biomimetic catalytic protocol had a broad substrate scope. Mechanistic studies revealed that the CuI-radical intermediate species generated from the intramolecular redox process of CuIILH2 was critical for O2 activation. Kinetic experiments showed that the activation of NHPI was the rate-determining step. Furthermore, activation of NHPI in the CuIIL–NHPI system was demonstrated by time-resolved EPR results. The persistent PINO (phthalimide-N-oxyl) radical mechanism for the aerobic oxidation of C–sp(3)–H bond was demonstrated.

Selective Aerobic Oxidation of P-Methoxytoluene by Co(II)-Promoted NHPI Incorporated into Cross-Linked Copolymer Structure

A wide series of copolymer materials with various contents of 4-vinyl-diisopropyl-phtalate ester (10–90 mol%), divinylbenzene (1–11 mol%) and styrene, as monomers, were obtained by radical copolymerization. In the last steps of the synthesis, diisopropyl ester functionalities were converted into the form of N-hydroxyphthalimide (NHPI) rings. The obtained materials with the NHPI groups immobilized in the copolymer structure were studied by various physicochemical techniques, including FT-IR, UV-Vis-DR, XPS, elemental analysis, and tested as catalysts in aerobic oxidation of p-methoxytoluene in the presence of Co(II) acetate co-catalyst. Conversion of the aromatic substrate was correlated with the NHPI content and cross-linking degree. The best catalytic performance (conversions higher than 23%) was achieved for the copolymer catalysts containing 60% and 30% of 4-vinyl-diisopropyl-phtalate ester. At too high concentrations of NHPI and DVB, some of the NHPI groups were transformed into inactive (C=O)-N=O species or not available due to embedding inside the copolymer structure. The mechanism of the process involving both NHPI centers, forming phthalimide N-oxyl (PINO) radicals, and Co(II) cations was discussed. Stability of the developed catalysts was also tested. The opening of imide rings took place during the catalytic process, resulting in the formation of carboxyl groups and the release of hydroxylamine molecules. The deactivated catalyst could be easily regenerated by repeating two last steps of closing imide ring.

Change of Selectivity in C-H Functionalization Promoted by Nonheme Iron(IV)-oxo Complexes by the Effect of the N-hydroxyphthalimide HAT Mediator.

A kinetic analysis of the hydrogen atom transfer (HAT) reactions from a series of organic compounds to the iron(IV)-oxo complex [(N4Py)FeIV(O)]2+ and to the phthalimide N-oxyl radical (PINO) has been carried out. The results indicate that a higher activating effect of α-heteroatoms toward the HAT from C–H bonds is observed with the more electrophilic PINO radical. When the N-hydroxy precursor of PINO, N-hydroxyphthalimide (NHPI), is used as a HAT mediator in the oxidation promoted by [(N4Py)FeIV(O)]2+, significant differences in terms of selectivity have been found. Product studies of the competitive oxidations of primary and secondary aliphatic alcohols (1-decanol, cyclopentanol, and cyclohexanol) with alkylaromatics (ethylbenzene and diphenylmethane) demonstrated that it is possible to modify the selectivity of the oxidations promoted by [(N4Py)FeIV(O)]2+ in the presence of NHPI. In fact, alkylaromatic substrates are more reactive in the absence of the mediator while alcohols are preferably oxidized in the presence of NHPI.

Mechanism of Electrochemical Generation and Decomposition of Phthalimide-N-oxyl.

Phthalimide N-oxyl (PINO) is a potent hydrogen atom transfer (HAT) catalyst that can be generated electrochemically from N-hydroxyphthalimide (NHPI). However, catalyst decomposition has limited its application. This paper details mechanistic studies of the generation and decomposition of PINO under electrochemical conditions. Voltammetric data, observations from bulk electrolysis, and computational studies suggest two primary aspects. First, base-promoted formation of PINO from NHPI occurs via multiple-site concerted proton-electron transfer (MS-CPET). Second, PINO decomposition occurs by at least two second-order paths, one of which is greatly enhanced by base. Optimal catalytic efficiency in PINO-catalyzed oxidations occurs in the presence of bases whose corresponding conjugate acids have pKa's in the range of ∼11-15, which strikes a balance between promoting PINO formation and minimizing its decay.

Mixed hetero-/homogeneous TiO2/N-hydroxyimide photocatalysis in visible-light-induced controllable benzylic oxidation by molecular oxygen

Homogeneous and heterogeneous types of catalysis are frequently considered as separate disciplines or even opposed to each other. In the present work, a new type of mixed hetero-/homogeneous catalysis was demonstrated for the case of selective alkylarene oxidation by molecular oxygen. The proposed catalytic system consists of two widely available components: N-hydroxyphthalimide (NHPI, a homogeneous organocatalyst for free-radical chain reactions) and nanosized TiO2 (heterogeneous UV-active photoredox catalyst). The interaction of NHPI with TiO2 allows for a shift from UV to visible light photoredox activity and generation of phthalimide-N-oxyl (PINO) radicals that diffuse into the solution where NHPI/PINO-catalyzed free-radical chain reaction can proceed without the additional light input providing a fundamental increase in energy efficiency. The NHPI/TiO2 ratio controls the selectivity of oxidation affording preferential formation of hydroperoxide or ketone from alkylarene.