N-hydroxyphthalimide Research Articles

Copper-Catalyzed Asymmetric C(sp3)-H Benzylation: Stereoselective Synthesis of Unnatural Aromatic Amino Acids.

The general synthesis of chiral unnatural aromatic amino acids has rarely been reported. We herein describe a visible light-promoted copper-catalyzed enantioselective C(sp3)-H benzylation of glycine derivatives. The method demonstrated compatibility in coupling various N-hydroxyphthalimide (NHP) esters derived from aromatic acids with glycine derivatives, providing a general protocol for synthesizing analogues of phenylalanine, tryptophan, and tyrosine. This protocol features mild conditions, high enantioselectivity, excellent functional group tolerance, and important impacts on the development of peptide drugs.

Metal‐free visible‐light‐induced direct synthesis of alkyl‐substituted phosphonodithioates from white phosphorus (P4)

The direct synthesis of organic phosphorus compounds from white phosphorus (P4) is a longstanding challenge in organic synthesis. Here, we present a novel visible light‐induced three‐component functionalization reaction that integrates P4, disulfide compounds, and N‐hydroxyphthalimide (NHPI) esters to produce alkyl‐substituted phosphonodithioates in a one‐pot process. Using 2,4,5,6‐tetrakis(carbazol‐9‐yl)‐1,3‐dicyanobenzene (4CzIPN) as a photocatalyst, blue LEDs (456 nm) as the light source, and N,N‐diisopropylethylamine (DIPEA) as the reducing agent in an acetone‐toluene solvent system, this method achieves moderate to good yields of structurally diverse phosphonodithioates. The reaction proceeds under mild conditions, ensures complete conversion of P4, avoids chlorination, and uses inexpensive, readily available starting materials, offering potential for large‐scale applications.

Synthesis of Diketopyrrolopyrrole Based Photoactive Materials via Photoredox C−H Activation

AbstractThe synthesis of diketopyrrolopyrrole (DPP) derivatives followed the well‐known conventional cross‐coupling methods such as Suzuki, Stille, Sonogashira, and Negishi cross‐coupling reactions. However, these methods required unfavorable reaction conditions, organometallic precursors, and high temperatures. In addition, the synthesis of conventional cross‐coupling partners including organoboranes, stannane, and acetylenes required drastic reaction conditions and strong bases. In this work, a wide variety of thiophene‐diketopyrrolopyrrole (TDPP)‐based semiconducting materials (36 compounds) were synthesized via Pd‐catalysed photoredox methodology by using N‐hydroxyphthalimide (NHP) based coupling partners, which can be readily prepared from N‐hydroxyphthalimide and carboxylic acid or aldehyde derivatives via single step C−O bond formation reactions with good yield (80–90 %). This methodology minimizes additional synthetic steps, harsh reaction conditions, and high temperature (100–150 °C). Optoelectronic studies suggest that the synthesized materials have suitable band gap, HOMO and LUMO levels for variety of optoelectronic applications. To the best of our knowledge, this is the first report on the synthesis of TDPP‐based π‐conjugated materials via the photoredox method.

NHPI-Catalyzed Electro-Oxidation of Alcohols to Aldehydes and Ketones.

A practical and recyclable electro-oxidation of alcohols to aldehydes and ketones by using N-hydroxyphthalimide (NHPI) as the catalyst is presented. Through an undivided pool, under constant current conditions, various alcohols can be oxidized to the corresponding aldehydes or ketones in a high yield. Compared with previous methods, this system has the following characteristics: (1) the catalyst, electrode, electrolyte, and solvent (mainly water) are recyclable; (2) it has many advantages such as mild reaction conditions, easy operation, and good tolerance of functional groups; and (3) it can be smoothly scaled up to kilogram-scale production.

The Aqueous and Acetonitrile Bond Dissociation Free Energies of N-Hydroxyphthalimide.

Widely cited values of 89 and 90.9 kcal/mol for the bond-dissociation free energy of N-hydroxyphthalimide (NHPI) in water and acetonitrile, respectively, are in error. The sources of the errors leading to these values have been explored and corrected. The corrected values are confirmed through new experiments in aqueous and acetonitrile media and are found to be 84.4 ± 0.1 and 80.04 ± 0.06 kcal/mol, respectively.

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.

Enantioselective 1,2-Carboamination of 1,3-Dienes with N-Hydroxyphthalimide (NHP) Esters Enabled by a Photoinduced Pd Catalysis.

Herein, a photoinduced, Pd-catalyzed direct 1,2-carboamination of conjugated 1,3-dienes has been successfully achieved. Sequential regioselective C-C bond and enantioselective C-N bond formation allows rapid assembly of a wide range of value-added chiral allylic amines from readily available N-hydroxyphthalimide (NHP) esters and 1,3-dienes under mild conditions. This developed protocol further demonstrates the versatility and potency of the photoexcited Pd catalytic system with a bifunctional reagent in the streamlined difunctionalization of C═C bonds.

3 + 2] Annulation of Vinyl Azides with Aldehydes for the Synthesis of 3-Oxazolines via the [CO + CCN] Strategy.

Despite the widespread utilizable value of 3-oxazolines, mild and efficient access to such a class of unique structures still remains, to date, a challenge. Herein, we present a [3 + 2] annulation strategy, guided by the retrosynthetic principle of [CO + CCN], that utilizes vinyl azides as the CCN module and aldehydes as the CO module. This approach enables the efficient construction of the 3-oxazoline framework with remarkable features, including operational simplicity, environmental friendliness, and high efficiency. Notably, it solely requires the addition of inexpensive and readily available N-hydroxyphthalimide (NHPI) and air oxygen to obtain the desired product. It also provides a new way to generate the hydroxyl radical, which is produced by the homolysis of peroxycarboxylic acid. In addition, control experiments, X-ray crystallographic analysis, high-resolution mass spectrometry (HRMS), and density functional theory (DFT) calculations afford evidence for the key intermediates (hydroxyl radical, carboxyl radical, imine radical, hydroxyl substituted amide derivatives), further confirming the path for realization of 3-oxazolines.

Re‐Examination of Self‐Decay Chemistry of Phthalimide‐N‐oxyl Redox‐Organocatalyst for Free‐Radical CH‐Functionalization – Puzzle Begins to Come Together

AbstractPhthalimide‐N‐oxyl radicals (PINO) are catalytically active hydrogen abstracting species generated from N‐hydroxyphthalimide (NHPI) – one of the most efficient and widely used organocatalysts for free‐radical oxidative CH‐functionalization processes. The self‐decay of PINO is one of the main limiting factors of NHPI usage, but currently there is no consensus on the mechanism of this important process. In the present work, quantitative EPR and NMR monitoring of PINO generation and degradation along with decay product analysis and control experiments allowed us to build a consistent picture of PINO decay chemistry and put together previously contradictory results. PINO yields achievable employing various oxidants were measured and compared for the first time. At least two PINO decay pathways were revealed: “trimerization” (with partial fragmentation, favored by high PINO concentrations at initial stage of decay), and medium oxidation favored by low PINO concentrations. The main PINO decomposition product, the “trimer” can easily be recycled back to NHPI.

A Metal-Free Cycloaddition of α-Diazoacetates with Amino Acid-Derived NHPI Esters for the Facile Synthesis of 1,2,4-Triazoles.

1,2,4-Triazoles are privileged scaffolds for many pharmaceuticals, and methods for structurally diverse compound libraries are of current interest. Here we report an efficient coupling of α-diazoacetates with amino acid-derived alkyl N-hydroxy phthalimide esters, under metal-free conditions involving 1,8-diazabicyclo(5.4.0)undec-7-ene as the base, with which highly functionalized 1,2,4-triazoles can be obtained in excellent yields with remarkable functional group tolerance. Preliminary studies revealed that 1,2,4-triazole 3a exhibits potent inhibition of tyrosinase activities in melanoma B16F10 cell lines, demonstrating promising skin-whitening properties.

An Investigation of N-Hydroxyphthalimide Catalyzed Aerobic Oxidation of Toluene without Metal Ions in Liquid Phase: Effect of Solvents and Phase Transfer Catalysts.

The selective oxidation of toluene to yield value-added oxygenates, such as benzyl alcohol, benzaldehyde, and benzoic acid, via dioxygen presents a chlorine-free approach under benign conditions. Metal-free catalytic processes are preferred to avoid metal ion contamination. In this study, we employed N-hydroxyphthalimide (NHPI) as a catalyst for the aerobic oxidation of toluene to its oxygenated derivatives. The choice of solvent exerted a significant impact on the catalytic activity and selectivity of the catalyst NHPI at reaction temperatures exceeding 70 °C. Notably, hexafluoroisopropanol substantially enhanced the selective production of benzaldehyde. Furthermore, we identified didecyl dimethyl ammonium bromide, featuring two symmetrical long hydrophobic chains, as a potent enhancer of NHPI for the solvent-free aerobic oxidation of toluene. This effect is ascribed to its unique symmetrical structure, extraction capabilities, and resistance to thermal and acid/base conditions. Based on the product distribution and control experiments, we proposed a plausible reaction mechanism. These findings may inform the industrial synthesis of oxygenated derivatives from toluene.

Efficient heterogeneous copper-catalyzed dioxygenation of alkenes under air conditions: Synthesis of α-oxygenated ketones

A heterogeneous copper-catalyzed dioxygenation of alkenes with N-hydroxyphthalimide (NHPI) is described, providing concise access to α-oxygenated ketones under air atmosphere without the addition of any extra additives. The heterogeneous catalyst consists of copper and bionic material polydopamine (CuCl2@PDA), which has nontoxic, stable, cheap and recyclable characters. The catalyst can be recycled and reused at least 7 times. This reaction shows mild and operationally simple conditions, high efficiency, good substrate scope, excellent functional group compatibility, green and sustainable virtues.

Photoinduced Alkenylation of Alkenyl Sulfones with EDA Complexes between NHPI Esters and HE

AbstractA novel alkenylation reaction between N‐hydroxyphthalimide (NHPI) esters and alkenyl sulfones is reported. It undergoes the formation of electron donor‐acceptor (EDA) complex and a series of alkenes are obtained in good to excellent yields. It has the advantages of simple operation, mild reaction conditions, and metal‐free.

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.

An Investigation on the Effect of N-Hydroxyphthalimde and Supercritical Carbon Dioxide on the Peroxide Degradation of Polypropylene

The peroxide degradation of polypropylene was studied in supercritical carbon dioxide (scCO2) in the presence of a N-hydroxyphthalimide (NHPI). Six levels of NHPI concentration and 6 levels of peroxide concentration were selected and each permutation was tested both with and without scCO2. It was observed that the NHPI would increase degradation at lower peroxide concentrations (<0.1 wt. %), but would suppress degradation at higher peroxide concentrations (>0.2 wt. %). Furthermore, it was discovered that at an NHPI concentration of 3.3 wt. %, the stereo regularity slightly decreased with increasing peroxide concentrations.

Time-temperature indicator of hydroxyethyl cellulose ink labels for assessing pork freshness

Pork is widely consumed worldwide, and many consumers now utilize sensory evaluation techniques to determine the freshness of pork when buying it. A color-changing ink label utilizing bromocresol purple (BCP) and N-hydroxyphthalimide (NHPI) had been created to help consumers better and more rapidly determine the freshness of pork while it is stored. The ink was easy to prepare and could be readily transferred to A4 paper using screen printing technology. This study delved deeper into the impact of hydroxyethyl cellulose (HEC) on the functional properties of inks to enhance printing performance. The experiment demonstrated that a 1 % mass fraction of HEC improved thixotropy and facilitated the even distribution of ink on A4 paper, as confirmed by scanning electron microscopy. Screen-printed labels with varying concentrations displayed distinct color change rates when stored at different temperatures, indicating their capability to assess pork freshness. FT-IR, laboratory, and stability tests verified the ink's exceptional color change capabilities and printing attributes. An analysis using the Arrhenius equation revealed a substantial synergistic effect between BCP and NHPI, resulting in improved sensitivity and accuracy of the ink. This study offers a practical and feasible method to monitor the storage quality of pork effectively.

Covalent bonding of N-hydroxyphthalimide on mesoporous silica for catalytic aerobic oxidation of p-xylene at atmospheric pressure.

The surface of SBA-15 mesoporous silica was modified by N-hydroxyphthalimide (NHPI) moieties acting as immobilized active species for aerobic oxidation of alkylaromatic hydrocarbons. The incorporation was carried out by four original approaches: the grafting-from and grafting-onto techniques, using the presence of surface silanols enabling the formation of particularly stable O-Si-C bonds between the silica support and the organic modifier. The strategies involving the Heck coupling led to the formation of NHPI groups separated from the SiO2 surface by a vinyl linker, while one of the developed modification paths based on the grafting of an appropriate organosilane coupling agent resulted in the active phase devoid of this structural element. The successful course of the synthesis was verified by FTIR and 1H NMR measurements. Furthermore, the formed materials were examined in terms of their chemical composition (elemental analysis, thermal analysis), structure of surface groups (13C NMR, XPS), porosity (low-temperature N2 adsorption), and tested as catalysts in the aerobic oxidation of p-xylene at atmospheric pressure. The highest conversion and selectivity to p-toluic acid were achieved using the catalyst with enhanced availability of non-hydrolyzed NHPI groups in the pore system. The catalytic stability of the material was additionally confirmed in several subsequent reaction cycles.

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters.

Due to their ease of preparation, stability, and diverse reactivity, N-hydroxyphthalimide (NHPI) esters have found many applications as radical precursors. Mechanistically, NHPI esters undergo a reductive decarboxylative fragmentation to provide a substrate radical capable of engaging in diverse transformations. Their reduction via single-electron transfer (SET) can occur under thermal, photochemical, or electrochemical conditions and can be influenced by a number of factors, including the nature of the electron donor, the use of Brønsted and Lewis acids, and the possibility of forming charge-transfer complexes. Such versatility creates many opportunities to influence the reaction conditions, providing a number of parameters with which to control reactivity. In this perspective, we provide an overview of the different mechanisms for radical reactions involving NHPI esters, with an emphasis on recent applications in radical additions, cyclizations and decarboxylative cross-coupling reactions. Within these reaction classes, we discuss the utility of the NHPI esters, with an eye towards their continued development in complexity-generating transformations.

Enantioselective C(sp2)-C(sp3) Bond Construction by Ni Catalysis.

ConspectusAfter decades of palladium dominating the realm of transition-metal-catalyzed cross-coupling, recent years have witnessed exciting advances in the development of new nickel-catalyzed cross-coupling reactions to form C(sp3) centers. Nickel possesses distinct properties compared with palladium, such as facile single-electron transfer to C(sp3) electrophiles and rapid C-C reductive elimination from NiIII. These properties, among others, make nickel particularly well-suited for reductive cross-coupling (RCC) in which two electrophiles are coupled and an exogenous reductant is used to turn over the metal catalyst. Ni-catalyzed RCCs use readily available and stable electrophiles as starting materials and exhibit good functional group tolerance, which makes them appealing for applications in the synthesis of complex molecules. Building upon the foundational work in Ni-catalyzed RCCs by the groups of Kumada, Durandetti, Weix, and others, as well as the advancements in Ni-catalyzed enantioselective redox-neutral cross-couplings led by Fu and co-workers, we initiated a program to explore the feasibility of developing highly enantioselective Ni-catalyzed RCCs. Our research has also been driven by a keen interest in unraveling the factors contributing to enantioinduction and electrophile activation as we seek new avenues for advancing our understanding and further developing these reactions.In the first part of this Account, we organize our reported methods on the basis of the identity of the C(sp3) electrophiles, including benzylic chlorides, N-hydroxyphthalimide (NHP) esters, and α-chloro esters and nitriles. We highlight how the selection of specific chiral ligands plays a pivotal role in achieving high cross-selectivity and enantioselectivity. In addition, we show that reduction can be accomplished not only with heterogeneous reductants, such as Mn0, but also with the soluble organic reductant tetrakis(dimethylamino)ethylene (TDAE), as well as electrochemically. The use of homogeneous reductants, such as TDAE, is well suited for studying the mechanism of the transformation. Although this Account primarily focuses on RCCs, we also highlight our work using trifluoroborate (BF3K) salts as radical precursors for enantioselective dual-Ni/photoredox systems.At the end of this Account, we summarize the relevant mechanistic studies of two closely related asymmetric reductive alkenylation reactions developed in our laboratory and provide a context between our work and related mechanistic studies by others. We discuss how the ligand properties influence the rates and mechanisms of electrophile activation and how understanding the mode of C(sp3) radical generation can be used to optimize the yield of an RCC. Our research endeavors to offer insights on the intricate mechanisms at play in asymmetric Ni-catalyzed RCCs with the goal of using the rate of electrophile activation to improve the substrate scope of enantioselective RCCs. We anticipate that the insights we share in this Account can provide guidance for the development of new methods in this field.